ORGAN SYSTEMS 1——————————————The Nervous System——————————————STRUCTURE OF THE NERVOUS SYSTEM •Central Nervous System is made of brain and spinal cord

•Brain can be divided into:•cerebrum — the top and the biggest part of the brain;

it has two distinct left and right hemispheres•brain stem — hooks onto the spinal cord, is itself

divided into midbrain (top), Pons (middle), and Medulla (bottom, also called medulla oblongata; this connects to the spinal cord)

•cerebellum — sits behind the brain stem and is connected to it

•Brain structures are sometimes referred to by what they developed from in the embryo:

•forebrain (aka prosencephalon) — becomes cerebrum (temporal lobe, frontal lobe, occipital lobe, parietal lobse)

•midbrain (aka mesencephalon) — becomes midbrain (top of the brain stem), substantia niagra

•hindbrain (aka rhombencephalon) — becomes the rest of the brain – pons, medulla, cerebellum

•Peripheral Nervous System is made of nerves and ganglia •Nerves carry the axons of neurons, while ganglia are lumps attached to

nerves that contain the somas of neurons •Afferent neurons carry information into the central nervous system•Efferent neurons carry information away from the central nervous system

to the periphery.•An impulse moving through a neuron that carries info from PNS —> CNS is an

afferent neuron impulse moving proximally•Nerves can be divided into different categories (and are in pairs on each side

of the body):•Cranial Nerves — exit the skull, primarily coming out of the brain and pass

through the skull on the way between the central and periphery nervous system. (12 pairs)

•Spinal Nerves — come out of the spinal cord and pass through the spine on their way between the central and peripheral nervous systems. (23 pairs)

•Spinal nerves form from spinal nerve roots. •Efferent neurons (carrying info away) go through spinal nerve root in the

front while afferent neurons (carrying into in) go through spinal nerve roots in the back.

•These come together in the spinal nerves, which we call mixed nerves.•As any of the nerves travel from their proximal (close to center of the body) to

their distal ends, they branch repeatedly, getting smaller and smaller.

FUNCTIONS OF THE NERVOUS SYSTEM •Can be divided into basic (lower) functions and higher (complex) functions

ORGAN SYSTEMS 2•Patterns of abnormal functions are called syndromes. Some syndromes are

more common than others because they’re caused by neurological or psychiatric disorders that occur more frequently.

•Functions are performed by both•Cranial nerves primarily perform basic functions for the head and neck•Spinal nerves primarily perform basic functions for the limbs and trunk

•Basic functions are performed by central and periphery nervous systems. Basic functions are associated with the senses, movement, and automatic function. Three main categories:

•Motor: control of skeletal muscle. These functions cause movement, tone, and posture.

•Sensory: deals with all senses (more than 5!), anything that the nervous system can detect

•Automatic: don’t require conscious involvement — includes reflexes, control of some body systems, etc. aka. Sweating

•Higher functions are performed by parts of the brain. Higher functions are associated with cognition, emotion, or consciousness.Three main categories:

•Cognition: thinking functions of the brain — thinking, learning, memory, language, exec. functions

•Emotions: feelings — play a major role in our experience of life ex. fear•Consciousness: related to awareness of being a person, experiencing life,

and controlling actionsMOTOR UNIT •Lower motor neurons — efferent neurons of peripheral nervous system (carry

info away); they synapse on and control skeletal muscle, which is the main muscle type of our body.

•One lower motor neuron unit = one lower motor neuron (soma, axon, and axon terminals) AND all the skeletal muscle cells that it contacts and controls.

•The place where a neuron contacts its target cell is a synapse. •The synapse between a lower motor neuron and skeletal muscle cell is

specifically called the neuromuscular junction. Lower motor neurons will typically have many neuromuscular junctions.

•When the neuron fires, all of these skeletal cells are activated and contracted together.

•The somas of LMNs are in the spinal cord or in the brain stem. Their axons pass out of the spine / brain stem from the spinal nerves / cranial nerves, respectively.

•These axons then continue to branch until they reach and synapse on all the skeletal muscle cells in their motor unit.

•The lower motor neurons in the cranial nerves primarily control skeletal muscle in the head and neck, while lower motor neurons in the spinal nerves primarily control muscles of the limbs and trunk.

•Small muscles that need rapid precise control (e.g. in the eyes or fingers) tend to have small motor units (synapse on few cells). Large muscles that don’t need precise control (e.g. those in the trunk or thighs) typically have large motor units — may include up to control hundreds of skeletal muscle cells.

•When there is any abnormality of a motor unit, symptoms may include weakness, or loss of strength of contraction of skeletal muscle.

ORGAN SYSTEMS 3•Abnormalities of the lower motor neurons, specifically, cause Lower Motor Neuron

Signs (LMN signs):•Atrophy — decreased bulk of skeletal muscle

•If muscle cells aren’t periodically stimulated by LMNs, the cells degenerate or are lost.

•Extreme weakness and shrunken muscle is an example of atrophy, which is a sign of lower motor neuron dysfunction.

•Fasciculations — involuntary twitches of skeletal muscle that can occur after some problem of the motor neurons. The occasional fasciculation is normal, but if we see a lot in one spot that suggests there could be something wrong with an LMN.

•Apparently, if muscle cells don’t receive periodic input from LMNs, the cells might start to contract on their own, without any input.

•Hypotonia — decrease in tone of skeletal muscle. Tone is how much a muscle contracts when you’re trying to relax it. (Ex: Remember the old picture of a doctor and patient. In a normal patient, even if doc tells the patient to relax, when he tries to move their leg he will feel a little resistance. With hypotonia, the leg will be especially floppy and not resistant to movement.)

•Hyporeflexia — decreased muscle stretch reflexes (MSR), which normally happen if you rapidly flex a skeletal muscle (like a pin hammer on a knee).

• Note: ALS affects both upper and lower motor neurons. PERIPHERAL SOMATOSENSATION •Somatosensation is simply senses of the body. We can divide this into five

categories.•Position — sense of body parts relative to each other (ex: If we close our eyes

and someone moves our arm over our head, we can know it’s over our head without seeing it.)

•Vibration — can feel vibrations (may be tested on a patient with a tuning fork)•Touch • Pain • Temperature

•To detect these things, we have a bunch of somatosensory receptors, which can be found in a number of places. We group these into 3 categories:

•Mechanoreceptors — respond to stimuli. Can detect position, vibration, and touch.

•These receptors have special structures (sort of look like a disc) at the end of the axon that help take information back to the central nervous system.

•Ex: Mechanoreceptors in the skin detect touch and vibration; those in the deep tissue of muscles can detect stretch.

•Other mechanoreceptors in the tendons and capsules around joints are important for position sense because they can send info back to central nervous system about the position of joints

•Nociceptors — can detect a number of different stimuli that give rise to the experience of pain.

•Thermoreceptors — detect temperature.•Nocireceptor and Thermoreceptors don’t usually have a specific structure at the

end like mechanoreceptors. Instead the axon just ends in uncovered terminals called bare nerve endings.

•Once a somatosensory receptor detects a stimuli it’s specific for, it will send that information back to the central nervous system in axons of the peripheral

ORGAN SYSTEMS 4nervous system. These are a type of afferent neuron called somatosensory neurons.

•Most of these have their somas in ganglia close to either the spinal cord or brain stem, depending on what they’re entering.

•There are several different types of somatosensory neurons: •Position, vibration, and some touch information tends to travel in certain

neurons with large diameter axons, with a thick myelin sheath. The Schwann cells that create myelin sheath are thus wrapped around the axon in many layers.

•Pain, temp, and the rest of touch tend to travel in other specific neurons with a smaller diameter, and either a thin myelin sheath (with less wrapping of Schwann cell membranes around the axon) or no myelin sheath at all.

•Because axons with a larger diameter and a thicker myelin sheath conduct action potentials more rapidly, the somatosensory neurons for position, vibration and some touch will conduct action potential much faster than the others.

•The sense of touch is a funny one because it travels in both types of neurons. Fine touch sense information tends to travel faster than larger, gross touch sense.

MUSCLE STRETCH REFLEX •Reflex is a response to a stimulus that doesn’t require the involvement of

consciousness.•All reflexes have two parts:

•afferent — brings info about the stimulus into central nervous system•efferent — carries info away from CNS to cause a response/effect in the

periphery.•Some reflexes, like the muscle stretch reflex, happen on the same side of the

body. Others (especially those in the brain stem) have an afferent limb that comes in on one side, and efferent responses that come out to both sides.

•If a muscle is rapidly stretched, the muscle stretch reflex will cause it to contract quickly. This type of reflex is what is tested when the doctor hits the tendon just below your kneecap with a little rubber hammer.

•Knee jerk reflex is a monosynaptic stretch reflex. A tap to the tendon that connects the quadriceps to the patella activates a sensory neuron that directly snyapses with the motor neuron in the spinal cord, causing the quadriceps to contract.

•When your doctor hits you in the tendon, it actually stretches (not very far, but rapidly) the group of muscles on the front of your thigh contract, the ones that make your leg extend.

•The receptors in skeletal muscle are called muscle spindles. Specialized little fibers in the muscle spindle get stretched when the muscle does, and special axons wrapped around these fibers can detect the stretch. They then send that info back through nerves of the peripheral system and enter the spinal cord or the brain stem.

•This afferent (stimulus) part of the reflex is caused by somatosensory neurons.

•Inside the central nervous system, these somatosensory neurons carrying muscle stretch info from an excitatory stimulus synapse with another nerve whose soma

ORGAN SYSTEMS 5is in the CNS. This neuron sends an axon out through nerves of the PNS back to the same muscle that was stretched. It synapses on and excites skeletal muscle cells there to contract, causing a response.

•This efferent (response) is caused by the lower motor neurons.•Recall, one LMN sign is hyporeflexia — occurs if LMN is unable to communicate

with the muscle, so it won’t know to contact in response to the stimulus. But you can also have diminished muscle stretch reflex if the somatosensory neurons aren’t functioning.

•This is true of all reflexes. If there is an abnormality or malfunction in the afferent or efferent part, you may have a diminished reflex response.

•Higher parts of the nervous system (cerebrum, e.g.) don’t ever have to get involved for a reflex like this to occur.

•When the muscles on the top of the thigh are contracted, the ones at the back that cause leg bending are relaxing. This is because the same somatosensory neuron that sends info of stimulus back to CNS inhibits the LMNs of the back thigh muscle.

•This isn’t necessary for the muscle to occur, but it does increase the response.

AUTONOMIC NERVOUS SYSTEM •ANS controls things without involving the consciousness. •It consists of efferent neurons in the peripheral nervous system that control three

types of cells:•Smooth muscle •Cardiac muscle•Gland cells

•We can divide the autonomic nervous system into sympathetic & parasympathetic.

•The autonomic nervous system has two functional differences. The sympathetic nervous system is associated with fight or flight, and the parasympathetic nervous system is associated with rest and digest.

•Rest and digest means that body functions promoting homeostasis are activated.•Fight or flight means that body functions promoting survival are activated.•When one system is activated, the other decreases activities.

•Sympathetic nervous system:•Starts in the middle part of the spinal cord•The first neuron off the soma of the spinal cord has a short axon and

synapses in a ganglia close to the spinal cord. The second neuron has a longer axon that then goes toward the desired target — i.e. a tissue that contains smooth, cardiac muscle, gland cells

•The chain of ganglia coming out of the first, short axons off the spinal cord is called the sympathetic chain.

•Sympathetic nerves originate in the center of the spinal cord and have a short axon to the synapse of another neuron. From there, there is a long axon to the target neuron.

•Parasympathetic nervous system:•Starts either in the brain stem or at the bottom of the spinal cord•First neuron sends a long axon out to synapse in a ganglion at a lengthy

distance from the first neuron soma. The second neuron then sends a shorter axon to the target cell.

ORGAN SYSTEMS 6•The parasympathetic nerves originate in the brainstem or at the bottom of the spinal cord.

Parasympathetic nerves have long axons to the synapse of another neuron, then a short axon to the target neuron.

•Functions of sympathetic nervous system: “Fight or flight” •causes changes that will help us fight or run away when threatened

•Functions of parasympathetic nervous system: “Rest and digest”•causes changes more important for homeostasis

•Consider the blood flow to the the gastrointestinal system, which plays a big role in the amount of digestion that can happen and the amount of blood available for other muscles.

•When the sympathetic nervous system “fight or flight” is activated, blood flow to the intestines is decreased and redirected towards skeletal muscle

•Most of the time, though, when you’re in a non-threatening situation and can “rest and digest,” the parasympathetic nervous system is activated which diverts blood away from skeletal muscle and brings it towards the intestines to help you digest food.

•Consider the heart output, or how much blood is pumped out in a give time period:

•When sympathetic nervous system is activated, heart output is increased to increased blood availability for skeletal muscle.

•When parasympathetic nervous system is activated, heart output is decreased because you don’t need as much blood flow to the rest of the muscles if you’re not using them.

•These examples of blood flow involve the activity of smooth muscle, which makes up blood vessels, and cardiac muscle, which obviously affects the heart.

•Consider the glands:•When sympathetic nervous system is activated, sweat glands are activated —

this cools us down and allows us to move faster and farther.•When the parasympathetic nervous system is activated, salivary glands are

activated — helps us digest food.•Most of the things the SNS does increases the ability of the body to turn stored

energy into movement! Whereas most of the paraSNS activities allows us to conserve energy and digest food.

•Autonomic neurons also play a role in changing pupil size of the eyes, in sexual functions, and more.

GRAY AND WHITE MATTER — GREY = SOMA; WHITE = AXONS •In the CNS, which is mostly the brain and spinal cord, gray matter contains most

of the neuron somas, and white matter contains most of the myelinated axons.•Looking at different cross-sections of the spinal cord, we see that most of the

gray matter (butterfly or H-shape) is on the inside of the spinal cord, and most of the white matter is on the outside.

•Looking at cross sections of the brain, we see that gray matter is mostly on the outside of the brain! This is called cortex. The gray matter over the cerebrum is thus called the cerebral cortex, while gray matter on the cerebellum is called cerebellar cortex. Most of the neuron somas are here.

•Most of the white matter of the brain is on the inside of the brain, under the cerebral cortex.

ORGAN SYSTEMS 7•There are some other areas deep in the brain that have also gray matter,

which we call nuclei.•In the white matter of the CNS are collections of axons that travel together

through the CNS; we call them tracts. (One tract can have many axons in it, often carrying similar sorts of information from one part of the CNS to another part).

•In addition to neurons involved in motor, sensory, and automatic functions, the CNS also has many neurons participating in higher functions of consciousness, cognition, and emotion. These take place particularly in the cerebral cortex.

UPPER MOTOR NEURONS •Recall, the LMNs have their somas in the brain or spinal cord and they send

nerves out to skeletal muscles. LMNs that pass through spinal nerves primarily control cells in the limbs and trunk, while LMNs that pass through cranial nerves primarily control cells in the head and neck.

•Turns out that while the LMNs control what muscles contract and when, the Upper Motor Neurons (UMNs) control the lower motor neurons!

•Somas of the UMNs are found mainly in the cerebral cortex (gray matter over cerebrum), and their axons descend down to synapse on LMNs in the brain stem or the spinal cord, depending on tract.

•Let’s think about a LMN at the top of a spinal cord on the left side. The soma will be in the spinal cord, and send an axon out into the muscles. The UMN that controls this LMN will start in the cerebral cortex on the opposite side, and send its axon down through the deep white matter, and into the brain stem (through the midbrain, pons, and medulla). Where the brain stem meets the spinal cord, most of these axons will cross over to the other side and travel down the appropriate left side until they reach the LMN to synapse on it and control it.

•We call this the corticospinal tract. •The left side of the brain controls, for the most part, the right side of the body.•Because of the crossover, we see that if there’s dysfunction of a tract at the

spinal cord site, there will be weakness on that same side of the body. If, however, there’s dysfunction in a neuron at the site of the cerebral cortex, there will be weakness on the opposite side of the body.

•Ex of LMN in the brain stem — one extends to each side of the head or neck. To reach these, some UMNs start in the cerebral cortex and send an axon down in a similar way as the corticospinal tract and they will similarly cross over and affect the LMN on the other side of the brain stem. We also see, however, that some UMNs will travel down to affect an LMN on the same side of the brain stem.

•We call this the corticobulbar tract. It includes UMN axons that innervate LMNs in brain stem. We can get different patterns of weakness with abnormalities of this tract.. more on that later.

•Dysfunction in either the UMNs or the LMNs can cause weakness. •Upper Motor Neuron signs can occur with or without weakness. These signs can

help us understand, if a patient does have weakness, whether the problem is in the upper or lower motor neurons.

•Hyperreflexia — an increase in the muscle stretch reflexes (opposite of LMN sign hyporreflexia). Would cause a patient to have an exaggerated response to a knee tap.

ORGAN SYSTEMS 8•Cause of hyperreflexia is not known. But apparently when muscle spindles

(receptors in skeletal muscle which are activated and their info is carried back by somatosensory receptors to elicit a response by UMNs), are not periodically stimulated by the UMNs, the LMNs may become super sensitive. This may mean a normal signal from a UMN causes an LMN to have an exaggerated reflex.

•Clonus — rhythmic contraction of antagonist muscles, which have an opposite effect on a joint.

•ex: Antagonist muscles in the front of your shin cause you to pull your foot up, while the counter muscles in the back of the leg cause you to push your foot down (like a gas pedal). If a doctor grabs the foot of a patient who has UMN dysfunction and rapidly pulls it upward, the foot may go into this involuntary movement (clonus) where it starts going up and down and up and down over and over.

•The cause of clonus is likely just hyperreflexia… each time the foot goes one way the muscles on the other side are stretched; and the muscles end up triggering each other

•The involuntary rhythmic contraction of antagonist muscles is known as clonus and is a sign of upper motor neuron dysfunction.

••Hypertonia — Increased tone (resistance) of skeletal muscles (opposite of

LMN sign hypotonia).•This can cause muscle spasms, different from the fasciculation of LMN

degeneration.•Muscle spasticity is a feature of hypertonia, or increased tone of skeletal muscle, and is an upper

motor neuron sign.•Extensor Plantar Response (aka Babinski sign) — If you take a hard object

and scrape along the bottom of the foot, the normal plantar response is flexor, to have the toes curl down towards the bottom of the foot. If a person has UMN dysfunction and you do this to them, though, the foot will respond with extensor, meaning the toes will extend away from the bottom of the foot. The extensor plantar response (or babinski reflex) is a sign of upper motor neuron dysfunction and can be seen when a noxious stimuli is placed on the bottom of the foot, causing the toes to go into extension away from the bottom of the foot, rather than flexing down in the direction of the bottom of the foot.

SOMATOSENSORY TRACTS •Somatosensory tracks are groups of axons that carry information about the

environment back to CNS.•Recall, the different types of somatosensory information tend to travel in different

pathways:•Position sense, Vibration sense, and fine touch sense — these signals travel in

large diameter, heavily myelinated axons. Fast response.•Pain sense, Temperature, and Gross, or less precise, touch sense — these

signals travel in smaller diameter, thinly myelinated (if at all) axons. Slower response.

•Somatosensory info from most of the body travels to CNS through (afferent) nerves in the PNS and then through spinal nerves that enter the spinal cord and deliver that info.

ORGAN SYSTEMS 9•Somatosensory info from the face will usually travel into the brainstem

through cranial nerves.•What happens once the info is delivered into the brainstem or spinal cord?

•For the somatosensory pain, temperature, and gross touch info — Inside the spinal cord, neural axons carry that information up to the brain in one of the somatosensory tracts that’s specific to that type of sensation.

•If, e.g. a noxious stimuli is experienced on the left side of the body, an axon will carry that pain sensation across to the right side of the spinal cord, and then up through the brain stem until it comes to a place deep down in the cerebrum. It enters the cerebral hemisphere on the other side from the part of the body where the receptor is on.

•The same is true for the somatosensations of the other category (position, vibration, fine touch), although their axons cross to the other side a little further up the body in the brain stem (instead of in the spinal cord)

•Pain, temp, gross touch, etc. sensations from receptors in the face (and some other parts of the head) can come into the brainstem through cranial nerves that will travel through axons that go down first, and then cross and then go up to about the same place in the cerebral hemisphere that the info from the rest of the body came from.

•This tract is also the case for position, vibration, and fine touch. They come into the brain stem from cranial nerves, go down first and then cross and then go up to about the same place.

•In this place deep in the cerebral hemisphere, all these different types of somatosensory information come back together and stay close to each other as they send that information on to areas of the cerebral cortex that will do more processing of the information.

•Because these somatosensory tracts have this sort of anatomy, if there’s an injury or disease to one side of the brain’s hemisphere, the other side of the body can have somatosensory loss.

CEREBELLUM •Recall, the cerebellum is behind the brainstem, underneath the cerebrum. It is

also divided into left and right hemispheres, and has many different functions.•Cerebellum is most notable for coordinating movement; it smooths moves out &

increases accuracy.•Three parts to how information travels into and out of the cerebellum to let it

coordinate movement:•Motor Plan — this involves which muscles need to contract and at what

intensity and duration.•While the movement is actually being executed by UMN through LMN,

information about the motor plan is delivered from the cerebrum to the cerebellum, as well.

•Position Sense — Muscle spindles, e.g. will send info through somatosensory neurons. Once it enters brain stem and cerebellum, the latter can tell if it’s going according to plan or if corrections are necessary. Usually that is the case, it needs some sort of correction to make the movement match the motor plan, so the cerebellum needs to send feedback..

ORGAN SYSTEMS 10•Feedback — After receiving info about the position sense, the cerebellum

may send feedback back to the motor areas of the cerebrum, the areas that came up with the motor plan in the first place, to try and correct the movement while it’s occurring by changing activity of the UMN.

•Note: cerebellum is set up such that the middle of the cerebellum tends to coordinate movement of the middle body, most notably walking. The part of the cerebellum more on the side is more involved in movement of the limbs. Many parts of the cerebellum also coordinate movements of speech and of our eyes.

BRAINSTEM •Brainstem basically connects all parts of the nervous system: the cerebrum,

cerebellum, and spinal cord. It also connects all the cranial nerves.•Inside of the brain stem has some similarities to the spinal cord, particularly in

the medulla. Most of the white matter is on the outside and most of the gray matter is on the inside, but it’s more mixed than in the spinal cord.

•Much of the brain stem gray matter are sort of distributed or scattered neurons not in distinct groups or bundles. This is the reticular formation of the brain stem. It plays an important role in many autonomic functions, such as circulation, respiration, and digestion.

•Reticular formation also sends lots of axons up to the cerebrum and it plays a role in some of the higher functions, as well, including cognition, emotion, and consciousness.

•A lot of the white matter passing through the brain stem is actually connecting different parts of the nervous system. Long tracts are collections of axons that often connect the cerebrum to the spinal cord. Two big categories of long tracts to which the brain stem plays host:

•Upper Motor Neuons (important for movement)•Somatosensory

•Most of the 12 pairs of cranial nerves humans have are attached to the brain stem.

•These nerves perform motor functions, sensory functions (many different kinds of sense functions), and a number of automatic functions.

•These nerves are related to a lot of the gray matter inside the brain stem. In addition to the reticular formation, there are collections of neuron somas that are distinct nuclei. Cranial nerves often carry info into or away from these nuclei. — ex: nuclei have neuron somas and axons leave the brain stem through cranial nerves to perform motor functions.

•Cranial nerves mostly perform their functions in the head and neck, but there are a few that travel down the brainstem all the way to the body and perform functions in the trunk and limbs

•Ex of cranial nerve functions: sensation of the face, movements of the eyes / face / jaw / throat, influence the heart and intestines.

SUBCORTICAL CEREBRUM •This is the deep part of the cerebrum, under the cortex of gray matter. Deep

white matter and deep gray matter (which are called nuclei) are subcortical

ORGAN SYSTEMS 11•Lots of white matter deep in the cerebrum, which contains axons going from

cerebral cortex gray matter and/or from deeper nuclei and/or to and from the brainstem

•Internal capsule (pink) - subcortical band of white matter, shaped like a V (if looking top-down). Contains corticospinal tract of UMN.

•Basal ganglia (blue) — collection of subcortical nuclei that function together; play a major role in motor functions. (They don’t contain UMN themselves but help out the motor areas of cerebral cortex). Also contributes to cognition and emotion.

•Corpus callosum (purple) — band of white matter connecting left and right hemisphere, allows info to travel across them.

•Thalamus (Diencephalon) (yellow) — Under the corpus callosum. Plays an important role in sensory functions. Almost all the senses have pathways that travel to the thalamus for sensory processing and then travel further on to areas of the cerebral cortex.

•Thalamus is also very important for all higher functions of the brain (cognition, emotion, and consciousness) bc it is connected to many brain areas and plays a role in passing info around between them and other areas / subcortical structures.

•Hypothalamus (green) — Under the thalamus. It is connected to and controls the pituitary gland (circled in green), aka “the master gland” that links nervous and endocrine systems and plays a major role in controlling glands. The hypothalamus is also involved in higher functions.

CEREBRAL CORTEX •Cerebral cortex is layer of gray matter on outside of the cerebrum. It has many

ridges called gyri (sing: gyrus), and small grooves on either side of a gyrus called sulci (sing: sulcus).

•Large grooves separating lobes are called fissures.•Cerebral cortex is divided into lobes, named for the bones of the

skull right above them.•Frontal — logic and decision making•Parietal — proprioception and sensory•Temporal — language and memory, olfactory, auditory•Occipital — vision

•A few senses and motor functions of cerebral cortex on one side of the brain tend to be involved with the other side of the body.

•Visual information coming in on the right side of a body will be processed on the left side of the brain (in the occipital lobe), and vice versa

•Somatosensory information, such as a hot or cold something applied to the skin on the right side, will end up being processed and brought to consciousness in the parietal cortex

•Motor functions for, e.g., the right leg will be processed on the left side of the brain (specifically, the back part of the frontal lobe).

•Other senses (besides vision and somatosensation) tend to get processed in areas of the cerebral cortex on both sides

ORGAN SYSTEMS 12•We can divide the areas of the cerebral cortex based on the function of that area:

•Primary cortex: performs basic motor or sensory functions•Association cortex: associates different types of info to do more complex

processing and functions.•ex: For areas of motor cortex, there’s primary motor cortex/cortices that do

basic motor functions, and then association motor cortices do more complex functions like planning of movements. Some areas of association motor cortices take in different types of information and integrate / process it to do higher level complex motor or sensory functions, and to produce higher functions of the nervous system such as cognition and emotion.

•One aspect of cognition is language (ability to turn thoughts into words), performed by certain areas of cerebral cortex in left hemisphere.

•Cerebral cortex on both sides plays a role in attention but, for most people, the right cerebral hemisphere’s cortex plays a role in paying attention to both sides of the body and the environment. (The left hemisphere just seems to pay more attention to the right side of the body).

NEUROTRANSMITTER ANATOMY •Recall, neurotransmitters are molecules that communicate between neurons and

their target cells at chemical synapses.•Some neurotransmitters are released by neurons that are distributed

throughout the nervous system. •Ex: glutamate (most common excitatory neurotransmitter), GABA (inhibitory, in the brain), and glycine (inhibitory, in spinal cord)

•Other neurotransmitters are more specific to certain areas.•Areas of the brain that have collections of neurons send axons diffusely to release

specific neurotransmitters into the cerebral cortex. (Also other areas, but mostly that)

•These widespread projections coming up towards the cerebral cortex dump lots of a specific neurotransmitter all over certain areas of the cerebral cortex; and they’re very important for functions of the higher nervous system (i.e. cognition, emotion, and consciousness).

•Glutamate — Some particular areas in the reticular formation of the brain stem and parts of the thalamus that project axons diffusely to cerebral cortex and release glutamate all over cerebral cortex.

•Reticular activating system = collection of neurons that have diffuse projection of glutamate

•Without this system, there is no consciousness•Acetylcholine — The basalis and septal nuclei send diffuse projections of

acetylcholine all over the cerebral cortex. [affects peripheral nervous system.]•Lower motor neurons that come out of CNS and have axons that synapse on

skeletal muscle cells release acetylcholine•Most neurons of the autonomic nervous system also release acetylcholine, a

smaller number release norepinephrine as their neurotransmitter.•Histamine — There are a number of neurons in the hypothalamus that send

projections to release histamine all over the cerebral cortex.

ORGAN SYSTEMS 13•Norepinephrine — The local ceuruleus is an area in the pons section of the

brainstem that sends neurons releasing norepinephrine all over the cerebral cortex. [affects peripheral nervous system]

•Most neurons of the autonomic nervous system also release acetylcholine, a smaller number release norepinephrine as their neurotransmitter.

•Serotonin — A number of raphe nuclei are present at all levels of the brain stem (midbrain, pons and medulla) that release serotonin up to cortex and other parts of the immune system.

•Dopamine —The ventral tegmental area is in the midbrain, and it diffusely projects dopamine onto the cortex. [affects central nervous system]

•There are also a couple of projection systems of dopamine that aren’t into the cerebral cortex but that are important for functions of the central nervous system, and can become problems for medications that affect dopamine neurotransmission.

•One such collection of neurons in the midbrain is called the substantia nigra, and it’s projecting dopamine to another part of the basal ganglia (specifically to a couple of nuclei deep in the cerebral hemisphere) called the striatum.

•Problems with this system of dopamine getting from substantia nigra to the striatum appear to be a big part of what happens in Parkinsons’ disease.

•There are also dopaminergic neurons in the hypothalamus that send dopamine down to the pituitary gland to control the release of prolactin.

•All these diffuse projection systems are very important to the higher functions of the nervous system.

•Many psychiatric disorders appear to involve dysfunction of these neurotransmitter systems and thus, many psychiatric drugs influence these systems.

•Dopamine is released from the ventral tegmentum (also known as the ventral tegmental area) to the limbic system through the nucleus accumbens. Dopamine is released from the substantia nigra to the striatum. Dopamine is released from the hypothalamus to the pituitary gland.

One specific type of antidepressant medication works by blocking the removal of neurotransmitters. Which of the following neurotransmitters is most likely the target of the antidepressant medication?

•The neurotransmitter must be classified as one of the types that is associated with attention, cognition, and emotion.

•The medication works by blocking the removal of the neurotransmitter; acetylcholine is not removed from the receptor, but is broken down by enzymes.

•Selective Serotonin Reuptake Inhibitors (SSRI’s) function by blocking the reuptake of serotonin, which allows more serotonin to be present.

EARLY METHODS OF STUDYING THE BRAIN

ORGAN SYSTEMS 14•Old study of phrenology thought brain areas were divided into different tasks /

characteristics, and this created bumps on the skull. By studying bumps, they thought they could learn about a person. Wrong.

•Autopsies — told scientists a lot about different structures of the brain, but was limited in that it can’t show how the brain functions or controls the body.

•Wait until someone has some kind of brain injury and then study the effect it has on the

•Ex: Phineas Gage in 1848 got a metal rod from the railroad through his head but survived! Actually walked away from the accident despite losing brain matter and lots of blood. However, the injury completely changed his personality (for the worse).

•Scientists learned cerebral localization from these types of studies — the idea that specific areas of the brain control specific aspects of behavior and emotion, even personality.

•We didn’t have much control over these types of studies though. Because strokes / accidents typically cause a lot of damage, it’s hard to tell what area is responsible for what behavioral change. But there are some areas around it.

•Paul Broca studied a patient he called “tan” who lost the ability to speak (except for that word), yet didn’t seem to suffer any other type of mental impairment. When the patient died, Broca discovered he had damage in a very particular part of the left frontal lobe. Broca then studied autopsied brains for a number of patients with speech impairment and while the type of damage varied, it was all in this particular region. He discovered this area must be involved in speech production.

•We now call this region in the left frontal lobe Broca’s area, •Aphasia = loss of ability to understand or express speech. •Broca’s aphasia = trouble with speech production because of damage to

Broca’s area.•Problem with these methods is the long time span (waiting until someone dies

means they may outlive doctor, may sustain other brain injuries by then, may lose touch with doctor, etc) and the lack of control over the types of injuries / damage done.

LESION STUDIES AND EXPERIMENTAL ABLATION •Ablation studies — method of deliberately destroying tissues (making lesions)

in order to see what effect this will have on an animals’s behavior. (This research obviously not done with humans.)

•Functions that can no longer be performed after the damage must be the ones that were controlled by those damaged regions.

Different methods of creating lesions:•Surgical removal, with a scalpel or aspiration (literally sucking out brain tissue).

•This is limited in that it can only remove structures on the surface of the brain. •Also, scientists aren’t always interested in actually removing tissue, but

instead damaging the tissue in place (e.g. through the following methods… less invasive)

•Severing the nerve with a scalpel — inhibits signals from the nerves so it can’t do its job

ORGAN SYSTEMS 15•Radio frequency lesions — can destroy tissue both on the surface and deep

inside•A wire that’s insulated except at the very tip, is inserted to a pre-determined

area in the brain. Then a high frequency current is passed through the wire, which heats up and destroys tissue just around the wire’s tip.

•This allows scientists to vary the intensity and duration of current to control size of resulting lesion. However, it destroys everything in the area — not just the cell bodies of neurons in that area, but also the axons of other neurons just passing through. Hard to determine which is responsible for any behavior change.

•Neurochemical lesions — very precise, and can be created through many different methods, including excitotoxic lesions… Excitotoxins are chemicals that bind to glutamate receptors and cause such an influx of Ca2+ ions that it kills the neuron, essentially exciting it to death.

•Ex: kainic acid. This method destroys cell bodies of neurons but not those of axons passing by, so you don’t need to worry about severing connections like in radio frequency lesions or knife cuts.

•Ex: Oxidopamine (6-hydroxydopamine) — selectively destroys dopaminergic neurons (release dopamine) and noradrenergic neurons (release norepinephine or adrenaline).

•Say you have a presynaptic cell that’s releasing dopamine to the synaptic cleft between cells. After dopamine binds with post-synaptic cell, the body wants to get rid of it or recycle it. It does this through re-uptake, where basically a little vacuum on the pre-synaptic cell sucks all the neurotransmitter back in. Oxidopamine looks a lot like dopamine, so when released into an area, it’s also taken up by re-uptake channels.. then it kills those cells.

•This is extremely useful because it gives us a lot of control, allowing us to destroy cell bodies (not axons) and to target specific populations of neurons in specific areas of the brain.

•Ex: researchers use this to model Parkinsons disease in lab animals (by targeting and destroying neurons in substantia nigra)

•Cortical cooling (cryogenic blockade) — cools down neurons until they stop firing / functions. Can be done many different ways, including with use of a cryoloop. This device is surgically implanted between skull and brain, and then a chilled liquid is circulated through the loop.

•Unlike other ablation techniques mentioned thus far, this is reversible!!•Temporary lesions can also be created through neurochemical means…

•Ex: A drug called muscimol temporarily binds with GABA receptors and winds up temporarily inhibiting those neurons so they can’t fire.

MODERN WAYS OF STUDYING THE BRAIN •Can be divided into two types of studies: those that tell us structures and those

that tell us function.Structural Recording:•CAT scans or CT scans (Computerized Axial Tomography) — Uses X-rays to

create images of brain. •Can show us if there’s a tumor or abnormal swelling in the brain.

ORGAN SYSTEMS 16•Can’t tell us what areas are active at a given time.

•Magnetic Resonance Imaging (MRI) — Uses radio waves to get picture of brain.

•A person’s head is exposed to a strong magnetic field, which aligns the atoms in their brain in a certain direction. Then a radio wave is added to the magnetic field, which disrupts that alignment.

•As the atoms then move back to realign with the magnetic field, they emit a signal. Different types of atoms emit different signals!

•This allows for a creation of a (much more) detailed picture of the brain.•Still can’t tell us anything about brain function, though.

Functional Recording:•Electroencephalography (EEG) — measures electrical activity generated by

neurons in the brain•Done by placing electrodes on someone’s scalp at predetermined positions

(usually by using a cap with electrodes that are filled with a conductive gel.•Pro: non-invasive. Con: Because it’s non-invasive, EEGs can’t really tell us

anything about specific neurons or groups of neurons; just looks at sum total electrical fields generated from the brain.

•Unlike structural methods (CT scans, MRIs), we don’t get a picture of the brain- just lots of squiggly lines that show if a person is awake/asleep or if they’re engaged in certain cognitive tasks

•Magnetoencephalography (MEG) — Records the magnetic fields produced by electrical currents in the brain.

•These fields are measured using SQUID (superconductive quantum interface devices).

•Gives better resolution than EEG, but this method is also more rare (especially in social sciences)… It needs a much bigger and more expensive set-up.

Combined methods:•fMRI (functional MRI) — gives the same structural images from the MRI, but

can also look at which structures are active.•Does this by measuring relative amounts of oxygenated / deoxygenated blood

in the brain, because neurons that are firing a lot require more oxygen than those that aren’t active. fMRIs thus tell us what parts of the brain are active, what parts we’re using to do a certain task.

•Positron Emission Tomography (PET scans) — On their own can’t give us a detailed structure of the brain, but are combined with CAT scans and MRIs.

•Involves radioactive glucose that’s injected into a person. Since active cells naturally use more glucose because they need more energy, we can see (with CAT or MRI scans) what areas of the brain are more active at a given point in time.

•fMRI is more popular (at least in social sciences), probably because PET scans are more invasive.

————————————————Neural Cells————————————————TYPES OF NEURAL CELLS

ORGAN SYSTEMS 17•Two types of neural cells: neurons (aka nerve cells) and glia (aka neuroglia, glial

cells).•Central nervous system = brain & spinal cord •Peripheral nervous system = nerves coming out of spinal cord

•Nerves of PNS are made of neurons, glial cells, and other cells (which is why calling neurons “nerve cells” is problematic)

•Neurons are in both CNS and PNS, but different types of glial cells are just in one or the other.

•Most neurons and glia found in the CNSs are derived from neural stem cells, while most neurons and glia in the PNS are derived from neural crest cells.

•Both types arise early in embryo development, in the ectoderm.•Most types of neurons and glia share structural features:

•soma — main body of cell that contains nucleus and most organelles•long processes / projections that come out of the soma and vary in

number, length, thickness, degree of branching, and terminal structures, as well as in their function.

•Function of neurons is to process and transmit information. Function of glia is to support the neurons in a variety of ways. (Even more glia than neurons.)

NEURON STRUCTURE •Neurons consist of soma and projections called neurites, which are divided into dendrites & axons.

•Dendrites are short, branched projections often covered in small spines that increase their surface area and perform other functions

•Axons are longer and unbranched until it reaches its end. Might be short, or as long as 1 m or more.

•The end of the axon branches to create multiple axon terminals.•Axon hillock = area where Axon leaves the soma•Axon initial segment (trigger zone) = right after hillock, the first part of the

axon projection•Large axons are usually wrapped in a myelin sheath. Gaps that regularly

interrupt the segments of myelin are called nodes of Ranvier.•Axon terminals come close to the target cells (which might be another neuron,

muscle cells, gland cells, or even capillaries (if releasing hormones to bloodstream), but don’t touch. This junction is called a synapse.

•Unipolar neurons — have soma and one projection (and axon) •In the CNS — these start as neural stem cells, which can become any cell of

nervous system, and then differentiate into (structurally similar) neuroblasts, which can only become neural cells.

•Neuroblasts then migrate away from other neural stem cells to the location their soma will be after development. They extend an axon, tipped with a growth cone, toward the target cell, which grows by following guidance cues in the environment until it reaches the target cell.

•In the PNS — both the original and migrating cells are neural crest cells instead of neural stem cells and neuroblasts

•Unipolar neurons are found in humans during fetal development, but not after.•Bipolar neurons — have a soma, one axon, and one dendrite

ORGAN SYSTEMS 18•Multipolar neurons — have a soma, one axon, and multiple dendrites. This is

most common type.•Pseudounipolar neurons —have a soma, with short process coming out of

soma that then divides into two long processes going in different directions. These are axons and the one bringing information in from the periphery is called peripheral axon, and axon bringing information into the CNS is called central axon.

•End of peripheral axon acts like dendrites do on other types of neurons. The part of the peripheral axon near the end is the initial segment / trigger zone, and the axon terminals are at the other end of the central axon.

Multipolar = motor neurons. motor neurons that conduct motor commands from the cortex to the spinal cord or from the spinal cord to the muscles

Pseudo-unipolar = sensory neurons. sensory neurons that receive sensory signals from sensory organs and send them via short axons to the central nervous system. Uni (one brain). Psuedo =PNS.

Bipolar neuron. Interneuron = . interneurons that interconnect various neurons within the brain or the spinal cord

NEURON FUNCTION •Function of neurons is to process and transmit information. •Most neurons have a resting membrane potential — a stable electrical charge

difference across their membrane (more negative in the cell). •This potential is how the neuron is able to be excited and to respond to input.

•Neurons receive excitatory or inhibitory input from other cells or from physical stimuli.

•Input info usually comes in through the dendrites, less often through soma or axon. The info from the input is transmitted to the axon with graded potentials

ORGAN SYSTEMS 19— changes to membrane potential away from the resting potential. These are small in size, brief, in duration, and travel short distances.

•The size and duration of the graded potential is proportional to the size and duration of input.

•Summation = adding together of all the excitatory and inhibitory graded potentials at any moment in time. This summation occurs at the trigger zone, the initial axon segment, and is how neurons process information from their input.

•If the membrane potentials at the trigger zone crosses a threshold potential, information will be fired down the axon.

•Graded potentials are like a finger on the gun.. once pulled back a certain distance, information (bullet) will be fired down the axon.

•Action potential — a different change in membrane potential that allows information to be fired down the axon. These are usually large in size and brief in duration (they travel quickly), and can be conducted down the entire length of the axon, no matter how long

•Action potentials are usually the same size and duration for any particular of neuron. This is unlike graded potentials, whose size and duration depend on size and duration of input

•Action potentials travel faster down larger (bigger diameter) and more myelinated axons. When it reaches axon terminals, information (i.e. neurotransmitters) crosses the synapse gap to target cell.

•Neurotransmitters are released at axon terminal to bind to receptors on the target cell to maybe change that target cell’s behavior.

•Neurotransmitters are then removed from the synapse (via re-uptake channels) to reset system.

•Input information that was converted to size and duration of graded potentials is converted to the temporal pattern of firing of action potentials down the axon. This firing info is then converted to the amount and temporal pattern of neurotransmitter release at the synapse.

•Above is the general way neurons function, but there are multiple types of neurons:

•Afferent / sensory neuron— pseudounipolar that neuron brings info (about a stimulus) into CNS

•Efferent neurons — carry info away from CNS to PNS. Two main kinds of efferent neurons:

•motor neurons (aka somatomotor neurons) — control skeletal muscle •autonomic neurons (aka visceromotor neurons) — control smooth muscle

(e.g. around blood vessels), cardiac muscle, and gland cells.•Autonomic neurons innervating the heart are responsible for releasing

norepinephrine, a neurotransmitter of the sympathetic nervous system•Most neurons of CNS aren’t like afferent/efferent, but are interneurons — they

connect other neurons and form complex pathways for information to travel.

ASTROCYTES: •Astrocytes are star shaped glial cells in the central nervous system (come from

neural stem cells)•Most common type of cell int the CNS•Have lots of highly branched processes, at the end of which are end feet.

ORGAN SYSTEMS 20•They perform many many functions, possibly the greatest variety of functions,

including the following:(1) Form the scaffold for the whole CNS - give structural support to other cells in brain/spinal cord.(2) Gliosis / astrogliiosis - involved in the repair and scarring process of the brain and spinal cord following traumatic injuries.

•If there’s an injury to the brain and/or spinal cord, astrocytes will divide and form more of themselves, migrate over to site of injury, and surround it.

•Their many projections then become hypertrophied and form a glial scar. (3) Homeostasis of interstitial fluid — astrocytes take in or release necessary ions to keep environment for neural cells in homeostasis.

•Also release lactate (made from astrocyte glycogen) into interstitial fluid because neurons have very little internal energy in their cells and need that for energy.

(4) Blood-brain barrier - The end-feet of astrocytes are plastered all over blood vessels of CNS. These end-feet structures, along with components of the vessels themselves, form an effective barrier that prevents large molecules from leaving blood to enter CNS unless they want it(5) Clears out synapses between neurons — Astrocytes place their end feet all over synapses and clear out neurotransmitters to reset the synapse for the next signal.(6) Influence neurons and other glia through exchanging substances. Most common cell type in the brain. Astrocytes have structural, metabolic, regulatory, and repair functions, and are the most abundant cell in the brain.

Astrocytes are found in areas of brain scarring.Astrocytes can supply lactate if the energy need arises.Astrocytes are involved in strengthening the blood brain barrier, but do not monitor the interstitial fluid for foreign pathogens. This is the job of the microglia.

MICROGLIA: •Derived from mesoderm, instead of the ectoderm like all the other neural cells.•Resting microglia have small soma and many highly branched processes

heading out in every direction. In this state, they’re basically just monitoring the interstitial fluid looking for inflammation (from injury or infection). When they detect trouble, they convert to active microglia.

•The active microglia are just larger and sort of blob shapes. They act like macrophages and scavenge the CNS for plaques, damaged neurons, and infectious agents.

•Microglia are the resident macrophages of the of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system. They do this by:

(1) Secreting cytotoxins — If a microglia finds a foreign cell it can secrete cytotoxic substances like reactive oxygen species that can kill a cell. (2) Phagocytosis — After macrophages kill the bacteria, it becomes debris. Microglia eat up all kinds of debris, from foreign or from its own cell and break it all down. yum.

ORGAN SYSTEMS 21•Note: these processes don’t necessarily happen in order… They could

phagocytose something and then secrete a cytotoxin.(3) Antigen presentation — After consuming debris, microglia will take a tiny pieces of it and stick tjos antigen out on its surface for other cells (specifically those of the immune system) to see.

•Ex: Lymphocytes can then recognize the antigens, and potentially increase inflammation and/or make it more specific to whatever foreign cell the microglia has identified.

•Thus microglia is both activated by inflammation and it contributes to it.(4) other cells of the immune system through exchange of substances.Microglia arise from monocytes, and are a part of the immune system, which arises from the mesoderm. However, the majority of the nervous system arises from ectoderm (CNS) or neural crest cells (PNS).Microglia are the macrophages, or phagocytes, of the central nervous system (CNS, or the brain). They will proliferate if there is an infection, such as bacterial meningitis.

EPENDYMAL CELLS: •These cells line the CSF-filled ventricles in the brain and the central canal of

the spinal cord. •Derived from neural stem cells•Ependymal cells are simple (one layer) columnar, cuboid epithelium-like cells.•The side of the ependymal cell that faces the cerebral spinal fluid has many

microvilli and cilia.•Main functions:

(1) Form barrier between CSF and interstitial fluid of the tissue itself, though it’s a relatively leaky area (this leakiness if helpful because it means doctors can sample it).(2) Secrete CSF — Specialized ependymal cells and capillaries form tufts in some of these brain ventricles. This is where CSF is secreted across ependymal cells to create cerebral spinal fluid.Ependymal cells help form the barrier that holds in and produces CSF, cerebrospinal fluid. Ependymal cells not only help form the barrier that separates CSF from the rest of the body, but help secrete it as well.The brain and spinal cord are cushioned by cerebrospinal fluid (CSF), which is kept separate from blood and lymph fluid.

OLIGODENDROCYTES: •Similar structure to astrocytes, but with fewer projections. Also in the central

nervous system.•main function: produce myelin sheath in the CNS•Each oligodendrocyte has maybe a dozen projections that extend towards nearby

axons of neurons. The structure at the end of these oligodendrocyte projections is myelin sheath.

•Each oligodendrocyte can produce myelin sheaths for multiple neurons (each projection makes one segment of the sheath, but they have multiple projections)

•The myelin sheath for a single neuron can come from multiple oligodendrocytes.

ORGAN SYSTEMS 22•Myelin sheath is made mostly of a lipid, the same substance that makes up fat, of

course. It’s basically the cell membrane for an axon… sort of like the rubber coating on a wire.

•Oligodendrocytes also influence other glial cells. Each nerve cell can have multiple myelin sheaths, which help speed conduction. Oligodendrocytes are myelin sheaths that wrap around nerve axons to help speed conduction.•

SCHWANN CELLS: •Schwann cells are glia of the PNS, derived from neural crest cells. They come in

different shapes.•Nonmyelinating Schwann cells are fairly shapeless, but have troughs on their

surface. Small diameter neurons can just sort of sit their axons in these troughs. •These types of Schwann cells provide some support for PNS axons, but don’t

myelinate them.•The main function of normal Schwann cells is to produce the myelin sheath for

PNS neurons.•Not all peripheral neurons have a myelin sheath, but most of those with a

larger diameter do. The structure and function of these myelin segments are the same in the PNS and in the CNS, but are produced by different cells.

•Schwann cells are also different from the oligodendrocytes of the CNS in that a single Schwann cell produces the myelin for a single segment of a single axon. They’re not myelinating multiple neurons like oligodendrocytes.

•Almost all the cell membrane of a Schwann cell is the myelin wrapped around an axon. It has just a little lump outside this wrapping, though, that contains the nucleus and cytoplasm for the Schwann cell

•Schwann cells also influence neurons, and vice versa, through exchange of various substances.

•Gangliosides are found on Schwann cells, the myelin sheath cells of the peripheral nervous system

•The majority of immune cells cannot cross the blood-brain barrier.•Conduction potential velocity increases with increased axon diameter and myelination.•Multiple sclerosis is an inflammatory disease, and is characterized by an increase in antibodies and a

decrease in myelination.

Other: •Tetanus is the maximum sustained contraction of skeletal muscle cells.•Heart rate is controlled by the autonomic nervous system.•Afferent nerve fibers bring signals back to the central nervous system.•A local nerve block would be an anesthetic, as it would block sensation, but would

not affect movement. Sometimes a nerve block is used to dull tooth pain when pain medication is contra-indicated.

————————————Neuron Membrane Potentials————————————

ORGAN SYSTEMS 23NEURON RESTING POTENTIAL — DESCRIPTION: •Positively charged cations are in layer all over outside of the cell membrane;

negatively charged anions are in a layer all over the inside of the cell membrane.•Well, really, there are anions and cations on both sides of the membrane…

but more cations on the outside and more anions on the inside.•Outside is called 0, and difference between outside and inside is usually around -

60mV•Resting potential is related to the concentration differences, or gradients, of

different ions across the membrane•Most important cations that are K+ Na+ and Ca+•Most important anions are chloride and organic anions (e.g. proteins)•Organic anions and K+ have a bigger concentration inside than outside the

neuron.•Na+, Cl-, and Ca2+ have a bigger concentration outside than inside the

neuron.•Each ion is therefore acted on by two forces:

•Electrical potential — ions will be attracted to the side with opposite charge•ex: OA- electrical force will try to drive it out of the neuron; K+ electrical

force will try to drive those ions in (because inside is more negative)•Diffusion potential — ions will be attracted to the side with lower

concentration •ex: OA- diffusion force has matched diffusion force with electrical force,

wanting to drive it out. K+ has opposite diffusion force to electrical force; diffusion force wants to drive it out of cell (even though the inside is more negative.

NEURON RESTING POTENTIAL — MECHANISM: •Let’s consider a neuron with no resting potential — it’s not more positive outside

or more negative inside the membrane, and all the key ions have the same [ ] inside and outside…

•Organic ions are created in the cell for release into the cytoplasm. As this happens, the OA- build up in the cell, creating a small negative membrane potential, but not enough for neuron to function. OA- ions now have electrochemical forces that make it want to leave but it can’t. so there are not further

•For other ions, they can pass through the membrane (unlike OA- ions) through leak channels that are open all the time.

•The Na+/K+ pump is also in the neuron membrane, and it transports 3 Na+ out and 2 K+ in. This also makes the membrane potential more negative, and increases diffusion gradient/potential for sodium and potassium as more K+ and less Na+ is inside the cell

•The concentration changed inside the cell but not outside because the extracellular fluid is huge, with tons of ions such that any movement into it is negligible.

•For K +, at typical neuron ion concentrations its diffusion force is bigger than smaller electrical force, causing a net movement of K+ out through the leak channels. As they leave, it makes the membrane potential more negative; until

ORGAN SYSTEMS 24equilibrium is reached with K+ ions. This typically occurs around -70 mV which is more than enough for the neuron to function.

•Equilibrium potential / reversible potential = the membrane potential at which there is no net movement of ions across the membrane.

•Doesn’t actually take much for this equilibrium potential to be reached with K+ (maybe 1% of all K+ ions in the cell have to leave), but it does take some time for them to get through leak channels

•For Na+ , at typical neuron ion concentrations, Na+ diffusion force and electrical force drive Na+ into the cell. If we had a cell that was only permeable to Na+, it would be driven into the cell to the extent that the membrane potential would switch to positive.

•It would have to be quite positive inside the neuron for the electrical force to balance this diffusion force. Equilibrium potential of sodium is ~ +50 mV.

•Without input, when membrane is at rest, the permeability of the membrane to sodium is much less than permeability to potassium.. It does affect potential a little bit through, so the equilibrium potential is around -60 mV instead of the -70 it would be with just potassium.

•For a cell whose membrane is permeable to multiple ions with electrochemical driving forces, the overall resting membrane potential is a weighted average of those ions’ equilibrium potentials. (weighted by permeability).

•The resting membrane usually has an intermediate permeability to Cl- ions. In contrast to Na+ and K+ whose concentration gradients determine resting membrane potential, the resting membrane potential determines the concentration gradient of Cl- ions. Membrane potential drives Cl- out of the ions until the concentration gradient is big enough to balance it.

•So normally there’s a very small concentration of Cl- inside the cell compared to outside.

•One way chloride is driven out is by the Cl-/K+ symporter, drives Cl- out by harnessing K+ ions’ diffusion force to leave the cell.

•Because of this, equilibrium conc. for chloride is slightly less than resting potential, usually -70mV.. this is usually negligible for overall resting potential, though.

•Ca2+ is also driven out of the cell so that there’s a small concentration of Ca2+ ions inside compared to outside. One way this is down is by the Ca2+/Na2+ exchanger, which harnesses the electrical and diffusion forces acting on Na+ (to bring Na+ in the cell) in order to pump Ca2+ out of the cell.

•This creates strong electrical and chemical gradients for Ca2+ that want to drive it into the cell.

•Equilibrium force of Ca2+ is ~ +120mV, very high, but permeability is very low, so it doesn’t really have an effect on resting potential.

•A neuron at rest (or resting potential) has a stable separation of charges across the membrane.

•At resting potential, there are more positive charges on the layer directly outside of the membrane, and more negative charges on the inside of the membrane.

•This separation of charges refers to polarization. The membrane potential of a neuron at rest is slightly negative, thus it is polarized.

ORGAN SYSTEMS 25

NEURON GRADED POTENTIAL — DESCRIPTION: •Graded potentials occur in response to input.•Resting neurons have a stable charge separation across entire membrane, where

a layer of cations is on the outside of the membrane (0) and a layer of anions is on the inside of the membrane (~ -60 mV)

•These potentials can be graphed as time vs. potential. •Inputs from certain types of stimuli may increase or decrease the membrane

potential for a brief period of time before it goes back to the resting potential — these are graded potentials

•Tend to occur in the dendrites and soma of the neuron•Size and duration of graded potential is determined by size and duration of the

inputs•Most graded potentials don't pass into the axons of neurons but instead most

axons have a different membrane potential change called the axon potential. •Axon potentials start at the trigger zone and occur when the combined effect

(summation) of the graded potentials brings the membrane potential of this trigger zone (the initial part of the axon) across a certain value called the threshold potential.

•Threshold potential varies between neurons (but a common one is around -50 mV)

•Summation at the trigger zone is how neurons process information from their inputs.

•Most neurons respond to inputs from other neurons in the form of neurotransmitter molecules released at synapses. Neurotransmitters then bind to receptors on other neuron to produce a graded potential called synaptic potentials.

•Depending on the neurotransmitter and receptor, it could be an excitatory or inhibitory input.

•Other neurons (and neuron-like cells) may also generate graded potentials from physical stimuli, such a slight or odorant molecules. These are receptor potentials.

•Depolarization / excitatory potentials = a graded potential that moves the membrane potential closer to zero (less negative). This moves it closer to the threshold, increasing likelihood of response.

•Hyperpolarization / inhibitory potential = graded potential that moves the membrane potential further away from the threshold, or in the more negative direction. Increases charge separation of the membrane, and decreases likelihood of an axon potential starting.

•Graded potentials decay with time and distance, such that their effect is brief and localized.

•The closer the potential is to the trigger zone, the greater likelihood there will be of it inducing an action potential.

•Therefore a synapse that’s closer to the trigger zone will have a greater influence on the behavior of the neuron

•Temporal Summation: •If two depolarizations happen slightly separated from one another, they wont’

have any effect.

ORGAN SYSTEMS 26•But if two happen right around the same time, we get an added effect called a

temporal summation that could produce a depolarization twice the size.•Spatial Summation:

•As graded potentials spread from the dendrites that accepted the neurotransmitters across the soma, they also decay.. so by the time the potential reaches the trigger zone it may not have much of an effect.

•If two graded potentials happen sort of far away from each other, they might not have any effect. But if two graded potentials occur close to each other on the membrane, it could cause spatial summation so you get a depolarization twice the size.

•If you have excitatory input and inhibitory input at the same time and sort of the same place, they may cancel each other out

•Synaptic potentials tend to be quite small, < 1mV in size. So neurons require the temporal and spatial summation of 10 synapses or more to reach threshold and have an effect.

•Electrical synapses do not have a gap between the neuron and target cell - the cells are physically connected.

•Chemical synapses have a gap between the neuron and target to facilitate communication.•electrical synapses have very different mechanisms to relay information from the

neuron to the target cell.

•

NEURON GRADED POTENTIAL — MECHANISM: •Neurotransmitter receptors are found at synapses and are what the

neurotransmitters released from other neurons bind to.•Many neurotransmitter receptors are a type of ligand gated ion channel•The graded potential produced depends on:

•What kind of ions pass into membrane (some channels allow just one type in, others allow multiple)

•How many channels are opened (depends on amount of neurotransmitter released into synapse and how long it stays in the synapse)

•If a channel opens that is selective for only one type of ion, the membrane permeability for that ion is increased, which causes the membrane potential for that ion to change around that synapse.

•If Na+ or Ca2+ channels cause a depolarization or excitatory potential, because the cations flow into the neuron and bring positive ions into the more negative internal environment of the cell.

•Force of diffusion and electrical difference drives it in.•Na+ channel is most common type of depolarization channel.

•If Cl- channel, hyperpolarization usually occurs because it flows into the cell and makes it more negative. (This is most common type of inhibitory channel.)

•Force of diffusion ([ ] outside cell much bigger than in) overcomes the electrical force to drive Cl– ions in.

•K+ channels also cause hyperpolarization because its larger diffusion overcomes small electrical force to drive it out of the cell once the channel if opened, which again makes the internal membrane more negative

ORGAN SYSTEMS 27•When a neurotransmitter, such as Na+, binds to the receptor and allows, for

example, Na+ inside, there will be a small cluster of Na+ ions around that channel that causes membrane potential there to increase.

•It doesn’t just continue increasing, though, because the neurotransmitter leaves and the ion channel closes again. This causes the graded potential to plateau.

•Why do they decay? The Na+ ions diffuse throughout the cell (because of electrical and chemical diffusion) and the depolarization decreases. Eventually that piece of the membrane goes back to its resting potential.

•The sodium-potassium pump pulls potassium ions in and moves sodium ions out of the cell.•Because potassium is positively charged and the inside of the cell is negatively charged, the

electrical gradient tends to pull potassium in, not out.•When a membrane is at rest, sodium ions or more concentrated outside of the

neuron; potassium ions are more concentrated inside. Concentration gradients move potassium ions out of the cell.

•negative sign on a resting potential signifies a relative difference in charge, not an absolute difference.•Potassium cation is found in greatest concentration inside a neuron in the resting state•At the resting potential, negatively charged ions will feel an electrical force pushing them out of the neuron,

Graded potentials cause action potentials.The size of a graded potential must reach a certain threshold in order to cause an action potential.The size of the action potential is independent of the size of the graded potential (this is known as the all-or-nothing rule). Amplitude doesn’t change. The best-fit line of the results most likely has the equation y = c.

Difference between action and graded potential: All potentials are determined by the flow of charged molecules across the neuron membrane.The difference between graded potentials and action potentials first and foremost has to do with where they occur.Action potentials occur in axons, while graded potentials occur in the dendrites and soma.

NEURON ACTION POTENTIAL — DESCRIPTION: •Multiple excitatory / depolarizing potentials are needed with temporal and spacial

summation to push the membrane of the trigger zone over its threshold potential. When this happens (often around -50 mV), an action potential well be conducted down the whole axon.

•Axon potentials are unlike graded potentials in that they’re the same size for a given neuron (though total size my vary between neurons), and that they’re unchanged (don’t degrade) as they go down the axon, no matter how long it is.

•Shape of an action potential is fairly characteristic:•After graded potentials reach threshold potential, action potential begins with

a rising phase that depolarizes the membrane so much the charge inside the cell membrane is positive, ~ +40mV

•Small plateau

ORGAN SYSTEMS 28•Rapid falling phase that goes even more negative than normal resting

potential, to ~ -70 mV•Slowly settles back up to resting potential of ~ -60 mV

•All-or-none property of an action potential — you either get one or you don’t (b/c size doesn’t vary for a particular neuron. Doesn’t matter how far over the threshold a graded potential gets, will cause the same size action potential)

•Duration of action potential is also pretty consistent for any particular neuron.•(Graded potentials have a wider range of duration depending on the duration

of their inputs.)•Speed at which action potentials are conducted can be very fast (1 - 100 m/s).

•Faster speeds usually happen in larger-diameter and more myelinated axons.•Saltatory conduction — peed of an action potential down a myelinated axon is

not consistent — it is conducted faster at the myelinated segments than through the nodes of Ranvier.

NEURON ACTION POTENTIAL — MECHANISM: •The membranes of axons have leak channels and voltage-gated channels

(which open when the membrane potential crosses a certain threshold potential)•Na+ channels are voltage-gated. So when a summation of graded potentials

causes depolarization of the trigger zone membrane past the threshold, Na+ flows in. This causes further depolarization at the trigger zone membrane, which then leads to more Na+ channels opening a little further down, and this effects cascades in a wave down the axon.

•Trigger zone has greatest density of Na+ voltage gated channels, which is why the action potential starts there.

•Membrane potential dramatically rises as it tries to increase membrane potential to Na+ eq. potential (around +50 mV). This is rising phase, and the inside of the cell membrane becomes positive.

•After the membrane potential gets depolarized to a certain extent, the Na+ voltage gated channels close, so the membrane potential never actually reaches +50 mV, usually just to +40 mV.

•After they close, they’re in an inactivated state — ion channels are unable to open for a certain period of time.

•After the rising phase and plateau, an exit of K+ through leak channels and voltage gated channels causes the falling phase of the membrane potential and it plummets to an even more negative potential (-70 mV) than at resting state.

•K+ leak channels — some K+ leaves when the membrane is at rest (without input), but after the membrane potential becomes so positive, both electrical and diffusion force drive K+ out of the membrane through leak channels quite quickly.

•Voltage-gated K+ channels — also open after membrane potential crosses threshold, but do so more slowly than the Na+ ones.

•So first, Na+ rushes in causing rising phase, then K+ voltage channels open (and exit through leak channels increases), causing the falling phase

•Once the membrane potential inside is negative again, it stops falling further because K+ leak channels drive out K+ much slower then, and because the

ORGAN SYSTEMS 29negative potential causes voltage gated K+ channels to close automatically, though again a bit slower than Na+ voltage channels did at positive potential, so the falling action extends past the resting potential for a bit until it settles back.

•This extension past resting potential is called the after-hyperpolarization, or refactory period (called refractory because it’s difficult or impossible to start a new action potential during this period).

•Refractory period has two parts: absolute and relative •absolute refractory period — when the voltage gated Na+ channels are

first closed and they’re in an inactive state. No matter how strong a graded potential comes in, it won’t trigger another action potential.

•relative refractory period — when the voltage gated Na+ channels are functional again, but membrane potential is hyper-polarized. It would take more excitatory input than normal to to cause an action potential.

•relative refractory periods can help us figure out how intense a stimulus is — cells in your retina will send signals faster in bright light than in dim light, because the trigger is stronger.

•An effect of refractory period is that action potentials travel down the axon from the trigger zone, and can’t travel immediately back.

•Refractory period determines the maximum frequency at which a single neuron can send action potentials.

•Movement of sodium and potassium ions across the membrane starts at trigger zone and spreads in waves. First wave of depolarization all down the axon, then of hyperpolarization, & eventually settling.

•Resting potentials are not associated with refractory periods. Graded potentials are not associated with refractory periods. Refractory periods (both relative and absolute) are times when a membrane is resistant to starting another action potential.

EFFECTS OF AXON DIAMETER AND MYELINATION: •Axon with larger diameter offers less resistance to ions moving down the axon

(more pathways through the cytoplasmic around other cell structures), and therefore allows action potential to be conducted faster (because speed of action potential is related to speed of ions moving down axon).

•Action potentials move faster in myelinated segments because the capacitance of the membrane is reduced. This decreases the number of ions and the time needed to change the membrane potential in these areas.

•Capacitance (in this context) = total number of charges along the membrane, or number of ions that can be stored in the layers on both sides of the membrane at any given potential (because potential represents strength of the charge separation for any particular ion carrier).

•The closer charges are to each other, the more charge can be stored.•At the nodes of Ranvier, an anion on the inside layer is strongly attracted to

cation on opposite side; It overcomes the repulsion of nearby like charges on either side of the membrane and thus in these nodes (at resting potential) more cations/anions can be packed in on either side. (low capacitance)

•In the myelinated segments, the membrane is essentially much thicker, so distance is much greater between oppositely charged ions on opposite sides of

ORGAN SYSTEMS 30the membrane and strength of that charge is less. In myelinated segments you can thus put fewer cations/anions on either side. (high capacitance)

•This means that as an action potential comes rushing by, it is easier to depolarize the areas that are sheathed, because there are fewer negative ions to counteract.

•As our action potential travels down the membrane, sometimes ions are lost as they cross the membrane and exit the cell. The presence of myelin makes this escape pretty much impossible, and so it also helps to preserve the action potential.

•Myelination also decreases the membrane permeability to ions, so fewer total ions cross the membrane during an action potential. Thus fewer ions than normal need to be pumped out through Na+/K+ pump after the action potential.

•Recall that these pumps require energy, myelination actually increases the efficiency of action potential conduction in terms of the energy needed to maintain these ion concentrations after action potentials.

•Myelinated axons have most of their voltage-gated ion channels at the nodes of Ranvier, so they can regenerate the full size of the action potential and keep it strong all the way down the axon.

•More myelin and larger = faster

• Voltage-gated sodium channels are found in lower concentration towards axon terminals.•Voltage-gated sodium channels are found in greatest concentration in the trigger

zones.

Reduced permeability of potassium leak channels would affect the time to reach maximum repolarization in a neuron. (more K+ would remain inside).

• In myelinated axons, action potentials only form in nodes.• Nodes that are close together might cause action potentials to slow down.•Nodes that are far apart might cause action potentials to stop.• Saltatory conduction refers to the the movement of action potentials from node to node.• Myelinated axons are axons covered with a myelin sheath.• Myelin sheaths are broken up by small nodes.•Saltatory conduction is the conduction of action potentials along myelinated

axons.

ACTION POTENTIAL PATTERNS: • Some neurons fire no action potentials until there is sufficient excitatory inputs.

And then the size / duration of depolarization over threshold is converted into the frequency and duration of a series, aka a train of action potentials

•Used by motor neurons that synapse on skeletal muscles.•Other neurons fire action potentials at a regular rate without any input. This

happens because they have differences in their leak channels and/or voltage-gated ion channels that spontaneously depolarize the membrane to threshold at a regular interval.

•Similar to pacemaker cells in the heart.

ORGAN SYSTEMS 31•With these types of neurons, excitatory input will cause them to fire action

potentials more frequently when excited; and when that goes away they go back to their regular rate of firing. Firing is slowed down during inhibition

•During absence of input, some neurons fire clusters of bursts of action, pause for a bit, and then fire more bursts.

•Excitatory input can increases frequency of these bursts (and maybe increase space between them)

•In the last two systems, where neuron fire regularly or in bursts, at resting potentials is that information passed along to target cells can be fine tuned in either direction. (unlike first case, which must be no action potential or train of action potential).

•The last two systems can also pass along info in a more fine-grained fashion.•The different temporal patterns of action potentials are then converted to the

amounts and temporal patterns of neurotransmitter release at the synapse.

•At the peak of an action potential, there is more sodium inside of the membrane than outside.

•Resting potential is approximately -70mV.•Action potentials peak around 40mV.•Sodium equilibrium potentials are around 50mV. Thus, the membrane potential is

slightly less positive than the sodium equilibrium potential at the peak of an action potential.

•Dendrites receive an action potential.•Axons transmit action potentials.

• Potassium leak channels allow potassium to exit a neuron in response to depolarization.• Reduced permeability of a leak channel to its natural ion means that the rate the ions are

able to cross the channel is reduced.•Reduced permeability of potassium leak channels would affect the time to reach

maximum repolarization in a neuron.

• Voltage-gated potassium channels play a central role in action potentials.• Voltage-gated sodium channels also play a central role in action potentials.•Voltage-gated calcium channels are central to the release of neurotransmitters

into the synaptic cleft.•

DEMYELINATION DISEASES: •Demyelination diseases degrade the myelin coating on cells.

•Ex: Guillain-Barre syndrome and Multiple Sclerosis. •Guillain-Barre syndrome is the destruction of Schwann cells (in the peripheral

nervous system)•MS is caused by a loss of oligodendrocytes (in the brain and spinal column). •These disorders have different causes and presentations, but both involve muscle

weakness and numbness or tingling.

ORGAN SYSTEMS 32•These symptoms occur because the nerves aren’t sending information the right

way. When the myelin coating of nerves degenerates, the signals are either diminished or completely destroyed.

•If the nerves are afferent (sensory) fibers, the destruction of myelin leads to numbness or tingling, because sensations aren’t traveling the way they should.

•When efferent (motor) nerves are demyelinated, this can lead to weakness because the brain is expending a lot of energy but is still unable to actually move the affected limbs.

•Limbs are especially affected, because they have the longest nerves, and the longer the nerve, the more myelin it has that can potentially be destroyed.

——————————————Neuronal Synapses——————————————

SYNAPSE STRUCTURE: •Recall, synapses are the junction between a neuron’s axon terminal(s) and the

target cell.•Chemical synapses have a gap b/n the neuron’s axon and target.

Neurotransmitters are used.•Electrical synapses are when the axon terminal and target cell are

physically connected. Gap junctions allow ions to flow between them. (These are fairly rare in humans)

•A typical neuron receives up to thousands of signals from other neurons. These synapses most often occur at the dendrites (part of the reason they’re branched is to increase surface area for synapses).

•However, there can also be synapses on the soma or the axon (usually the axon terminals)

•In the central nervous system, end feet of astrocytes cover most of the synapses.

•Synaptic cleft = gap between axon terminal and target cell•It is bordered by the pre-synaptic membrane (of the axon terminal) and post-synaptic membrane (of the target cell)

•Just on the inside of the pre-synaptic membrane are synaptic vesicles, bubble-like structures that are full of neurotransmitters.

•The pre-synaptic axon terminal also has voltage-gated calcium channels that allow Ca2+ in.

•On the post-synaptic membrane are receptors that are specific for the neurotransmitters.

NEUROTRANSMITTER RELEASE: •A protein known as complexin acts like a brake, and stop the vesicles from

fusing into the membrane and releasing their contents [remember: complexin complicates the process of vesicle fusion]

•The vesicle protein synaptotagmin can bind and release complexin in the presence of calcium

•As the action potential travels down the axon, positive ions continue to flood the cell. Eventually, this influx reaches the very end of the neuron – the axon terminal. When this happens, the membrane potential of the axon terminal is depolarized.

ORGAN SYSTEMS 33•This opens the Ca2+ to channels at the axon terminal; and calcium flows into

the axon (because/c of its diffusion gradient)•The calcium ions can then activate synaptotagmin to release the brake, and the

vesicles fuse with the cell membrane, and the vesicle contents (neurotransmitters) are released into the synaptic cleft.

•Neurotransmitter then diffuses across the cleft and binds to receptors on the target cell.

•An increased frequency of axon potentials reaching the terminal causes increased opening of Ca2+ voltage gated ion channels. This causes more Ca2+ to enter the cell, which means more synaptic vesicles fuse and more neurotransmitter is released.

•Increased duration of axon potential means neurotransmitter is released for a longer duration.

•These two things (frequency & duration) affect how much neurotransmitter is in the synaptic cleft for how long, which in turn affects the cell it is firing on.

•When the train of action potentials stops firing, voltage-gated ion channels will close, Ca2+ will stop entering cell, and Ca2+ will start to exit via usual methods; neurotransmitter will stop being released.

Action potentials determine how much information is released into the synaptic cleft.Action potentials also determine how long information is present in the synaptic cleft.Action potentials open voltage gated calcium channels, which results in calcium flowing into the axon terminal.Action potentials do not result in calcium leaving the target cell at the post synaptic membrane.

TYPES OF NEUROTRANSMITTERS: •Neurons tend to have just one type of neurotransmitter that they release, but

many neurotransmitters can bind to multiple types receptors.Amino Acid Neurotransmitters: •Have an amino group and carboxylic acid group.•Glutamate — most common excitatory neurotransmitter of the nervous system•GABA and Glycine — most common inhibitory neurotransmitters of the nervous

system. •GABA the most common inhibitory neurotransmitter in brain•Glycine is most common in spinal cord

•Glycine is the most common inhibitory neurotransmitter in the spinal cord•Glutamate is the most common excitatory neurotransmitter in the nervous system.•Gamma-aminobutyric acid, or GABA, is the most common inhibitory neurotransmitter in

the brain.

••These AA neurotransmitters are involved in most processes of the nervous

systemPeptide Neurotransmitters:

ORGAN SYSTEMS 34•Peptides are polymers of amino acids; they’re much larger than other types of

other neurotransmitters•One group of peptide neurotransmitters are called the opiods. (ex: endorphin)

•These play a big role in our perception of pain, and thus those types of neurotransmitters are a target for many pain meds.

Monoamine Neurotransmitters (aka biogenic amines):•Organic molecules with an amino group connected to an aromatic group by a 2-

carbon chain.•Serotonin, Histamine, Dopamine, Epinephrine, and Norepinephrine

•Three monoamines (dopamine, epinephrine, norepinephrine) are specifically called catecholamines; they have a catechole group (benzene + two hydroxyl groups)

•Are involved in many processes, especially in the brain; including process of consciousness, attention, cognition and emotion

•Norepinephrine in particular is released by some autonomic neurons in the PNS

•Many disorders of the nervous system involve abnormalities of the monoamine transmitters; and thus they are often a target for drugs.

Other:•Acetylcholine — one of the most important nervous system that is not a

monoamine or peptide.•Performs a number of functions in the brain of the CNS•In the PNS, this is released by most neurons in autonomic nervous system, and

by motor neurons.

TYPES OF NEUROTRANSMITTER RECEPTORS: •Combination of neurotransmitter released and receptor on post-synaptic

membrane that determines whether a signal to the target cell is excitatory or inhibitory

•Many neurotransmitters can bind to multiple types of receptors; some cause excitatory response and others cause inhibitory response.

•When the target cell is another neuron, excitatory or inhibitory synapses can be scattered all over the neuron, or there are many neurons where the dendrites receive predominately excitatory synapses and the soma receives inhibitory synapses at the soma. And when the synapse happens on another neuron’s axon terminal, there’s a mix of excitatory and inhibitory synapses.

•This allows fine-tuning of neuron output at multiple levels, from the dendrite to soma to the axon terminals.

•Two major types of neurotransmitter receptors: •Ionotropic — ligated gated ion channels. When the ligand (neurotransmitter)

binds to the receptor, they open and let certain ions pass through.•These ionotopic receptors cause graded potentials (brief, local) when they

open.•Excitatory response is usually caused in target cell if the ionotropic ion channel

allows Na+ or Ca2+ in (because their positive charges cause depolarization)•Inhibitory response is usually caused in the target cell if the ionotopic ion

channel allows Cl_ or K+ ions to pass. (Cl goes in to the already negative cell; K+ travels out)

ORGAN SYSTEMS 35•Metabotropic — When neurotransmitter binds, it activates second messengers

inside the neuron•Second messengers can open ion channels, change protein activity, or affect

gene transcription.•When metabotropic receptors are activated, the response is slower than with

ionotropic ones, but the overall effect may be larger and more widespread because of the amplification that secondary messengers can cause.

•Overall response of target cell after a metabotropic receptor binds a neurotransmitter may be brief, or it may affect the cell permanently.

••Metabotropic neurotransmitter receptors move more slowly than ionotropic neurotransmitter

receptors. Metabotropic neurotransmitter receptors move more slowly than ionotropic receptors, but their results may be larger and more widespread.

•Ionotropic neurotransmitter receptors are the type of receptor that directly allows ions to pass through the membranes.

•Metabotropic neurotransmitter receptors are the type of receptor that activate a second messenger inside the neuron.

•

NEUROTRANSMITTER REMOVAL: •As action potentials travel down axons, the information they contain is really

contained in the frequency of firing and duration of the chains of axon potentials. •When the action potential reaches the axon terminal, neurotransmitter is

released to bind to receptors on target cell. Eventually, it needs to be removed from the receptors and from the synaptic cleft:

•If neurotransmitter lingers in the synaptic cleft, it will mostly continue to bind to the receptor, and the duration of the trains of action potential signals won’t be able to be transmitted.

•The synapse will not be functional.•Structure of neurotransmitter may be changed before it’s removed, so that it

is not recognized by the receptor. Ex: acetylcholine (in motor neurons) is deactivated by acetylcholinesterase, which is an enzyme that breaks down acetylcholine into choline and acetate.

ORGAN SYSTEMS 36•Neurotransmitter removal can be by diffusion — leftover neurotransmitter just

passively diffuses out of the synapse. This only works action potentials are firing slowly.

•If action potentials are firing quickly, the rate of neurotransmitter release may be greater than the rate at which neurotransmitters can diffuse.

•Neurotransmitter removal can also be active:(1) Enzymes break down the neurotransmitter in the synapse into its component parts (2) Reuptake pumps — some pre-synaptic membranes contain special active transport channels that actively pump neurotransmitters back into the axon, where it can be recycled & used in future releases. (3) Astrocyte end-feet — in CNS, astrocytes put their end feet all over synapses. The end feet also contain pumps/channels that actively pump the neurotransmitter out of synapse and into the astrocyte.

•Sometimes the neurotransmitter will be broken down or used in the astrocyte, or parts of it may be transferred by the astrocyte back to the axon terminal of the neuron so it can be recycled.

•All these methods allow the synapse to be rapidly turned on and off, so it can convey more information from neuron to target cell.

•When the structure of a neurotransmitter is changed, it is not recognized by the receptor.Acetylcholine is deactivated by acetylcholinesterase, which is an enzyme that breaks down acetylcholine into choline and acetate.

NEUROPLASTICITY: •Neuroplasticity refers to how the nervous system changes in response to

experience. •Nervous system is constantly changing (e.g. when we form new memories). •This involves changes in synapses and/or other parts of neurons that affect

how information is processed and transmitted int he nervous system•Potentiation — increase in the strength of info flowing through a particular part

of the nervous system•Each action potential has a larger effect on target cell•Happens with parts of neurons and chains of neurons that are used often; they

grow stronger•Depression — decrease in the strength of info flowing through a particular part

of the nervous system•Each action potential has less of an effect on target cell•Happens with parts of neurons and chains of neurons that are used rarely;

they grow weaker•Amount of neuroplasticity is highest when the nervous system is developing (and

lower afterward), but it’s present throughout life. Also increases transiently in response to nervous system injury.

ORGAN SYSTEMS 37Synaptic neuroplasticity — neuroplasticity changes that happen at the synapse•Potentiation changes from lots of activity: increase in target cell response for

each action potential•For each action potential reaching the axon terminal, more neurotransmitter

may be released in the synapse, so a bigger response is seen in the target cell.•May be an increase in the number or type of membrane receptors in the post-

synaptic membrane, or in the responses that occur through second messengers so that for any given amount of neurotransmitter released from the axon, the target cell has a bigger response because it is more sensitive to that neurotransmitter

•Seems like there’s communication going from axon terminal to post-synaptic membrane and backwards… details haven’t been figured out yet.

•Depression changes from inactivity: decrease in target cell response for each action potential•For each action potential reaching the axon terminal, less neurotransmitter

may be released in the synapse, so a lower / depressed response is seen in the target cell.

•Neurotransmitter receptors may decrease in number, or change type to a less responsive receptor; or there may be changes in the response of second messengers such that they elicit a weaker response than they used to.

Structural neuroplasticity — neuroplasticity changes that happen at the level of an entire cell, where the total number of synapses between a neuron and its target cell are changed.•If two neurons are firing together frequently (one often stimulated by the other),

we may see an increase in the number of synapses between pre-synaptic neuron and post-synaptic neuron•Dendrites may get longer or growing more branches; dendritic tree becomes

more complex•Pre-synaptic neuron may sprout more axon branches and terminals so it forms

more synaptic connections with dendritic tree.•If two neurons are not firing together very frequently, we may see a decrease in

the number of synapses between pre-synaptic neuron and post-synaptic neuron•Dendrites may get shorter or lose branches, such that the dendritic tree

becomes simpler •Pre-synaptic neuron may lose some of its axon terminals.•If this neuron is not firing very often at all, we might even lose the whole

neuron:•Pruning — process of losing neurons or parts of neurons because they’re not very

active•Potentiation and depression can happen over a wide spectrum of time.. We often

categorize it into short term changes (over the course of seconds or minutes) or long term (over months or years).

•Synaptic neuroplasticity can contribute to both short term & long term potentiation and depression

•Structural neuroplasticity tends to be more associated with long term potentiation and depression

•By changing the strength of information flow between individual synapses or the between cells by changing the total number of synapses, neuroplasticity plays a

ORGAN SYSTEMS 38very important role in the development of the nervous system as it’s wiring itself together based on the experience it’s receiving during its formative time.

•Neuroplasticity also plays a huge role in memory and learning, as well as recovery from injury to the nervous system

Depression refers to neuroplasticity that results in activity and response growing weaker.Potentiation refers to neuroplasticity that activity and response growing stronger.Synaptic refers to neuroplasticity that occurs at a synapse.Structural refers to neuroplasticity that affects whole neurons or groups of neurons.In this example, the loss of entire neurons due to inactivity would refer to structural depression.

————————————————Biosignaling————————————————MEMBRANE RECEPTORS •Membrane receptors = integral proteins that interact with outside environment•Signaling molecules (aka ligands) such as neurotransmitters, hormones, etc. bind to the

membrane receptor (with specificity) and make a ligand-receptor complex. •This complex then triggers a response in the cell.•This process explains how hormones function, how / when cells divide, when they die,

etc. Also explains how cells communicate with each other•Membrane receptors are a common target for pharmaceutical drugs; this is why some

cells can target specific cells (like your liver or heart)•Signal transduction — an extracellular signal molecule (ligand) binds to membrane

receptor, which then triggers an intracellular response•The binding causes conformational change in the protein, which induces other

changes that eventually lead to a cascade of signals in the cell, trigger a specific response.

•Each receptor can only bind with specific / certain types of molecules. This is especially important in hormonal signaling.

•Used to be called lock-and-key, but induced fit is now the model, which means the ligand and receptor can change shape to better fit one another.

•Three main types of membrane receptors:•Ligand gated ion channels•G-protein coupled receptors•Enzyme linked receptors

LIGAND GATED ION CHANNELS •Also called ion channel linked receptors, these are transmembrane ion channels

that open or close in response to the binding of a ligand.•Commonly found in excitable cells like neurons, because these channels react

quickly to binding of a ligand, and thus the cells can respond quickly to a stimulus.

•Only specific ligands can bind to specific channels (lock and key / induced fit)•Note that the binding site of a ligand is not in/on the actual ion channel… the ligand

binds to allosteric site on the receptor, and causes opening / closing of the channel by conformational change.

ORGAN SYSTEMS 39•The receptor allosteric binding site can also be inside the cell, but that’s rare.•It’s also possible for there to be multiple binding sites for ligands.

•Once the ions move in or out of the cell, an intracellular electrical signal happens•Ligand gated ion channels are not the same as voltage gated ion channels.. those

only depend on a different in membrane potential, not the binding of a ligand•Ligand gated ion channels are also different from stretch activated ion channels.. which open / close in response to deformation or stretching of the cell membrane.

• Generally, ligands are not directly involved in any aspect of intracellular signaling.• Ligands do not directly influence the production of cyclic AMP and do not hydrolyze GTP to GDP.• A ligand is a small molecule, usually a protein, that binds to a membrane-bound receptor, which triggers downstream changes within the cell.• A molecule that attaches to a receptor, triggering changes within the cell is the correct answer.

•Cells that respond to mechanic forces typically possess stretch-activated ion channels. An example would be a cardiac cell.

•Terminally differentiated cells comprise multiple cell types, some of which may possess ion channels, but this is not the best choice here.

•The importance of the ligand-gated ion channel is that it allows for rapid response to a stimulus, so cells that need to respond quickly (like neurons) are those that possess ligand-gated ion channels.

•Cells that need to respond quickly to external stimuli is the correct answer.•Allosteric binding is an important feature of ligand-gated ion channels.•Ligand-gated ion channels actually can have intracellular binding sites. React quickly to

stimuli or ligand

G-PROTEIN COUPLED RECEPTORS •Only found in eukaryotes; are the largest class of membrane receptors. Each has

a specific function•Ligands that bind to these range from light sensitive compounds to

pheromones, hormones, neurotransmitters, etc.•GCPRs can regulate immune system, growth, sense of smell / taste /

behavioral / visual and our moods. Many G-proteins and GCPRs still have unknown functions.

•Most important characteristics:

ORGAN SYSTEMS 40•GCPRs have 7 transmembrane alpha helices.•They’re also linked to G-proteins, which have the ability to bind to GTP / GDP

and be activated•G-proteins have 3 subunits: Gα, Gß, and Gγ. Gα and Gγ are attached by lipid

anchors.(1) When the ligand binds to the GCPR, it undergoes a conformational change. (2) Because of the conformational change, the Gα exchanges its GDP for a GTP, becoming activated. (3) The GTP causes the Gα subunit to dissociate and move away from Gßγ dimer. (4) Gα subunit then goes on to regulate target proteins(5) Target protein then relays signal via second messenger.

•So target protein could be an enzyme that produces second messengers (e.g. adenylase making cAMP), or an ion channel that lets ions be second messengers

•Some G-proteins stimulate activity, others inhibit.•This chain of events, with a Gα protein subunit dissociating and going on to

activate further response in the cell, will happen repeatedly as long as the ligand is bound. So how do we turn it off?

(6) GTP on the Gα is hydrolyzed to GDP •This often occurs internally, by GTPase

within the Gα–protein itself, but can also be regulated (accelerated) by RGS protein

•Ex with epinephrine (aka adrenaline):•Epi binds to ß-adrenergic receptor (GCPR),

which causes it to undergo conformational change and switch GDP to GTP on the Gα subunit of the G-protein.

•The Gα subunit dissociates and binds to adenylate cyclase, which then makes the secondary messenger cAMP from AMP.

•cAMP goes on to increase heart rate, dilate blood vessels, and break down glycogen —> glucose

ENZYME LINKED RECEPTORS (aka catalytic receptors)•Enzyme-linked receptors are transmembrane proteins that uniquely function as

receptors for signaling molecules and enzymes — binding of ligand activates enzymatic activity.

•General structure includes extracellular “ligand binding domain” and intracellular “enzymatic domain”

•Shaped sort of like a Y (the V part is extracellular, where ligand binds)•Most common enzyme linked receptors are tyrosine kinases (also called RTKs), which regulate cell growth differentiation and survival; and they can bind and respond to ligands such as growth factors.

•Unique because Tyrosine is on the enzymatic intracellular receptor. •RTKs have ability to transfer phosphate groups to intracellular proteins, which

activates them, and they go on to trigger additional change.•RTKs occur in pairs. When ligands bind, the RTKs come together and act together

in a cross-linked dimer. This helps activate the Tyr phosphorylation activity.

ORGAN SYSTEMS 41•Each Tyrosine in one dimer activates a Tyrosine on the other dimer! This is cross phosphorylation.

•Tyr causes an ATP —> ADP + Pi•Other Tyr then pick up the free phosphate group.•Once activated, these phosphorylated Tyr allow different proteins to come by

and attach themselves to them. •The only thing these proteins need to dock is an SH2 domain, which allows

them to bind.•Multiple docking of different proteins allows changes to multiple different

intracellular signaling pathways at the same time. •The cellular changes often end at nucleus, signal from docking protein

affecting transcription.

•RTKs are useful / famous for their role in growth factors, such as in regulating surface proteins called epinephrines, which can guide developmental processes in tissue architecture, placement of nerve endings, and blood vessel maturation. Other growth factors (like platelet derived) and hormones (such as insulin) also bind to RTKs.

•When the RTKs fail to regulate properly, they can cause issues in cell growth and differentiation. Many cancers involve mutations of RTKs

•Many chemotherapies thus target RTKs. For example, the breast cancer drug Herceptin binds to and inhibit an RTK that is overexpressed in many breast cancers.

 RTKs are often associated with growth factors.———————————————Endocrine System———————————————ENDOCRINE GLAND HORMONE REVIEW •How do different parts of the body communicate with each other? Some

communicate through nerves, but not everything is connected by nerves. The endocrine system connects everything!

ORGAN SYSTEMS 42•Endocrine system is a system of glands that secrete hormones (chemical

messages) and release them into the bloodstream so they can circulate to different parts of the body and initiate an effect.

•Hypothalamus — major endocrine gland in the forebrain, is about the size of a grape

•As a member of the forebrain, it receives many nerve signals from the brain. •Called “control center” b/c it directs pituitary and plays a dual role b/n nervous

& endocrine system •In addition to stimulating the pituitary gland, the hypothalamus makes

hormones: •ADH - antidiuretic hormone, mainly regulates fluid volume in our body•Oxytocin — stimulates uterus to contract for females during pregnancy•note: although hypothalamus makes these, they’re stored in & secreted

from posterior pituitary•Pituitary gland — right below the hypothalamus, is about the size of a green

pea•Called “master gland” because it takes signal from hypothalamus and directs

it to almost all the other endocrine glands, such that their function is ultimately dependent on the pituitary

•Thyroid gland – located in the neck, wraps around trachea (windpipe)•receives signal from pituitary and regulates metabolism through thyroid

hormones T3 (triiodothyronine) and T4 (thyroxine); it uses these to stimulate the body’s metabolism

•Parathyroid - four spots, right behind the thyroid•responsible for regulating our body’s blood calcium level. (recall: calcium is

involved in muscle contraction, bone growth, and other important, sensitive functions)

•Adrenal glands — located on top of the kidneys•cortex (outer part): makes adrenal cortical steroids, such as cortisol and aldosterone

•cortisol is a stress hormone that increases blood sugar in times of stress so we have energy; also has anti-inflammatory functions

•aldosterone is major regulator of our body’s blood volume•medulla (inner part): makes catecholamines such as epinephrine and norepinephrine, which are involved in our body’s fight or flight response.

•Gonads — release sex hormones, which are mainly involved in development of secondary sex characteristics and developmental stages associated with those characteristics (puberty, menopause)

•Ovaries in females produce estrogen and progesterone; testes in male produce testosterone

•Pancreas — isn’t as directly involved with the pituitary as other glands but still uses its hormones (insulin and glucagon) to stimulate an effect: control of blood glucose levels.

•How do hormones get to their destination organs when there’s so many hormones around the body?

•Hormones won’t be received unless there’s a specific receptor on the target cell

•The receptor and its location are important in determining hormone function

ORGAN SYSTEMS 43•Hormone classes help us identify which hormones have which functions:

•autocrine hormones function at the cell that makes them•ex: T cells in the immune system secrete leukine hormones that signal the

T cell itself to increase effectiveness and immune function•paracrine hormones function regionally

•ex: hormones released by hypothalamus that affect the pituitary•endocrine hormones function at a distance

•ex: pituitary gland stimulating the gonads

HYPOTHALAMUS AND THE PITUITARY GLAND (AND THEIR HORMONES) •The pituitary has 2 parts, which the hypothalamus interacts with in different

ways.•Hypothalamus gets signals from the brain and sends hormones / signals to

different parts of the pituitary. Hormones it sends include:•Gonadotropin releasing hormone (GnRH)•Corticotrophin releasing hormone (CRH)•Thyrotropin-releasing hormone (TRH)•Growth hormone releasing hormone (GHRH)•Prolactin inhibitory factor (PIF) — unlike other hormones, PIH is constantly

being released and when it stops being released, the pituitary gland is signaled to release prolactin

Anterior pituitary — hypothalamus interacts with this primarily through the hypophyseal portal system, a capillary system into which the hypothalamus secretes hormones [paracrine signaling]•Some anterior pituitary hormones go on to stimulate other endocrine glands;

others have a direct effect on parts of the body. Use the pneumonic FLAT PEG to remember which is which.

•FLAT hormones (FSH / LH, ACTH, and TSH) are tropic hormones - they stimulate other endocrine glands

•PEG hormones (Prolactin, Endorphins (which are not unique to the anterior pituitary), and GH) are direct hormones - they directly stimulate a part of the body

•GnRH received by anterior pituitary stimulates release of follical stimulating hormone (FSH) and luteinizing hormone (LH), which travel to the gonads & stimulates them to release their hormones

•CRH from the hypothalamus stimulates the release of adrenocorticotrophic hormone (ACTH), which travels to the adrenal gland and stimulates it to release its own hormones

•TRH from hypothalamus stimulates anterior pituitary to release thyroid stimulating hormone (TSH), which travels to thyroid and stimulates it to release its own hormones (T3 & T4, namely)

•When PIH stops being released from the hypothalamus, the pituitary gland is then stimulated to release prolactin, which is involved in milk production in moms

•GHRH from hypothalamus stimulates anterior pituitary to release growth hormone (GH), which travels directly to the long bones and big muscles in our body to stimulate growth

ORGAN SYSTEMS 44Posterior Pituitary — hypothalamus interacts with this primarily through the stimulation of nerves that run down the pituitary stalk.•The nerve stimuli from the hypothalamus causes the posterior pituitary to release

hormones that are actually made in the hypothalamus but stored in the pituitary, including:

•ADH (antidiuretic hormone) — stimulates collecting ducts in the kidneys to retain water

•Oxytocin — involved in uterine contractions in women

HORMONE METABOLISM AND REGULATION •One of the ways hormone concentration is controlled is through metabolism and excretion:

•liver — metabolizes extra / unneeded hormones and turns them into bile, which is ultimately excreted in the digestive system

•kidneys — filter your blood all the time and remove waste products in the blood through urine

•blood — some hormones are just broken down in the blood (and their products go on to the liver or kidneys)

•sweat — some hormones can just be sweat out•Concentrations are also controlled through negative feedback loops —

conditions resulting from the hormone’s action suppress further release of those hormones

•Example of negative feedback loop with thyroid hormones:•The hypothalamus releases TRH (thyrotropin releasing hormone) into the

pituitary gland and, in response to TRH, the pituitary then releases its hormone TSH (thyroid stimulating hormone) which travels to the thyroid gland.

•The thyroid gland then releases its hormones T3 (triiodothyronine) and T4 (thyroxine), which travel all throughout the body in search of their receptors to, e.g., upregulate metabolism.

•Some of the receptors of T3 and T4 are located on the pituitary gland and hypothalamus. When/as the thyroid hormones reach those receptors, it signals the hypothalamus and pituitary to stop producing TRH and TSH, respectively; more thyroid hormones are clearly not needed.

•Why does the pituitary gland need to be turned off if the hypothalamus is? Redundancy is just indicative of how important feedback regulation is, to keep level of hormones in the body controlled.

TYPES OF HORMONES •Hormones can be classified by where they function (autocrine, paracrine,

endocrine) and, more importantly, can also be classified by their structure. •Structure is key to how a hormone works.

•There are three major types of hormones based on structure:1) Proteins and Polypeptides•Made of amino acids linked by peptide bonds•P & P type hormones are most of the body’s hormones•They range in size from small (3 AA) to large (many hundreds of AA). After about

50 AAs, we go from calling them polypeptides to proteins.

ORGAN SYSTEMS 45•These are made in the rough endoplasmic reticulum (RER) of the cell and then go

to the golgi apparatus, where they’re repackaged into vesicles that can eventually be excreted from cell.

•Because proteins and polypeptides are made of AAs, they’re typically charged. This makes them water soluble but also makes it difficult to cross cell membranes. For this reason, P & P hormone receptors are usually located in or on a cell surface

•When they bond to a receptor, P & P hormones can initiate a response inside the cell by initiating of a cascade of secondary messengers

•ex: insulin is a relatively large protein hormone2) Steroids•largely used for signaling•made from lipids (mostly from cholesterol), and thus have a characteristic

structure that they all share: a four-ringed carbon backbone (three cyclohexane, one cyclopentane)

•Because they’re made from lipids, steroids can enter a cell without much trouble. Unlike proteins and polypeptides, the receptors for steroid hormones are thus located inside the cell.

•Steroids act as primary messengers; they’re doing the signaling themselves. Receptors are often in the cytoplasm or the nucleus of the cell.

•Steroids can effect change at the level of DNA transcription and translation, make new proteins form.

•ex: hormones from adrenal cortex (cortisol, etc) and from gonads (testosterone, estrogen, etc.)

3) Tyrosine Derivatives•Recall: Tyrosine is an amino acid.

•Why is it not of the polypeptides and proteins type, then? Well, they’re only made of derivatives from a single amino acid. Additionally, they sometimes act like P & P hormones, but other times act like steroids. They’re a class of their own.

•ex: thyroid gland hormones like T3 (triiodothyronine) and T4 (thyroxine); these stimulate metabolism

•act very similarly to steroids, and bind to receptors inside the cell•ex: catecholamines like epinephrine and norepinephrine, which are produced in

the medulla and are involved in our fight or flight response. •act very similarly to P & P proteins in that they bind to the outside of a cell and

stimulate secondary messengers inside the cell.•Act like proteins

CELLULAR MECHANISM OF HORMONE ACTION •After traveling through the body, a hormone eventually reaches the receptor on a target

cell•One mechanism: action by secondary messengers — Hormone binds to a

receptor on the outside of a cell. Instead of stimulating an effect directly, it sets off a chain of secondary messengers within the cell that themselves stimulate the effect.

ORGAN SYSTEMS 46•When hormone binds with receptor, it causes the receptor to change

conformation and interact with the G-protein to form a complex. When this happens, the GDP bound to G-protein is transformed to GTP .

•This transformation to GTP allows the G-protein to move through the membrane and activate the adenylate cyclase. The adenylate cyclase then transforms ATP —> cyclicAMP (cAMP).

•cAMP is then what triggers the effect inside the cell that the hormone is targeting in the first place.

•Signal amplification: in theory one hormone can bind to a receptor, which sets off chain reaction leading to a lot of cAMP being produced.

•Because we are unable to communicate directly•Second mechanism: action by primary messenger — Certain hormones like steroids and thyroid hormones can cross the cell membrane and effect change themselves.

•Steroid and thyroid hormones can typically cross the membrane on their own because, unlike other polypeptide hormones, e.g., they are lipid based.

•Hormone crosses cell membrane and binds to a receptor in the cytoplasm or the nucleus.

•When the hormone binds to this receptor, it directly affects transcription (if receptor is in nucleus) or translation (if in cytoplasm) of the protein that’s being activated by the hormone.

TERPENES, CHOLESTEROL, AND STEROIDS •Terpenes are a class of lipid molecules made from repeating isoprene units•An Isoprene unit has 5 carbons — 4 are bonded in a chain, the 5th branches off a middle

carbon•monoterpene = 2 isoprene units, forming 10-C molecule (ex: menthol) •sesquiterpene = 3 isoprenes form a 15-C molecule (ex: ginger)•diterpene = 4 isoprenes (essentially 2 monoprenes) form 20 carbon

molecule•sesterterpene = 5 isoprenes form a 25 carbon molecule•triterpene = 6 isoprenes form a 30 carbon molecule (ex: squalene)

•Biosynthesis of steroids uses isoprene pyrophosphate (recall: pyrophosphate is a weak base and makes a good leaving group)

•Dimethylallyl pyrophosphate and isopentyl pyrophosphate combine head-to-tail (displacing a pyrophosphate in the process) to make geranyl pyrophosphate, a 10-C molecule

•Geranyl pyrophosphate then combines head-to-tail with a third isoprene to make 15-C farnesyl pyrophosphate; another pyrophosphate is released.

•Two farnesyl pyrophosphates combine head-to-head to make 30 carbon squalene. Squalene is the precursor for all the steroid hormones.

•After a series of ring-closing reactions, squalene turns into cholesterol, a four-ringed molecule.

•In the case of endocrine organs that use steroid hormones to communicate, cholesterol can be altered to form the characteristic steroid backbone

•Two important classes of steroids for endocrine glands: sex hormones and adrenal cortex steroids:

ORGAN SYSTEMS 47•Sex hormones: estrogens (estradiol and estrone, made in ovaries);

progesterone (pregnancy hormone); androgens (testosterone, androsterone)•Adrenal Cortex: cortison and cortisol (stress hormones, have various effects

from anti-inflammatory to increasing carbohydrate metabolism); aldosterone (one of the main hormones that regulates blood pressure and fluid volume).

——————————————Circulatory System——————————————THE HEART Intro•Thorax = includes heart enclosed within ribcage, a lung on either side, & diaphragm muscle underneath

Jobs of the heart:(1) Systemic flow — Delivers the oxygen, nutrients, and other things that the cell needs to live; and takes away its waste (like CO2).

•Blood enters hear through the superior / inferior vena cava; the aorta sends it back out.

•Systemic flow includes coronary blood vessels around the heart that serve the heart cells itself.

(2) Pulmonary flow — Before sending blood out through the aorta, the heart sends it through the right and left lungs so it becomes oxygenated.Flow through the Heart•Blood comes down from arms, neck, head (upper half) into superior vena cava of the heart, while blood from the legs, belly (lower half) into inferior vena cava. Both enter into the right atrium.

•After the right atrium, blood flows down into the right ventricle (through the tricuspid valve).

•From the right ventricle, blood passes through the pulmonary valve into left and right pulmonary arteries. These arteries travel through the lungs, where CO2 is exchanged for O2.

•The newly oxygenated blood then re-enters the heart through the pulmonary vein to enter the left atrium, after which it flows through the mitral valve to enter the left ventricle.

•From the left ventricle, blood flows through the aortic valve to enter the aorta, which sends it out to the body (aorta has branches into head/neck and each arm, through the midsection and then into each leg).

Layers of the Heart•Blood flow: RA —> RV —> lungs —> LA —> LV• Atrioventricular valves help keep blood flowing (they’re the two valves between atria and ventricles).

•tricuspid — RA/RV•mitral — LA/LV•These valves face downward; are tethered to the walls by chordae tendinae (chords) and papillary, that keep the valves from flapping back and forth. Without these, blood would flow back in wrong direction during systole (ventricular contraction).

ORGAN SYSTEMS 48•The intraventricular septum is basically a wall that divides the left and right ventricles of the heart

•Has two different areas: membraneous area closer to the atria, and muscular area.

•One of the most common heart defects in infants is a hole in the membraneous intraventricular septum, so blood flows from left ventricle to right ventricle (big problem) — this is a called VSD.

•Heart muscle has three layers (starting inside heart —> out)• Endocardium — thin layer that’s very similar to the lining of blood vessels; is what the red blood cells bump up against

• Myocardium — thickest layer. This is where all the contractile muscle is, and thus where a lot of the energy is being used up.

• Pericardium — a little thinner, has two layers with a gap in between them. There might be a little fluid in that gap, but no cells.

•This happens when the heart is growing in a fetus, it grows into a sort of ballon sac so a pancaked balloon surrounds the heart

•Visceral pericardium — layer closer to the heart•Parietal pericardium — layer further from the heart

Lub Dub of the heart:•Four valves of the heart: tricuspid, pulmonary, mitral, aortic.•As blood flows from RA —> RV, blood (from a previous cycle) also flows form LA —> LV

•Mitral and tricuspid valves [atrioventricular valves] thus open simultaneously. And when these are open, the pulmonary and aortic valves [semilunar valves] are closed.

•Ventricles are then filled with blood, and so they squeeze (contract) to pump it out.

•Blood then flows through pulmonary and aortic valves from the ventricles. When those are open, the pulmonary and aortic valves snap shut.

•The shutting of valves makes the lub dub noise.•Lub = first heart sound (S1) —> caused by T and M valves snapping shut

•S1 is when semilunar valves open; blood has just emptied from the atria into the ventricles.

•Dub = second heart sound (S2) —> caused by P and A valves snapping shut•S2 is when tricuspid and mitral (atrioventricular) valves open. Immediately after S2, the atria and ventricles fill with blood.

•S2 indicates the beginning of diastole, so at the end of it; all valves are closed.

• Diastole is a complete relaxation of the ventricles, and represents the time lag between pairs of lub dubs, when the blood refilled from the atriums into ventricles

• Systole is the time lag between S1 and S2, during which heart pumps blood from the ventricles out, so AV valves are closed to prevent regurgitation into the atria..

BLOOD VESSELS Layers of a Blood Vessel

ORGAN SYSTEMS 49• Tunica Intima — The lumen of the blood vessel is surrounded by a layer of endothelial cells. These are the first type of cells that blood will interact with. Outside of that layer of endothelial cells is a layer of protein (e.g. collagen), called a basement membrane, that keeps everything from falling out of place.

• Tunica Media (middle) — a layer of smooth muscle cells outside the basement membrane

• Tunica Externa (adventia) — on the very outside is another layer of protein. It’s like the basement membrane but a different composition (still lots of collagen though).

•On larger vessels, you sometimes find vasa vasorum, tiny blood vessels that supply the tunica externa itself. It also has nerve endings.

• Veins — have all three layers, pretty straight forward.• Large / middle size arteries — Have a normal tunica intima layer, but the tunica media is much larger; a thick layer of smooth muscle that also contain elastin, a protein that makes arteries more elastic for high pressures. Tunica externa is then pretty normal (with vasa vasorum and nerve endings)

• Small arterioles — Also have a normal tunica intima and a large tunica media. Instead of having elastin in the media layer, though, it just has a ton of smooth muscle cell which makes it very strong. Makes sense because arterioles are the vessels that create resistance to change blood pressure. Tunica externa is also pretty normal (with vasa vasorum and nerve endings)

• Capillary — unlike the veins and arteries, this is down to the single cell level. So the endothelial layer is made of just one cell that envelopes the lumen.

Arteries vs Veins•Systemic circulation: Arteries take blood from the heart out to all the capillary beds in all parts of the body; then veins bring the (now deoxygenated blood) back to the heart.

•Pulmonary circulation: Pulmonary artery takes deoxygenated blood to the lungs; pulmonary vein brings it back. arteries take blood

•Note: In the lungs there is mixing b/n pulmonary & systemic circulation - lungs receive oxygenated blood from Bronchial Arteries, which are a part of the systemic circulation. Some of the blood drains back through the Bronchial Veins, but some of it joins the deoxygenated blood in the lungs from the Pulmonary Arteries, becomes re-oxygenated, & re-enters heart through Pulmonary Veins..

•Direction of flow between arteries and veins is different:•Arteries — take blood away from heart. Veins take it towards the heart.

•Type of blood the arteries and veins carry is different:•Usually Veins carry deoxygenated blood, and Arteries carry of oxygenated blood.

•exception: Pulmonary artery carries deoxygenated blood; pulmonary vein carries oxygenated blood.

•Pressure and volume in veins and arteries different:•Arteries are high pressure (like a fast flowing river), and don’t carry much volume.

•Veins are low pressure, and carry a lot of volume.

ORGAN SYSTEMS 50•How much blood is where in your body? ~ 5% in the heart, ~ 5% in the capillaries, & 10% in the lungs. Only 15% is in the arteries, then the remaining 65% of body’s blood is in the veins at any given time.

•Veins have valves; arteries do not. •In veins, the valves keep the blood flowing in the right direction.•This is not really necessary for arteries because the pressure is so high. But that means if you cut an artery, you just have a fountain of blood spewing out. If you cut the vein, you get more of a pool of blood that eventually clots.

• The papillary muscles contract during systole to prevent blood from flowing backwards within the heart. • Semilunar valves are not actively closed. • Instantly after second heart sound, all valves are closed• All blood vessels have a tunica intima. This layer is made of endothelial cells, and is an essential structural component.• Intracellular calcium is the cellular messenger resulting in the contraction of smooth muscle.• The tunica media is a muscular layer, which can be contracted and relaxed to enact changes in blood pressure.• A thick tunica media is characteristic of large systemic arteries.• A thick tunica media explains the responsiveness of large systemic arteries to changes in intracellular calcium concentrations.• P =QR

PRESSURE, FLOW, RESISTANCE •Dr. Poiseuille: If you know the length (L) and radius (r) of a tube, as well as the viscosity (eta, η) of the fluid, you can calculate the resistance (R) of flow through that tube.

• R = 8Lη / πr4

•So, if two tubes have same length and are carrying the same fluid, resistance is proportional to 1/r4

•So for a tube with half the radius (r/2) of another tube with radius r, resistance will be 16 times greater in the smaller radius tube.

•In arterioles, when smooth muscle is relaxed (vaso-dilation), the radius of the tube is much greater than when it is constricted (vaso-constriction). This means we have low resistance of blood flow during vaso-dilation, and high resistance during vaso-constriction.

• Flow: blood flows from aorta to brachial artery, then to an artery, eventually a capillary bed where it comes out the other side, now deoxygenated, in a venule and then a vein, and eventually gets back to the heart through the superior vena cava.

•The pressure that blood is exerting at any given point on the blood vessel walls can be described by systolic vs. diastolic pressure, upper and lower range. Below, let’s look at average pressure over time as the blood flows through the body:

•Overall pressure continues to decrease as blood flows through the body.

ORGAN SYSTEMS 51•The biggest drop occurs when flowing from the arteriole into the capillary bed.

•Consider resistance to flow? ∆P = Q x R•∆P = pressure at the beginning of a tube (PS) – pressure at the end of the tube (PE)

•Q is blood flow in volume / min •Q = stroke volume x heart rate, aka the volume of blood that’s pumped out in each beat, and the beats per min. (volume / beat) x (beat / min) = volume / min

•For an average male, there are 70 mL / beat, and 70 beats / min, so Q = 4900 mL/min = 5L/min

•R is proportional to 1 / r4 •What is total body resistance? Well we know that when blood comes out the aorta, the pressure is 95 mmHg, and when it goes back in through the vena cava, it is about 5 mmHg.

•∆P = Q x R•95 – 5 mmHg = 5L/min x R•R = 90/5 = 18 mmHg*min / L

THERMOREGULATION IN THE CIRCULATORY SYSTEM •How does your body maintain its core temperature when, e.g. you’re exercising under the hot sun? One way is by sweating. Another way involves in the skin.

•Below the skin is blood vessels, an arteriole supplies your skin with blood and oxygen through capillary beds, very fine blood vessels with high surface area.

•For our purposes, the skin acts as insulation. [Think of a house, with walls that insulate it] But capillaries go into the skin layer and lose heat easily. [windows in the house]

•When your body is hot, it will dilate the capillaries in your skin [open the windows] to allow more heat out. When capillaries are vasodilated, more blood can pass through them, and thus more heat is lost to the surroundings.

•When it’s cold out, your capillaries will vasoconstrict, so you lose less heat to the environment. This also means you have less heat at the surface of your skin, then, which is why partly your skin gets so cold.

•Body regulates the size of blood vessels through the smooth muscles cells, which are told to contract or relax through nerves.

———————————————Hematologic System———————————————WHAT ’ S INSIDE OF BLOOD? •Blood is drawn into a tube that’s lined with a chemical so the blood doesn’t clot, then it’s centrifuged so the blood parts separate out. There are now three different layers.

ORGAN SYSTEMS 52• Plasma is the least dense and the largest layer, making up about 55% of the blood.

•It’s made of 90% water, 8% proteins (Albumin, antibody, fibrinogen [+ other clotting factors]) and 2% hormones, electrolytes, nutrients.

•Note: Plasma and serum are very similar, but serum does not have fibrinogen. •The next layer (< 1%) is white blood cells / platelets.• Hemoglobin is the last, most dense layer, making up about 45% of the blood (lots of hemoglobin)

• Hematocrit = volume of RBC / total volume. What a normal hematocrit level is changes depending on your age, sex, and even if you live at a high altitude.

•polycythemia = person has a really high level of red blood cells•anemia = person has a really low volume of red blood cells.

HEMOGLOBIN •Oxygen enters a blood vessel from the alveolus in the lung, and within blood vessel diffuses into a RBC.

•Hemoglobin protein has 4 parts to it, and each part can bind a protein.•Once a single O2 is bound, it’s easier for other O2 to bind. (cooperativity)

•Two ways O2 transported in blood: HbO2 (oxyhemoglobin; most common) or O2 dissolved in plasma.

•A muscle cell has high pC O2, and low p O2 - so when oxyhemoglobin enters it releases O2

•Also inclined to released O2 because protons (H+) and CO2 compete with O2 for hemoglobin:

•When CO2 enters the red blood cell, it reacts with a water molecule (catalyzed by carbonic anhydrase in a reversible reaction) to become HCO3- and H+

•The HCO3- exits the cell, and the H+ binds to hemoglobin, causing the oxygen to fall away.

•Note: An increase in HCO3- would remove free H+ ions from blood and thus increase its pH, ultimately increases O2 affinity for Hb.

•When CO2 binds to red blood cells (competing with O2), a proton is also created.

•When blood is returning to the lung, what is it carrying with it?•Hb-COO- (carbaminohemoglobin)•H+Hb (with corresponding HCO3- in the plasma)* biggest way CO2 comes back•CO2 dissolved in plasma.

•When in the lung, an oxygen rich tissue, O2 diffuses into the red blood cell and tries to enter hemoglobin; we basically push the reactions to the left and O2 competes for hemoglobin again.

•When carbaminohemoglobin enters the lung, with high pO2 and low pCO2, it releases CO2

•Also inclined to release CO2 because O2 competes with H+ / CO2 for Hb•In the lungs, HCO3- reenters RBC and re-combines with H+ to form the CO2 (through a couple intermediates) that diffuse out into the alveolus, and can be expelled through the lungs.

BOHR EFFECT VS HALDANE EFFECT Bohr effect: CO2 and H+ affect the affinity of Hb for O2

ORGAN SYSTEMS 53•As pO2 is increased, the O2 content bound to Hb slowly increases until Hb gets saturated (O2 content starts to plateau).

•The amount of O2 that has been delivered in the tissue by Hb can be determined by subtracting the O2 content from a place of low pO2, (e.g. thigh tissue) from a place of high pO2 (e.g. lungs)

•The Bohr effect (right shifted green curve) says that increased CO2 and H+ (e.g. in muscle tissue) makes O2 delivery higher than it would be just from low pO2 there.

Haldane effect: O2 affects the affinity of Hb for CO2 / H+•As you increase pO2, the content of CO2 increases. (Note: Not S shaped like O2 b/c there’s no cooperative binding.)

•Can determine the amount of CO2 delivered in the same way as O2 before, by subtracting the CO2 content at two different pCO2’s

•Haldane effect says that with increased O2 (like in the lungs), the affinity of Hb for CO2 and H+ is decreased, so more CO2 content will be delivered there than it would from just the highpO2 there.

BLOOD TYPES •Embedded in the cell membranes of red blood cells are all kinds of proteins and molecules — two of which are very important for determining blood type: A and B glycolipids.

•Some people have both A and B glycolipids (AB blood type), others have just A (A type) or B (B type), and others have none of these glycolipids (type O).

•Recall: antibodies of the immune system tag specific foreign bodies (like bacteria) for destruction, but they’re careful not to make antibodies for its own helpful molecules.

•For this reason, a person with type AB blood does not have A or B antibodies. Meanwhile, a person with type A blood does not have A antibodies, but will have B antibodies.

•Those with B type blood have A antibodies, but no B ones.•A person with type O blood has both A and B antibodies, because their body doesn’t recognize either type of glycolipid.

•If a person with type A blood receives a transfusion from AB blood, that person’s antibodies would bind to this transfused blood and his body would start to destroy it, causing a huge amount of inflammation.

•The chart to the right shows which blood types can donate to which. O is universal donor; AB is the universal recipient.

HOW WE MAKE BLOOD CLOTS •Blood vessels are made of endothelial cells (each with a nucleus). What happens if a blood vessel breaks?

• Part 1 — Platelet plug: when/where there’s a break, platelets come together to coagulate & block hole.

ORGAN SYSTEMS 54•Platelets are tiny pieces of cells - with no nucleus - floating around in your blood all the time

•How do they know to clump up at the break and not elsewhere in the blood? The environment in the blood vessel is different than the environment outside of the blood vessel.

•Outside of the blood vessel there is collagen, which chemically interacts with platelets and causes them to stick together to plug the hole.

• Part 2 — Fibrin enters to strengthen platelet plug; forms mesh of protein that holds platelets together.

•Fibrin strands are made of subunits that naturally like to polymerize, or stick together.

•How does fibrin not polymerize while floating around in blood? Because we don’t exactly have fibrin floating around, but fibrinogen (basically fibrin, with an extra bit that keeps it from sticking).

•Fibrin is turned into fibrinogen at the site of break, thanks to a whole cascade of coagulation factors that starts with tissue factors (e.g. factor III — like collagen, which are only found outside blood vessel), and ends with activated thrombin (aka factor II) coming into site of break to catalyze fibrinogen —> fibrin.

•Note: a lot more thrombin is activated that there is/was tissue factor, because of the cascade

Details on coagulation cascade:•Thrombin is itself activated from its inactive form prothrombin. • Intrinsic pathway: XII —> XI —> IX + VIII —> X + V —> II (thrombin) —> I (fibrin)

•Note: This is not XII becoming XI, becoming IX… Instead, activated XII catalyzes the conversion of XI from its inactive form into its active form, and active form of XI catalyzes IX into its active form, etc…

•Factor X is the very important enzyme that activates thrombin•As you move down the intrinsic pathway, the amount of each enzyme present increases, thus increasing the active forms of each until you end up with a ton of thrombin (and thus lots of activated fibrin)

• Extrinsic pathway: III (tissue factor) —> VII —> X + V —> II (thrombin) —> I (fibrin)

•The extrinsic pathway is the original spark that sets off the cascade, while the intrinsic pathway is the workhouse that gets most of the coagulation done. How?

•Tissue factor III sets off a little bit of VII, which activates a little X, which then activates a little bit of thrombin. Thrombin is then what really gets the workhorse going by activating many other enzymes [Think of thrombin activating 5 odd numbers starting with 5: 5 7 9 11 13 … but actually it activates 8, not 9. almost.]

•What is factor XIII? Well, factor I activates fibrinogen —> fibrin so the fibrin can form strands, but then factor XIII comes in to connect the fibrin strands together (cross-links them) so they actually form a tight mesh.

•Negative feedback loops (governed by thrombin) prevent the enzyme activation pathways from spiraling out of control such that you become one walking blood clot.

ORGAN SYSTEMS 55•Thrombin helps create plasmin from plasminogen, which works directly on on the mesh of fibrin to break the cross-links apart. Helpful, but doesn’t prevent the rest of the enzyme pathways from continual activation.

•Thrombin also stimulates production of antithrombin, which decreases the amount of thrombin produced from prothrombin, and impedes the production of activated X from inactive X.

•If these pathways aren’t working you can’t clot very well and have haemophilia, aka you bleed a lot. There are three different types of haemophilia, associated with 3 different factor deficiencies

•A — VIII • B — IX • C — XI

Plasmin breaks down fibrin and fibrinogen, which serves to limit clot formation.The intrinsic pathway is initiated by components which are already ‘in’ the blood.Factor XII is associated with the intrinsic pathway, and catalyzes the formation of factor XI, which catalyzes the formation of IX, which catalyzes the formation of X.Factor X is common to both pathways, but is not ‘upstream’ so to speak.The extrinsic pathway proceeds in the presence of tissue factor (TF) which is released in response to tissue injury or insult.Endothelial cell insult is the principal component which activates and drives the extrinsic pathway of the coagulation cascade.

RED BLOOD CELLS AND PLATELETS

ORGAN SYSTEMS 56•Red blood cells last ~120 hours, which is about 4 days. Platelets last even less time, only 1-2 days.. So your body constantly needs to produce more of these — which it does in the bone marrow.

• Erythropoiesis: Red blood cells are made from a precursor cell which has a nucleus (RBCs don’t). The precursor divides many times, and eventually some of the daughter cells turn into erythrocytes / RBCs

•Platelets are fragments of cells that bud off from a huge cell called a megakaryocyte. So platelets are basically bits of cytoplasm surrounded by a membrane. A megokaryocyte can yield many platelets.

•What does your body do with old RBCs and platelets it doesn’t want? Breaks them down via the spleen.

•When blood (coming from the heart) passes through the spleen, a spleen cell called a monocyte (which is basically a macrophage) will recognize and engulf any old red blood cells, chew them up, and recycle anything important (such as iron, and some amino acids).

•Most of the old RBC and platelet breakdown happens in the spleen, but some also happens in the liver, through a similar process.

•How does the body know how many new RBCs and platelets to make? •Low oxygen levels stimulates the release of a hormone called erythropoietin (aka EPO) in/from the kidney, which tells the bone marrow to produce more RBCs via erythropoiesis.

•Some athletes take EPO so their body makes more RBCs and they get more oxygen to their muscle.

•If you need more platelets, your body releases the hormone thrombopoietin, which signals the megokaryocytes to make more.

BLOOD CELLS LINEAGES •In the blood vessels, you have about 10 different kinds of blood cells, from RBCs to T-cels, to B-cells, to platelets, and more… where do they all come from? Bone marrow! Specifically from the heads of long bones and from different flat bones (like the sternum) throughout the body.

• All blood cells have a single precursor: a pluripotent hematopoietic stem cell

•This pluripotent cell gives rise to two different lineages: myeloid and lymphoid• Myeloid lineage yields red blood cells and megakaryocytes (from which platelets are made), as well as mast cells (which release histamines in allergic reactions)

•The myeloid lineage also yields monocytes, which then become macrophages (part of the immune system) when they settle in the tissues.

•This monocyte lineage also yields three other types of cells: neutrophils (most common immune cell), eosinophils, and basophils.

ORGAN SYSTEMS 57• Lymphoid lineage yields B-cells (which make antibodies), T-cells, and “natural killer” cells.

•Dendritic cells can come from either lymphoid or myeloid (monocyte) lineages.

————————————————Respiratory System————————————————THE LUNGS: •Whether you breathe in through your nose or mouth, it will follow a path to the back of your throat to the Adam’s apple, or the voice box. Air passes through the voice box into the trachea.

•From the trachea, air goes into the right and left lungs. •The right lung has three lobes (upper, middle, lower) and the left lung has two lobes.

•The left lung also has a cardiac notch, where the heart sits.•Around the lungs are the ribs and rib muscles. Below the lungs and the heart is the diaphragm muscle.

•Within each lung are many branches (basically an upside down tree), which we call the bronchial tree.

•If we zoom in on a little branch, we would see a bunch of sacs called the alveoli. The air you inhales runs into the alveoli, takes a U-turn, and you exhale it back out. Before you exhale, your lungs give up O2 and take away CO2 from tiny blood vessels that run next to to the alveoli.

•Note: the conducting zone is simply a series of tubes through which gases travel, while the respiratory zone directly participates in gas exchange.

INHALING AND EXHALING: •Whether you breathe in through your nose or mouth, it will follow a path to the back of your throat to the Adam’s apple, or the voice box. Air passes through the voice box into the trachea.

•Recall, the more frequently collisions are happening between air molecules, the higher the pressure is.

•For the general atmosphere, P = 760 mmHg.•When you inhale:

•Volume of the lungs increases, which causes pressure of molecules inside the lungs to decrease (bc there are fewer collisions). P = ~757 mmHg now, which some call “negative,” by comparison to 760.

•Air molecules move into the lungs, causing pressure to increase back up to 760 mmHg.

•When you exhale:•Volume of the lungs decreases, which cause pressures to increase because now there are more molecules than before (763 mmHg) for the same initial volume.

•This pressure causes air molecules to leave until you have about the same amount as before, and

•pressure decreases back to 760 mmHg.

ORGAN SYSTEMS 58HOW DOES LUNG VOLUME CHANGE? •In the middle of the chest is a large bone called the sternum (aka breast bone); 7/12

pairs of ribs attach to the sternum. Between the ribs are intercostal muscles.•When you start to inhale:

•Your intercostal muscles contract and your ribs move outwards. •At the same time, your diaphragm contracts and goes from being curved upwards to flattened out.

•As these muscles contract, your lungs and heart will physically be drawn downwards and out.

•The expansion of your lungs is really all your alveoli expanding (you have ~500 million of them); they’re pulled outwards as your muscles move down and out.

•Note that the muscles do not physically pull open the alveoli; their enlargement is caused indirectly through a decrease in pressure and influx of air.

•Alveoli are covered in elastin, a protein that helps them stretch open.•The energy for contraction / inhalation comes from chemical energy, ATP.

•When you exhale, your muscles relax.•The alveoli then recoil (the elastin molecules “snap back” into their original size).. which is the driving force behind brining lungs back open to normal size.

•The energy for relaxation / exhalation comes from elastic potential energy.

HENRY ’ S LAW AND THE SOLUBILITY OF O2 AND CO2 •Look at the interface between a gas and a liquid, H2O — what happens at that surface layer?

•Total pressure is 1 atm = 760 mmHg, but if we’re just looking at green molecule,s which make up about 50% of the air, we say its partial pressure = 760mmHg(.50) = 380mmHg

•If the number of green molecules increases, that’s basically saying the partial pressure increases.

•As partial pressure rises, more of those green molecule will enter the water. So partial pressure tells you about likelihood that a molecule will enter the solvent.

•Meanwhile, the constant KH tells you the likelihood of a solute leaving the liquid layer. It takes into account solute, solvent, and temperature.

•The concentration of a solute dissolved in solvent can be determined by the equation: C = Psolv / KH.

•This is Henry’s law. It basically says there’s a relationship between partial pressure and concentration.

•Now let’s look at two cups of water placed in two different atmospheres: One is made of 21% O2, the other is made of 21% CO2, both at 25º C.

•The concentration of O2 that dissolves in the surface layer of water is much lower (0.27 mmol/L) than the concentration of CO2 that dissolves (7.24 mmol / L).

•We can even rearrange Henry’s law to KH = Psolv / C and calculate that the KH of O2 is 769 L•atm / mol, while the KH of CO2 is lower: 29 L•atm / mol.

•Henry’s law tells us that the partial pressure is a measure of what’s going into the water, while the constant is a measure of what’s going out — So it what’s going in on both sides is equivalent, the difference is in what’s leaving.

ORGAN SYSTEMS 59•With O2, there was low concentration, so O2 was constantly leaving the water.•Not much CO2 went out of the water though; it’s concentration was higher. Recall, CO2 + H2O—> H2CO3 (reversible) —> HCO3- + H+ (reversible)

•We can directly compare KH values, and say 769 / 29 = 26, so CO2 is about 26 times more soluble than O2 in water

•In our lungs, which are about 37º C, and have a solvent of blood instead of water, CO2 is about 22 times more soluble.

FICK ’ S LAW OF DIFFUSION •Consider a bunch of molecules trying to diffuse over a short distance (like from one wall to another) over time… how can you maximize the number that diffuse across? Some ideas:

•Less thick wall•Smaller molecular weight (MW) molecules (We know from Graham’s law that

smaller molecules move faster)•Increase partial pressure P1 of molecules•Increase surface area for molecules to diffuse across

•Fick’s law: V = [(P1 – P2) x A x D] / T•V is rate of particles moving (amount like moles, or volume)•P1 is pressure on first wall, while P2 is the pressure on the second wall. Of course, if the pressure of P2 is < P1, more molecules will want to diffuse from wall 1 to wall 2.

•A is surface area, the higher it is the more molecules that can get across.•D is diffusion constant, which is basically a ratio of solubility (from Henry’s law) by molecular weight; D = KH / √(MW)

•T is thickness of the wall. •This formula can also be written as [V/A] = [(P1 – P2)/T] x D, or [flux] = [gradient] x D.

• Flux can be defined as the “net rate” of particles moving through an area.• Gradient is the change in pressure (or in particles in a volume) over a distance.

OXYGEN MOVEMENT FROM ALVEOLI TO CAPILLARIES •Recall, after oxygen enters through your mouth/nose and eventually gets to either your left or right lungs, it will enter the alveoli. What happens then? ————————>

•The O2 molecules leaves the alveolus lumen and enters a layer of fluid lining before passing through into the epithelial cells of the alveolus.

•After leaving the epithelial cells, O2 encounters the basement membrane of the alveolus (which provides support), a thicker layer of connective tissue (more structural support), and then a 2nd basement membrane.

•After passing through the basement membrane of the capillary, O2 goes through the endothelial cells of the capillary wall and finally enters the lumen, where it can bind to a red blood cell (at 1 of 4 spots).

•Note: all these layers are basically liquid, and are made of mostly water… so O2 goes from gas phase and must diffuse across lots of liquid before reaching the capillary.

•Fick’s law can be used here to figure out the amount of O2 diffusing over time.

ORGAN SYSTEMS 60•P1 of this equation can be found from the alveolar gas equation, which takes into account the percent of O2 in the air they’re breathing, atmospheric pressure, PH20, and more.

•Area can be affected by how effectively a person’s alveoli is working; if half don't work then not as much O2 can get across.

•Thickness is also very important — if the amount of fluid in the layer increases (such as with infection), then the O2 that can get across will be lower

•Diffusion constant will stay the same, though.•Basically, if a person is not getting enough oxygen, there could be many factors affecting the problem.

THE RESPIRATORY CENTER •The respiratory center of the brain is in the brain stem. There are two clustered areas in the respiratory center, with neurons that communicate between them.

•Respiratory gathers information from different places and executes commands (such as how fast and how deep you breathe) based on that info

•Central and Peripheral chemoreceptors send info on different chemicals to the respiratory center.

• Central chemoreceptors are adjacent to the respiratory center. They gather info on CO2 levels, pH (but not O2 levels) and send it to the respiratory center for processing.

• Peripheral chemoreceptors (outside the brain) detect O2 levels as well as CO2 and pH. These include CN 9 (glossopharngeal) nerve from the carotid body chemoreceptor, and CN 10 (vagus nerve) from the aortic body — which send their info through nerves into the brain.

• Mechanoreceptors send information about pressure to the respiratory center.•Mechanoreceptors are found all over, in the lungs, nose, GI tract, etc; and they send their information through a bunch of different pathways.

•Those in the lungs and GI hitch a ride on the vagus nerve, while the one in the nose connects to the respiratory center via CN 5 (trigeminal nerve).

•Ex: If you inhale some pollen, that will trigger the mechanoreceptor in your lung, which will send info through CN 5 to trigger a response from the respiratory center.

•Ex: Lungs have smoke receptors, stretch receptors, and more. • Hypothalamus also sends information to the respiratory center — things like fear which may trigger a change in breathing.

• The cerebrum — which controls all voluntary actions including things like yelling, or singing, where you would need to control your breath — also sends info to the respiratory center.

•What does the respiratory center do with all this information? It executes changes in breathing by controlling different muscles through motor nerves in the spinal cord: Motor nerves Muscles

•C1 – C3 • accessory muscles•C3 – C5 • diaphragm•T1 – T11 • intercostal muscles•T6 – L1 • abdominal muscles

ORGAN SYSTEMS 61

THERMOREGULATION IN THE LUNGS •Humans lose heat by sweating and also by, like furry animals, taking in cool air and expelling hot air.

•When we inhale cool air, it enters into the lungs and alveoli, and will equilibrate with the temperature of the blood that's passing by the capillaries.

•The air we exhale will thus be about our internal body temperature, 98.6 ºF.•This coincides well with oxygen — because we’ll need to breathe more heavily to thermoregulate from the heat of exercising, but we also need more oxygen, which breathing heavily will allow us to get!

CONSIDER: •Two ‘broad’ categories must be considered which may affect hemoglobin saturation: 1. Is there enough oxygen present to saturate the hemoglobin, and 2. physiological factors which affect Hb’s oxygen affinity.

•An increase in temperature, pCO2, 2,3-BPG concentration, or a decrease in pH will decrease O2 affinity.

•If the pO2 in the afferent capillary is low (the capillary coming TO the alveoli), concentration gradients will favor greater diffusion of oxygen into the vessel, thereby increasing the amount of oxygen available to bind.

•Factors affecting gas diffusion into the capillaries include wall thickness, wall surface area, partial pressure difference, and the ventilation-perfusion ratio.

•The longer blood ‘hangs around’ in the alveolar capillaries, the longer the hemoglobin has to recruit oxygen. If blood is flowing too quickly for ventilation to match it, the hemoglobin saturation will decrease.

•Many respiratory diseases affect pulmonary function by altering the ability of alveoli to participate in gas exchange. What physical change would most greatly reduce the degree to which a particular alveolus is ventilated?

•Ventilation would be decreased in any setting which does not allow adequate airflow, including obstruction and structural/mechanical changes to the lung which prevent alveolar filling.

•Increased pressure within an alveolus would prevent airflow into the alveolar space.

•Gas pressure is increased with increasing temperature and decreasing container volume.

•Increased elastic recoil of the alveolar wall would increase the inward force of the wall on the gas as the wall tried to collapse, which would increase the pressure of gases within an alveolus, which would hinder airflow into the space. This would most greatly reduce ventilation of an alveolus.

————————————————Lymphatic System————————————————WHAT IS THE LYMPHATIC SYSTEM: •High pressure in blood vessels forces fluid out through the endothelial cells (particularly in capillaries).

•Big particles like red blood cells cannot get out, but other fluid (water, small proteins) then accumulates extracellularly around the capillaries.

ORGAN SYSTEMS 62•The lymphatic system is just another plumbing system — made of vessels that sort of start in the middle of nowhere and collect the accumulated fluid, and then bring it back into the blood.

•Unlike blood vessels, the lymphatic system is not a closed loop. It starts at the lymph region, where fluid is collected, and then ends where it reenters the blood vessel to deposit said fluid.

•Shortly after the lymph region, after some fluid has left the vessels, the capillary vessel is left with a higher concentration of red blood cells and solutes than the extracellular space with the lymph fluid.

•Consequently, some fluid actually flows back into the capillaries.•This is because of this concentration gradient (aka this increase in osmotic pressure pushing fluid into the vessels), as well as the fact that the overall hydrostatic pressure in capillaries is lower here compared to earlier.

•Overall, though, more fluid still goes out than comes in — so the net result is lymph squeezed out.

•Why don’t these cells just tighten up connections to prevent things from getting out? Well, the cells around the blood vessel need the nutrients (glucose, etc.) and they get that from the lymph. The lymphatic system also has important immune system and circulatory (for fats/proteins) functions.

•Lymph vessels are all over your body, and are similar to capillaries / blood vessels in that different branches come together to eventually dump all the lymph back into circulation.

HOW LYMPHATIC VESSELS MOVE FLUID: •How can lymphatic vessels pump all the fluid up your body in one direction? How do they pump it back into the high pressure system? Two answers:

•(1) Location of re-entery — The lymph vessel re-enters the blood at the very end of the venous system, which has about the lowest pressure of anywhere in your body. (120 mmHg in arteries out of your heart, ~5 mmHg where lymphatic vessels reenter.)

•(2) One-way valves — Within the lymph vessels, valve structures prevent fluid from moving in the opposite direction.

•But how does motion begin?•a) Smooth muscle at the beginning of the lymph system — small contraction of this pushes fluid on

•b) Skeletal muscle throughout the body — the natural movement / contraction of our muscles throughout the day is bound to affect some nearby lymph vessels, helps push fluid on its way.

•Lymph vessel starts at what looks like closed ends, but they’re very porous — these ends sort of act like valves themselves, allowing fluid to enter, but (when pressure builds up), these ends prevent fluid from going out.

•Lymph re-enters the circulatory system at subclavian veins, which are right near the superior vena cava.

LYMPHATIC SYSTEM ’ S ROLE IN IMMUNITY: •Infection is when your body gets attacked by a foreign invader, e.g. bacteria or virus.

ORGAN SYSTEMS 63•Infections aren’t usually in the blood itself, but in the tissues around it (proof: infections stay localized; if it was in your blood it would go all over the body)

•Local immune cells called macrophages fight the bacteria present in that tissue area, but the body also pulls in more powerful T-cells and B-cells that react to the specific invader. Problem: These immune cells aren’t just sitting around everywhere.

•In order for them to specialize, a special environment is required that can’t occur in the tissues where any bacteria may enter. So how do we get B and T-cells to see the bacteria and react to them? Lymphatic system!

•Any bacteria present in the tissue, as well as some macrophages that may have gobbled up the bacteria are swept into the lymphatic vessel along with fluid. It takes them to the lymph node, where B and T-cells are stored. There, those immune cells will basically ready themselves to fight the specific bacteria.

•The lymph vessel also continues on after the nodes — so a side effect of the lymph system is that it basically filters the fluid / blood in the body. If bacteria were to flow through the lymphatic system and then deposit bacteria at the subclavian veins, it could infect the blood and get all over the body.

•Lymph nodes are very small, and not considered organs. There are about 600 of them in the body, and some are so close to the skin you can feel them (particularly those between the thigh and abdomen, and along your clavicle / neck).

•Any lymph coming out of any tissue in your body will pass through at least one lymph node before depositing back into the blood.

LIPID AND PROTEIN TRANSPORT IN THE LYMPHATIC SYSTEM: •We know lymphatic system aids in fluid collection and deposit, as well as in immunity. A third function is in the transport of important molecules from digestions . . .

•Consider the small intestine, which carries food (glucose, fats, etc) that the body needs for energy.

•Glucose diffuses into the cells lining the small intestine, and then is pumped out, where it can then diffuse into the capillaries.

•Fatty acid chains are pumped into the cells of the small intestine’s wall, where they are packaged and exit as chylomicrons — those are too big to diffuse into capillaries.

•The lymphatic vessels in the small intestine, called lacteal, allow chylomicrons to diffuse in, travel through the lymphatic system, and be deposited back into the circulatory system.

•A little further away from the small intestine, you may have other cells proteins, waste products, etc. that have difficulty entering the capillaries. But the body needs them in blood circulation so it can deposit the hormones (or whatever) where needed, deposit waste products in the liver / kidneys, etc.

•So these peptides and waste products and other necessary molecules that are too big to enter the capillaries will be picked up by the lymphatic system!

•They, too, will eventually be deposited back into the circulatory system at the subclavian vein.

•Lymph from the lower body, the left arm, and the left side of the head drains into the circulation via the largest lymph vessel, the thoracic duct. Lymph from the

ORGAN SYSTEMS 64right arm drains into circulation via the right lymphatic duct. These ducts then enter systemic circulation at the junction of the left (or right) subclavian vein and the jugular vein.

WHAT IS ACTUALLY IN LYMPH: •Note: lymph is only called lymph once it enters the lymphatic system; before that its just extracellular fluid — the makeup is basically the same, though.

•We know that lymph comes from blood vessels originally; it’s the fluid squeezed out between the cells in the capillaries. But blood has a lot of different molecules in it (~45% red blood cells, water, proteins of varying sizes, etc.)

•Lymph has 0% red blood cells, and only about 1/2 – 1/3 the amount of protein as blood does (you might think the percentage is more, but water diffuses out much more easily than proteins, thus diluting any proteins present in lymph.)

•Note: this 1/2 - 1/3 ratio is just an average — really, concentrations differ throughout different branches of the lymph system. Ex: liver makes a lot of proteins, so the lyphatic vessels around it will have a much higher concentration of protein than elsewhere in the system. Similarly, the concentration of fats in the lacteal (small intestine area) part of the lymphatic system is going to be much higher there than elsewhere.

•Smaller proteins also have an easier time getting out of the blood vessels and into lymph. The ratio of small protein (albumin, e.g.) to big protein (like immunoglobin) is greater in the lymph that in the blood, even if you have more albumin molecules in the blood.

•Why is it important there be less protein in the lymph? Recall, some fluid goes back into the blood vessel after it exits in capillaries, instead of being absorbed by the lymph. This is because of a higher osmotic pressure pulling fluid back in because there’s more protein in the blood than in the lymph.

•About 3L of net lymph is produced in a day! (much more is initially squeezed out, then reenters.)

————————————————Immune System————————————————INNATE / NONSPECIFIC IMMUNITY: •Immune system has two lines of (nonspecific or innate) defense:

• first: Keep pathogens out — skin (and oils on the skin), mucous membranes, acidic stomach acid

• second: If pathogens enter, kill them to prevent widespread infection. — inflammatory response (brings blood and fighter cells to site of infection), phagocytes, white blood cells.

•Phagocytes are a class of cell that can eat up other things, most namely pathogens.

•It has receptors that respond to foreign things. Once the pathogen binds to these receptors, it is engulfed by the the phagocyte and enters the cell in a vesicle called a phagosome.

•Then other vesicles that contain things that can destroy phagosomes (such as lysosome, reactive oxygen species) then merge with the phagosome and break up the pathogen.

• Some of those constituent molecules of the consumed pathogen are then taken and attached to other proteins, in phagocytes its the major

ORGAN SYSTEMS 65histocompatability complex type II, and presented onto the membrane surface of the phagocyte.

•These antigens are crucial to our immune system, because they allow specific immune cells to know what is in the body and to come up with a specific response to that threat. Thus many phagocytes are also called antigen presenting cells.

There are many types of white blood cells , aka leukocytes , some of which are also phagocytes:• Neutrophils (most common; fast and abundant) — phagocytic cells that are also classified as granulocytes because they contain granules in their cytoplasm. These granules are very toxic to bacteria and fungi, and cause them to stop proliferating or die on contact

• Macrophages • Mast Cells — important for wound healing & defense against pathogens via inflammatory response.

• Found in mucous membranes and connective tissues• When activated, they release cytokines and granules that contain chemical molecules to create an inflammatory cascade. Mediators, such as histamine, cause blood vessels to dilate, increasing blood flow and cell trafficking to the area of infection.

• Cytokines released during this process act as a messenger service, alerting other immune cells, like neutrophils and macrophages, to make their way to the area of infection, or to be on alert for circulating threats.

• Eosinophils — granulocytes that target multicellular parasites. They secrete a range of highly toxic proteins and free radicals that kill bacteria and parasites. Can also phagocytose.

• use of toxic proteins & free radicals also causes tissue damage during allergic reactions, so activation and toxin release by eosinophils is highly regulated to prevent unnecessary damage.

• found in many locations, including the thymus, lower gastrointestinal tract, ovaries, uterus, spleen, and lymph nodes.

• Basophils — also granulocytes that attack multicellular parasites. They release histamine like mast cells. The use of histamine makes basophils and mast cells key players in mounting an allergic response.

• Natural Killer cells (NK cells) — do not directly attack pathogens, but instead destroy infected host cells in order to stop the spread of an infection. Infected or compromised host cells can signal natural kill cells for destruction through the expression of specific receptors and antigen presentation.

• Dendritic cells — antigen-presenting cells that are located in tissues, and can contact external environments through the skin, the inner mucosal lining of the nose, lungs, stomach, and intestines.

• Since dendritic cells are located in tissues that are common points for initial infection, they identify threats & act as messengers for the rest of the immune system via antigen presentation.

• These are most effective at eliciting adaptive immune response.

THE COMPLEMENT SYSTEM:

ORGAN SYSTEMS 66•Also called the complement cascade, this is a mechanism that complements other aspects of the immune response. Typically, the complement system acts as a part of the innate immune system, but it can work with the adaptive immune system if necessary.

•The complement system is made of a variety of proteins that, when inactive, circulate in the blood. When activated, these proteins come together to initiate the complement cascade, which starts the following steps:

1. Opsonization: A process in which foreign particles are marked for phagocytosis. All of the pathways require an antigen to signal that there is a threat present. Opsonization tags infected cells and identifies circulating pathogens expressing the same antigens.

2. Chemotaxis: The attraction and movement of macrophages to a chemical signal. Chemotaxis uses cytokines and chemokines to attract macrophages and neutrophils to the site of infection, ensuring that pathogens in the area will be destroyed. By bringing immune cells to an area with identified pathogens, it improves the likelihood that the threats will be destroyed and infection will be treated.

3. Cell Lysis: The breaking down or destruction of the membrane of a cell. The proteins of the complement system puncture the membranes of foreign cells, destroying the integrity of the pathogen. Destroying the membrane of foreign cells or pathogens weakens their ability to proliferate, and helps to stop the spread of infection.

4. Agglutination: Agglutination uses antibodies to cluster and bind pathogens together. By bringing as many pathogens together in the same area, the cells of the immune system can mount an attack and weaken the infection. Other innate immune system cells continue to circulate throughout the body in order to track down any other pathogens that have not been clustered and bound for destruction.

ADAPTIVE IMMUNE RESPONSE: HUMORAL VS. CELL-MEDIATED: •Unlike the innate immune system, which attacks only based on the identification of general threats, adaptive immunity is activated by exposure to pathogens, and uses an immunological memory to learn about the threat and enhance the immune response accordingly.

•The adaptive immune response (which uses B and T cells) is much slower to respond to threats and infections than the innate immune response, which is primed and ready to fight at all times.

ORGAN SYSTEMS 67•Lymphocytes (another type of leukocyte) can be divided into B lymphocytes and T lymphocytes.

•B-cells are produced in bone marrow. T-cells also start off in the bone marrow, but mature and become what they are in the thymus.

•B-lymphocytes participate in the humoral response; while T-cells participate in cell-mediated response (include helper T-cells).

• “Humoral” refers to the bodily fluids where these free-floating serum antibodies bind to pathogens (before they infiltrate cells) and assist with elimination.

• Someone who has never been exposed to a specific disease can gain humoral immunity through administration of antibodies from someone who has been exposed, and survived the same disease.

• “Cell-mediated” refers to the fact that the response is carried out by cytotoxic cells. Much like humoral immunity, someone who has not been exposed to a specific disease can gain cell-mediated immunity through the administration of T cells from someone that has been exposed, and survived the same disease.

B-CELLS •B-cells have many protein complexes on their surface (up to 10,000 of them!) called membrane bound antibodies. (antibodies are also called immunoglobulins).

•Each B-cell has one type of membrane bound antibodies on it. There is a variable portion of the antibody structure that is different between B-cells. There’s 1010 combinations of variable portions!

•During development, potential self-responding combinations, for your own cells, are weeded out.

•How do all these combinations arise if they come from the same B-cells with the same DNA? In the development of the B-cells (hematopoesis), there’s a lot of intentional reshuffling of DNA that codes for the different variable parts.

ORGAN SYSTEMS 68• These different combinations practically ensure that some B-cell will bind to a foreign pathogen, even if it’s never been seen before. The part of the bacteria / pathogen it binds to is the epitope.

•As soon as one of these epitopes are bound, the B-cell becomes activated (though in order to really become activated, helper T-cells are needed), and starts cloning himself, repeatedly!

•When the specific B-cell divides over and over, the daughter cells start to differentiate. They become:

• Memory cells — these cells stick around a long time, with the perfect variable receptor on them (these are in higher quantities than the original B-cell, so if this pathogen ever re-enters, there are more specific B-cells to recognize it.)

• Effector cells — These turn into antibody factories; they start spitting out tons and tons of the variable proteins that can uniquely bind to the infecting pathogens. When these antibodies bind, they:

• (a) Cause opsonization: tag pathogens for pick up, make it easier for phagocytes to identify / engulf

• (b) Might make it harder for the pathogen to function — viruses, e.g., won’t be able to enter a host cell as easily with a big antibody hanging off of it.

• (c) Can join pathogens together — on each antibody is two identical heavy chains and two identical light chains, with a specific variable portion on each one. Each of these branches can bind to the epitome, so one branch may bind to one virus, and another to a second virus, effectively joining them (which makes it harder for the viruses to infect, and easier for the phagocytes to identify.

• The TH cells act to activate other immune cells, while the TC cells assist with the elimination of pathogens and infected host cells.

SOME VOCABULARY: • Self — particles, such as proteins and other molecules, that are a part of, or made by, your body. They can be found circulating in your blood or attached to different tissues.

•Something that is self should not be targeted and destroyed by the immune system.

•The non-reactivity of the immune system to self particles is called tolerance.• Non-self — particles that are not made by your body, and are recognized as potentially harmful (aka foreign bodies). Non-self particles can be bacteria, viruses, parasites, pollen, dust, and toxic chemicals.

•The non-self particles and foreign bodies that are infectious or pathogenic, like bacteria, viruses, and parasites, make proteins called antigens that allow the human body to know that they intend to cause damage.

• Antigens — anything that causes an immune response. Can be entire pathogens, like bacteria, viruses, fungi, and parasites; or smaller proteins that pathogens express.

•Antigens are like a name tag for each pathogen that announce the pathogens’ presence to your immune system. Some pathogens are general, whereas others are very specific.

ORGAN SYSTEMS 69•A general antigen would announce “I’m dangerous”, whereas a specific antigen would announce “I’m a bacteria that will cause an infection in your gastrointestinal tract” or “I’m the influenza virus”.

• Cytokines — molecules that are used for cell signaling, or cell-to-cell communication. Cytokines are similar to chemokines, wherein they can be used to communicate with neighboring or distant cells about initiating an immune response.

•Cytokines are also used to trigger cell trafficking, or movement, to a specific area of the body.

• Chemokines are a type of cytokines that are released by infected cells. Infected host cells release chemokines in order to initiate an immune response, and to warn neighboring cells of the threat.

PROFESSIONAL ANTIGEN PRESENTING CELLS (APC) AND MHC II COMPLEXES: • Recall, that when a phagocyte engulfs a pathogen, they take some of digested pieces of it and attach it to the major histocompatability complex type II, then present this onto the phagocyte’s membrane.

•A very similar process happens in B-cells, which have certain variable ends on membrane-bound antibodies that are specific to the epitomes of certain pathogens.

•After a specific pathogen binds to a specific B-cell, it gets engulfed, which starts the activation process. The B-cell then proliferates itself and activates (usually with helper T-cells) into memory cells and plasma / effector cells that produce lots of antibodies

•The B-cell will also take pieces of the broken down pathogen, attach them to MHC II proteins, and present them on their membrane.

•Cells that use MHC II to present bits of pathogen are called professional antigen presenting cells, this includes phagocytes and B-cells.

HELPER T CELLS: •Adaptive immune system has humoral response (pathogens floating around) & cell-mediated response

•B-cells are humoral response; T-cells are involved in cell mediated response•T-cells mature in the thymus. We’ll focus on two types of T-cells: helper and cytotoxic

•When activated, helper T-cells sound an alarm to generate antibodies, which go on to disable a specific pathogen (that is still floating around, not in cells)

• Cytotoxic T-cells attack cells that have been infiltrated (or are abnormal in some way, like cancer cells) and kill them to prevent spread of the pathogen / cancer.

•Once an antigen is presented on a macrophage or a B-cell, the helper T-cell recognizes it.

•Let’s say we have a dendritic cell (phagocyte) and it’s already consumed a pathogen and put an antigen from it on an MHC II complex on its membrane.

•The helper T-cell has a T-cell receptor on it that bonds to the MHC II + antigen complex. Just like the B-cell, this T-cell receptor has a variable portion, so different T-cells are specific to certain MHC II complexes and certain parts of the pathogen.

ORGAN SYSTEMS 70•Once the T-cell identifies and bonds its receptor to the MHC II complex, it is activated.

•Note: Dendritic cells are actually the best at activating helper T-cells, especially naive helper T-cells (means they’re non-memory, non-effector and have never been activated nor had anything bound to it).

•When a helper T-cell is activated, it divides into many many copies, and starts to differentiate into:

•(1) memory T-cells: Like memory B-cells, these stay around for many years in case the pathogen returns. They have the same receptor as their parent, but last much longer.

•(2) effector T-cells: These release cytokines. There are many types of cytokines (which are peptides), but they all essentially raise the alarm of the immune system. When cytokines enter other immune system cells, it makes them multiply or strengthen their immune response.

•This is a central role, tells both activated cytotoxic T-cells to get in gear, and activated B-cells.

•The effector T-cells also activate the B-cells (for the same species of virus) so they start proliferating and differentiating. The variable portion of the T-cell connects to the same specific virus as the B-cell that engulfed the pathogen; the combination of antigen + MHC II is the same.

•That combination is usually what activates the B cell and allows it to divide and differentiate.

•Why do we have this double system? A fail safe mechanism… The likelihood of both the T-cell and B-cell having the same variable receptor + MHC II for a specific pathogen is very small; this prevents lymphocytes from accidentally mutating a receptor / trying to kill one of your own cells.

CYTOTOXIC T CELLS: •Recall, antigen presenting cells (like various phagocytes, B-cells) present pieces of a pathogen they’ve consumed from the humoral space just floating around on their membrane with MHC II.

• All nucleated cells in the human body have another major histocompatibility complex type I, or MHC I

•even cells with MHC II also have this•Because it’s on pretty much every cell (except RBCs), any cell in the human body that has wacky stuff going on (cancerous cells, or ones that have been taken over by a virus), will take parts of those proteins (from the cancer cell, virus, etc.) and present them on MHC I.

•Helper T-cells (with the correct variable portion) bond to MHC II complexes, get activated, divide and differentiated, and effect a specialized immune response to them.

•Cytotoxic T-cells bond with MHC I complexes (also with a specific variable portion), get activated, and differentiates and divide. Like the other T-cells, these differentiate into

•memory: stick around in case this mutation / cancer / pathogen shows up again

•effector: go on to kill any infected / mutated cells with that specific MHC I complex they recognize

ORGAN SYSTEMS 71•effector cytotoxic T-cells work by exocytosing perforin proteins that make holes in the membrane of the infected cell, or releasing granzymes that induce mechanisms for cell death.

REVIEW OF B CELLS, CD4+ T CELLS, CD48+ T CELLS: •B-cells — each one has uniquely specific membrane bound antibodies (bc of unique variable portion)

•For activation, the B-cell needs binding of a pathogen /antigen on to its antibody and helper T-cell stimulation. (helper T-cells come in because B-cell consumes the pathogen and presents a piece of it on an MHC II complex, which the helper T-cell recognizes)

•Once activated, the B-cell starts dividing and differentiating into memory cells (so there’s more of this variable receptor / a faster response if this pathogen were to return), and effector B-cells (which basically turn into antibody making machines — these are commonly called plasma cells).

•The antibodies made from these plasma cells then go around and kill or impede growth of those specific pathogens floating around, tag them for pickup from macrophages, etc.

•T-cells — two main types. All have T-cell receptors, and either CD4 receptors or CD8 receptors.

•Unlike antibodies, which can bind to pathogens directly, T-cell receptors can only recognize antigens that are bound to MHC I or MHC II membrane surface receptor molecules.

•The CD4 receptor helps bind the MHC II complexes; so most CD4+ T cells are helper T cells. Likewise, CD8+ T-cells bind to MHC I complexes, so most CD8+ T-cells are cytotoxic.

•Recall, every nucleated cell can present antigens on MHC I complexes, the CD8 protein recognizes that and kills infected / “bad” cells.

•And CD4 proteins bind to MHC II complexes that have bits of pathogens on them.

•When these T-cells get activated, they divide and differentiate into effector and memory cells

•effector [CD4] helper T-cells can activate B-cells, and also releases cytokines — alarm bells that tell other immune cells to get in gear.

•effector [CD8] cytotoxic T-cells kills cells with the specific MHC I complex on them

•memory CD4 and CD8 T-cells stick around in case that specific pathogen / cancerous mutation comes up again.

CLONAL SELECTION: How are the B and T cells prepared to fight infection? (1) They are made, and are very specific.•B-cells divide and form millions of descendants in the bone marrow.

•Unlike other parts of the body, each daughter cell that grows up is different from its parents and all of the other daughter cells, because each daughter cell has a different / unique receptor (which eventually becomes their antibody). This is because in the process of being made, there’s a shuffling of DNA that codes for this variable receptor.

ORGAN SYSTEMS 72•T-cells divide and form millions of descendants in the thymus, which has 2 lobes and is located behind the sternum. Similar to B-cells, they have a unique receptor. Each daughter T-cell also has a unique receptor that identifies a unique antigen.

•So we end up with many many genetically different T-cells and B-cells that are responsive to many things that may or may not even exist, because the creation of the variable receptor piece is sort of random. After this, the B- and T-cells go to the lymph nodes.

•In the lymph nodes, the B and T cells are essentially just waiting for that specific pathogen, which they can identify, to enter the body.

(2) They recognize a specific invader •Let’s say a part of tissue gets infected. Dendritic cells engulf and digest them, and present the antigen from it on their membrane with MHC II. They, along with some of the bacteria, get swept into the lymph system and eventually end up in the lymph nodes.

•In the lymph nodes, only the specific T-cells, which can recognize the very specific pathogen on the dendritic cell (or other antigen presenting cells), will bind to the antigen and become activated.

•B-cells react directly to the specific bacteria, not to antigen presenting cells, by binding with their antibody.

•None of the other B and T-cells do anything about the infection because they can’t bind to these specific pathogens that were brought into the lymph node.

•(3) After binding their antigen, the B and T cells jump into action, replicating like crazy, differentiating into effector / memory cells, etc. and do their thing.

•This process is called clonal selection (because the B and T cells select specific antigens and then clone themselves to respond.

SELF VS. NON-SELF IMMUNITY: •How does your immune system know not to attack itself? How does it distinguish foreigners?

•This answer is not always obvious. Think back to the B-cell and its receptor antibodies, which bind to foreign pathogens (specific receptors for specific pathogens — those are generated at random).

•The fact that the variable receptors are created at random means they might create an antibody that reacts to something important in your own body.

•There’s no way to keep the B-cell from creating antibodies that would react to yourself, so we need to figure out the self-antibodies are and kill them. (This is applicable for both T and B cells, of course.)

•In the bone marrow is where B cells get their unique (randomized) receptor. How can we figure out if a B-cell has an antibody that reacts to self (e.g. say it reacts to insulin)? Keep around various proteins your body uses in the bone marrow that the body uses while these B-cells are being vetted.

•Your body can then respond and kill any B-cell that binds to anything while still in the bone marrow. [ex: you’ll have a little bit of insulin, hemoglobin, etc. floating around in the bone marrow and one B-cell with a randomized variable receptor might recognize and binds to that insulin. As a result, that B-cell dies.]

•A similar process happens for T-cells in the thymus.

ORGAN SYSTEMS 73•In order to make sure T cells will perform properly once they have matured and have been released from the thymus, they undergo two selection processes:

• Positive selection ensures MHC restriction by testing the ability of MHCI and MHCII to distinguish between self and nonself proteins. In order to pass the positive selection process, cells must be capable of binding only self-MHC molecules. If these cells bind nonself molecules instead of self-MHC molecules, they fail the positive selection process and are eliminated by apoptosis.

• Negative selection tests for self tolerance. Negative selection tests the binding capabilities of CD4 and CD8 specifically. The ideal example of self tolerance is when a T cell will only bind to self-MHC molecules presenting a foreign antigen. If a T cell binds, via CD4 or CD8, a self-MHC molecule that isn’t presenting an antigen, or a self-MHC molecule that presenting a self-antigen, it will fail negative selection and be eliminated by apoptosis.

•After positive and negative selection, we are left with three types of mature T cells: Helper T cells (TH), Cytotoxic T cells (TC), and T regulatory cells (Treg)

•Helper T cells express CD4, and help with the activation of TC, B cells, and other immune cells.

•Cytotoxic T cells express CD8, and are responsible for removing pathogens and infected host cells.

•T regulatory cells express CD4 and another receptor, called CD25. T regulatory cells help distinguish between self & nonself molecules, and by doing so, reduce risk of autoimmune diseases.

•The B-cells and T-cells that have been vetted can go on to a lymph node or somewhere where it waits to recognize pathogens.

•Sometimes, a B cell that reacts to self will escape, though. (Maybe you don’t have all the possible proteins in your bone marrow / thymus, maybe the body made a mistake, whatever).

•When this happens, that B-cell will find the protein it was made to react with (which is a part of your own system), bind to it, ingest it, and present a piece of it on an MHC II complex. It then needs a T-cell with the same receptor to come along that will recognize the same piece in order to activate.

•Without that T-cell, nothing will really happen. So even if a B cell escapes, unless a T-cell with the same specific receptor has also escaped (which is even more unlikely, of course), there’s not an issue.

Ways it can go wrong:•What if bacteria got into the bone marrow? The B-cell will bind to it and be killed as if it responded to self — thus it wont’ get out into the lymph system to trigger immune response to that bacteria.

•Not too much of an issue, because even if you have bacterium in the bone marrow for a couple weeks or a month, it will eventually go away and your bone marrow can make those specific antibodied B-cells again. (and hopefully you already had some B-cells for that pathogen in your lymph nodes).

•When the process goes wrong, you get an autoimmune disease, where the body attacks itself.

•Ex: Myasthenia Gravis: •Muscle fibers have receptors on them that receive neural stimulation to activate/contract the fiber.

ORGAN SYSTEMS 74•In myasthenia gravis, you develop antibodies against that muscle receptor. When those antibodies bind, it either stops the muscle fiber from functioning or destroys the receptor. So it’s harder for muscles to contract and be stimulated. You slowly become paralyzed.

HOW WHITE BLOOD CELLS MOVE AROUND: •Neutrophils circulate in the blood, but only do their work in the tissues at the site of an infection.

•How do they know where to squeeze out of the blood vessels into tissues? •Macrophages at the site of infection will gobble up bacteria and release chemical signals that tell endothelial cells of a nearby blood vessel that there’s an infection there.

•As a result, the endothelial cells express proteins that stick to the neutrophils. And then, because they’re stuck, the neutrophils squeeze through endothelial cells in an active process. In the tissue, they phagocytose the bacteria and then die. (When they die neutrophils become pus.)

•Immune cells only ever cross from the blood into the tissue; it’s impossible for them to go the other way. To enter circulation (such as for macrophages to present antigens to T and B cells), they must enter the lymphatic vessel and go to the lymph nodes. In the lymph node is antigen presentation, which causes B and T cells to activate and go to the side of the infection. How do they get there?

•The activated T cells enter the thoracic duct (final, fat lymphatic vessel) and eventually drain back into the blood. Once in circulation, those cells act similarly to neutrophils; they can see from endothelial proteins where the infection is, and then squeeze out between cells to fight bacteria in the tissue.

•B cells don’t really need to be in the tissue, though, so they mostly hang out in the lymph nodes. Their job is to release antibodies that can float around the body themselves and go to the infection site on their own.

BLOOD CELLS LINEAGES •In the blood vessels, you have about 10 different kinds of blood cells, from RBCs to T-cels, to B-cells, to platelets, and more… where do they all come from? Bone marrow! Specifically from the heads of long bones and from different flat bones (like the sternum) throughout the body.

• All blood cells have a single precursor: a pluripotent hematopoietic stem cell

•This pluripotent cell gives rise to two different lineages: myeloid and lymphoid• Myeloid lineage yields red blood cells and megakaryocytes (from which platelets are made), as well as mast cells (which release histamines in allergic reactions)

•The myeloid lineage also yields monocytes, which then become macrophages (part of the immune system) when they settle in the tissues.

•This monocyte lineage also yields three other types of cells: neutrophils (most common immune cell), eosinophils, and basophils.

ORGAN SYSTEMS 75• Lymphoid lineage yields B-cells (which make antibodies), T-cells, and “natural killer” cells.

•Dendritic cells can come from either lymphoid or myeloid (monocyte) lineages.

—————————————————Renal System—————————————————

KIDNEY FUNCTION AND ANATOMY •Humans have 2 kidneys, each about the size of a fist, that sit around the midsection (closer to the back than the front of the body).

•Kidneys receive blood from the heart (over a liter per minute!), filter it and reabsorb what is needed, then produce urine with the waste products to expel from the body.

•Kidneys can hold about 22% of your whole body’s blood supply!•Each kidney has an oxygenated blood vessel (renal artery) and a renal vein.

•The artery holds onto everything in the blood, from nutrients (Na+ ions, AA, glucose, etc.) to oxygen, to waste products (urea, toxins, extra electrolytes like

Na+ that we don’t need, etc). — Note: if you have too much of a nutrient, it becomes waste product.

•The vein then takes filtered blood, which still has the nutrients and some (but less) oxygen, away.

•Kidneys are critically important in maintaining homeostasis by regulating pH level (via H+ ions), blood pressure (via Na+ and Cl- ions), as well as osmolarity and expulsion of waste. It also makes hormones!

•How is it that the kidneys do this? Each kidney has two capillary beds:•The Vasa Recta delivers O2 to kidney tissue •The Peritubular Capillaries recollect nutrients to filter and then return via the veins.

•Two main functions of the kidney: filtration (gets rid of waste products) and collection of those waste products into the urine.

•The nephron is the functional unit of a kidney — it’s responsible for both functions.

•The nephron is situated in both renal cortex (the outside area / shell of the kidney) and the renal medulla (middle area).. It sort of dances between the cortex and medulla and where it is determines what role it’s playing: reabsorption of nutrients or collection of waste.

•The nephron part that’s situated in the renal medulla is called the renal calyx (plural: calyces). This is the first part where urine is present.

•The renal pelvis is a central area where all the calyces collect together.•Urine exits the kidney through the ureter off the renal pelvis and sends it into the bladder.

ORGAN SYSTEMS 76•For any organ with “tubes” (artery, vein, and ureter in this case), the tubes are collectively known as the hilum.

THE KIDNEY AND THE NEPHRON — OVERVIEW OF THE FILTRATION PROCESS •Each kidney contains around a million nephrons!•The blood enters the kidney through the afferent arterial, goes into a windy place called the glomerulus, and leaves through the efferent arterial.

•Kidneys have two arteries, in contrast to other capillary systems where blood enters by an artery and leaves by a vein. This maintains necessary pressure.

•The glomerulus is surrounded by a structure called the Bowman’s capsule, which has many cells called podacytes.

•When blood enters the glomerulus, about a fifth of it goes into the Bowmans’ space. This fluid is the filtrate, & contains things that are easily dissolved (ex: Na+, glucose, amino acids, etc.). Things that do not dissolve easily (ex: RBCs) aren’t filtered into Bowman’s space.

•Bowman’s capsule is sort of the beginning of the nephron. From there, the filtrate enters the proximal tubule (this has a convoluted part, then becomes straight), where important nutrients are reabsorbed. [ATP is used to pump out Na+, which helps bring in other things.]

•Close to the cells that line the proximal tubule is another capillary system that pumps blood that doesn’t go into the filtrate (and a little water from the filtrate) back to the body.

•After the proximal tubule, the blood enters the Loop of Henle. This section makes up most of the nephron, and extends into both the renal cortex and the renal medulla.

•One function of the loop of Henle is to make the renal medulla space salty, or hypertonic, by actively pumping out salts (Na+, K+, Cl-, etc). It uses ATP to do this.

•The ascending part of the Loop is only permeable to salts, whereas the descending part is only permeable to water.

•The descending part is thus where H2O molecules diffuse out; that’s where/how a lot of our water that is initially filtered out in the Bowman’s space is gained back. (This explains why the loop of Henle is so long, to allow enough H2O to diffuse out… see countercurrent mult. section for more)

•After the Loop of Henle, our blood reaches the distal convoluted tubule, which actually loops around close to the Bowman’s capsule again. This is where more nutrients (& a bit more water) are reabsorbed.

•After going through the distal tubule, our filtrate has been processed. A lot of the water has been taken out / reabsorbed (so the filtrate is more concentrated), and we’ve reabsorbed the nutrients we don’t want to lose. It’s now mainly waste products and water we don’t need any more.

•This processed filtrate is then dumped into collecting ducts, which go back down to the medulla.

• Anti-diuretic hormones dictate how porous the collecting duct is.. if it’s more porous then we lose more water from the filtrate into the medulla (b/c of concentration gradient). This makes the filtrate even more concentrated.

•Eventually, the collecting ducts dump this concentrated filtrate into the ureter, where it exits the kidney.

ORGAN SYSTEMS 77•Main substances excreted in urine are:

•Metabolic waste products (e.g. urea, creatinine), •Electrolytes —inorganic compounds (eg. sodium, potassium, calcium, chloride, and bicarbonate) that your body uses to control the fluid content / levels inside your body fluids.

•Water•Urine production is obligatory, it happens regardless of what is going on with your body because of the need to remove various solutes in order to keep internal conditions stable and relatively constant (homeostasis). This ensures that the body’s physiological processes continue operating effectively.

GLOMERULAR FILTRATION IN THE NEPHRON — DETAILS •The first step in making urine is for the glomerulus to separate the liquid part of your blood, from your blood cells and turn it into filtrate, and then let the rest of the blood go on.

•Filtrate contains all sorts of ion and nutrients, basically anything that can be dissolved in water. Things that cannot be dissolved in water, such as red blood cells, do not leave the capillary.

•Blood that is about to be filtered enters the glomerulus, which is basically a tuft of blood capillaries.

•The glomerulus is nestled inside a cup-like sac located at the end of each nephron, called the Bowman’s capsule, or the glomerular capsule.

•So, how does the Glomerulus capillary actually determine what is filtered and how much is filtered into Bowman’s capsule? Capillary walls are made up of three layers of filtration:

• Endothelium - this has relatively large pores (aka fenestrations, 70-100 nm in diameter), which solutes, plasma proteins and fluid can pass through, but not big things like red blood cells.

• Basement membrane - this membrane is also made up of three layers, and is fused to the endothelial layer. Its job is to prevent plasma proteins from being filtered out of the bloodstream.

• Epithelium (Tubular cells) - this layer consists of specialized cells called podocytes, which are attached to the basement membrane by foot processes (pedicels)

•Podocytes wrap around the capillaries, but leave slits between them, known as filtration slits.

•A thin diaphragm between the slits acts as a final filtration barrier before the fluid enters the glomerular space to the Bowman’s capsule.

•Together, the glomerulus and Bowman’s capsule filtering unit are known as a renal corpuscle.

•In addition to the unique glomerular capillary bed, the kidneys have other specialized capillaries called peritubular capillaries — tiny blood vessels that run parallel to and surround the proximal and distal tubules of the nephron, as well as around the loop of Henle, where they are known as the vasa recta.

•The vasa recta is important for countercurrent exchange, the process that concentrates urine.

ORGAN SYSTEMS 78

CHANGING GLOMERULAR FILTRATION RATE •Recall that the glomerulus is sandwiched between two arterioles - afferent arterioles deliver blood to the glomerulus, while efferent arterioles carry it away.

•This is unlike most capillary beds, which are are sandwiched between arterioles and venules rather than two arterioles.. In those, the hydrostatic pressure usually drops as blood travels through the capillary bed into the venules and veins.

•The constriction of efferent arterioles as blood exits the glomerulus provides resistance to blood flow, preventing a pressure drop, which could not be achieved if blood were to flow into venules, which do not really constrict. The two arterioles change in size to increase or decrease blood pressure in the glomerulus.

•In addition, efferent arterioles are smaller in diameter than afferent arterioles… This means pressurized blood enters the glomerulus through a relatively wide tube, but is forced to exit through a narrower tube

•If diameter of efferent arteriole is bigger, filtration rate is lower. If diameter of efferent arteriole is smaller, filtration is higher!

•These unique features (plus the heart supplying the kidneys with > 1L blood per min), maintain a high glomerular capillary pressure filtration function, regardless of fluctuations in blood flow.

•Example: the sympathetic nervous system can stimulate the efferent arteriole to constrict even during exercise when blood flow to the kidney is reduced.

•Example: In renal artery stenosis, we have a very narrow/stenosed renal artery, there is less blood that runs across our capillaries and is filtered away.. there’s going to be some blood / nutrients backed up, which is bad.

• Glomerular Filtration Rate = rate at which kidneys filter blood • The main driving force for the filtering process, or outward pressure, is the blood pressure as it enters the glomerulus. This is counteracted to some extent by inward pressure due to the hydrostatic pressure of the fluid within the urinary space, and the pressure generated by the proteins left in the capillaries that tend to pull water back into the circulatory system (colloidal osmotic pressure).

ORGAN SYSTEMS 79• The net filtration pressure is the outward pressure minus the inward pressure.

Regulation of glomerular filtration rate: It’s normal for your blood pressure to fluctuate throughout the day, but this has no effect on the glomerular filtration rate.. how? • Renal autoregulation — the kidney itself can adjust the dilation or constriction of the afferent arterioles, which counteracts changes in blood pressure. This intrinsic mechanism works over a large range of blood pressure, but can malfunction if you have kidney disease.

• Neural (nervous system) control and hormonal control — these extrinsic mechanisms can override renal autoregulation and decrease the glomerular filtration rate when necessary.

• Ex: If you have a large drop in blood pressure, which can happen if you lose a lot of blood, your nervous system will stimulate contraction of the afferent arteriole, reducing urine production. If further measures are needed your nervous system can also activate the renin-angiotensin-aldosterone system, a hormone system that regulates blood pressure and fluid balance.

• Hormonal control — The atrial natriuretic peptide hormone can increase your glomerular filtration rate. This hormone is produced in your heart and is secreted when your plasma volume increases, which increases urine production.

• Glomerular filtration rate (GFR) can be estimated by measuring creatinine! • Creatinine is a waste product made in muscle when it is metabolized to generate energy.

• Creatinine is not reabsorbed or secreted, but is then exclusively filtered through the kidneys. Its rate of excretion from your blood is directly related to how efficiently your kidneys are filtering!

• By measuring the amount of creatinine in a blood sample, and combining this with other information (e.g. age, ethnicity, gender, height, weight), the GFR can be estimated, which gives doctors a good idea of how well your kidneys are working.

TUBULAR REABSORPTION IN THE NEPHRON •If the fluid that filters through the glomerulus and Bowman’s capsule (glomerular filtrate) flowed straight to your bladder and then out your body, you would lose more than 10-times the entire volume of your extracellular body fluids (plasma and interstitial fluid) every day.

•Fortunately, tubular reabsorption mechanisms in the nephrons move solutes and water out of the filtrate and back into your bloodstream. [It’s called reabsorption because the first time these nutrients/solutes were absorbed was into the bloodstream from the digestive tract after a meal.]

•Recall, nephrons are divided into five segments, with different segments responsible for reabsorbing different substances —————————————>

•Reabsorption is a two-step process:

ORGAN SYSTEMS 80 (1) Passive or active movement of water & dissolved solutes from the fluid inside the tubule through the tubule wall into the space outside. (2) Movement of water and these substances through the capillary walls back into your bloodstream, again, either by passive or active transport.•The walls of the nephron are made of a single layer of cuboidal epithelial cells; their ultrastructure changes depending on the function of the segment they are in.

•Ex: The surface of the cells facing the lumen of the proximal convoluted tubule are covered in microvilli (tiny finger-like structures); called a brush border. This border (along with the extensive length of the proximal tubule) dramatically increases the surface area available for reabsorption of substances into the blood. (~80% of the glomerular filtrate is reabsorbed in this segment.)

•Cuboidal epithelial cells are also densely packed with mitochondria (the cell’s energy generators), which ensure enough energy is available to fuel the active transport systems needed for efficient reabsorption.

•Recall, sodium is the major positively charged electrolyte in extracellular body fluid.

•The amount of sodium in fluid influences its volume, which in turn determines blood volume and blood pressure.

•Most of the solute reabsorbed in the proximal tubule is in the form of sodium bicarbonate and sodium chloride, and about 70% of the sodium reabsorption occurs here.

•Sodium reabsorption is tightly coupled to passive water reabsorption, meaning when sodium moves, water follows.

• Reabsorption of Na + in the early proximal convoluted tubule : The most essential substances in the filtrate are reabsorbed in the first half of the proximal convoluted tubule (early proximal tubule). These include glucose, amino acids, phosphate, lactate and citrate, which “piggy-back” on Na+ co-transporters that move sodium down its electrochemical gradient into tubule epithelial cells.

•For this to continue, the sodium gradient must be maintained, which means sodium cannot be allowed to build up inside the epithelial cells of the proximal tubule wall. This is achieved using:

• Sodium/potassium ATPase, a sodium pump (active transporter)— moves 3 Na+ ions out of the cell for reabsorption, and 2 K+ ions in. This is located on the opposite side of the epithelial cell.

• Sodium/proton exchanger — enables reabsorption of bicarbonate. Glucose, AAs and other substances passively diffuse out of the epithelial cells and are then reabsorbed by the blood capillaries. By the time the filtrate has reached the mid part of the proximal tubule, 100% of the filtered glucose and amino acids have been reabsorbed, as well as large amounts of sodium, bicarbonate, phosphate, lactate, and citrate ions.

• Reabsorption of Na + in the late proximal convoluted tubule : The fluid entering the late proximal tubule has been depleted of the essential substances, and chloride ions have been left behind in the tubule. Due to extensive reabsorption of water in the early section of tubule, the concentration of chloride ions is high and its

ORGAN SYSTEMS 81ions are highly concentrated, and it is now their turn for reabsorption.Chloride is transported into the tubule epithelial cells through the following processes:

• Chloride/formate anion exchangers driven by the high concentration of chloride in the filtrate. Chloride diffuses out of the cell through channels in the cell wall, then on into the bloodstream.

• Passive movement through spaces between epithelial cells of the tubule wall, aka tight junctions.

•This is another important route for reabsorption of small solutes such as NaCl and H2O. Sodium continues to be reabsorbed in this part of the tubule via sodium/proton exchangers, and actively transported through the tubule wall to the bloodstream by the sodium/potassium ATPase.

•After proximal convoluted tubule, ~15% of phosphate is reabsorbed in the proximal straight tubule.

• Reabsorption of Na + in the loop of Henle : The filtrate then enters the loop of Henle (descending and ascending limbs), which is responsible for concentrating or diluting the tubular fluid using a process called countercurrent multiplication.

•The distal convoluted tubule and collecting ducts are then largely responsible for reabsorbing water as required to produce urine at a concentration that maintains body fluid homeostasis.

•Reabsorption of Na+ in the thick ascending limb: A further 25% of the Na+ and K+ is reabsorbed through walls of the thick ascending limb of the loop of Henle via the three-ion cotransporter (sodium/potassium/chloride); Na+/K+ ATPase again maintains the Na+ concentration gradient.

•Sodium is actively pumped out, while potassium and chloride diffuse through channels in the tubule wall and into the bloodstream. Recall, the walls of the thick ascending limb are impermeable to water, so none is reabsorbed here.

•Reabsorption of Na+ in the distal tubule and collecting duct: The tubular fluid now enters the distal tubule and collecting duct, or terminal nephron. The early distal tubule reabsorbs a further 5% of the sodium, and the late distal tubule and collecting duct fine tune reabsorption of the last little bit (around 3%), determining exactly how much sodium will be excreted.

•These segments of the nephron have slightly different transporters, as well as the sodium/potassium ATPase that drives reabsorption of calcium and chloride.

•Sodium reabsorption in the late distal tubule and collecting duct is regulated by hormones, which stimulate or inhibit sodium reabsorption as necessary.

ORGAN SYSTEMS 82

• Other ions : Calcium reabsorption throughout the nephron is largely similar to sodium reabsorption with over 99% being reabsorbed, while phosphate reabsorption is similar to that of glucose in that it primarily occurs within the proximal tubule. Reabsorption of magnesium differs in that the majority of the reabsorption occurs in the ascending limb of the loop of Henle.

• Consider: The importance of the kidneys in maintaining body fluid composition is clear when we look at what the impact on the body when our kidneys start to fail. Retention of waste products causes disturbances in multiple organ systems. Loss of water and electrolyte homeostasis lead to elevated extracellular body fluid volume, which may produce edema and hypertension, reduced phosphate excretion, loss of bone calcium, and symptoms of lethargy, nausea, diarrhoea and vomiting.

• Diabetes insipidus is a rare disorder that causes you to feel very thirsty (despite drinking a lot), and to produce large amounts of urine. It is usually caused by a malfunction in the production of antidiuretic hormone (ADH), a hormone that prevents the production of dilute urine (i.e., retains water in the body). This can happen for a number of different reasons, including damage to the pituitary (e.g., caused by a tumor, surgery, or infection) that disrupts the normal production, storage and release of ADH. However, it may also occur due to a defect in the tubules themselves that prevents them from responding to ADH, or during pregnancy, when a placental enzyme destroys ADH in the mother.

COUNTER CURRENT MULTIPLICATION IN THE KIDNEY • Countercurrent multiplication in the kidneys is the process of using energy to generate an osmotic gradient that enables you to reabsorb water from the tubular fluid and produce concentrated urine.

•The kidneys contain two types of nephrons, superficial cortical nephrons (70-80%) and juxtamedullary nephrons (20-30%).

•These names refer to the location of the glomerular capsule, which is either in the outer cortex of the kidney, or near the corticomedullary border.

•Loop of Henle of cortical nephrons penetrates only as far as the outer medulla of the kidney, but that of the juxtamedullary nephrons penetrate deep within the inner medulla, so the latter is largely responsible for countercurrent multiplication. (although both types regulate solute / water levels)

Overview of Countercurrent Multiplication•Blood comes into to a nephron through the afferent arteriole, circles around the glomerulus, and exits through the efferent arteriole. In circling around the glomerulus, a ton of fluid filters out of the blood and into Bowman’s capsule.. this fluid is then filtered to become urine.

•After the fluid enters the Bowman’s capsule, it flows into the proximal convoluted tubule, where ions (Na+, Cl-, etc) and other builders of macromolecules (AAs, glucose) are reabsorbed, along with water.

•Proximal convoluted tubule reabsorbs about 65% (most, by far) of the nutrients from the filtrate.

ORGAN SYSTEMS 83•From the proximal convoluted tubule, the filtrate flows into the loop of Henle, which has two limbs going in opposite directions — the descending limb and the ascending limb.

•This portion of the nephron extends into the renal medulla of the kidney, which is very salty

•Descending limb is only permeable to H2O.•Ascending limb is the exact opposite; it’s impermeable to water but allows reabsorption of ions such as Cl-, K+, Na+

•These characteristics lead to counter-current multiplication, a process by which actively reabsorbing ions in the ascending limb makes the medulla salty (b/c it doesn’t allow reabsorption of H2O, and this saltiness of the interstitium allows H2O to be reabsorbed passively in the descending limb.

•The amount of water passively absorbed is multiplied by the saltiness of the medulla, which occurs as a result of actively pumping ions out of the ascending limb.

•After the ascending loop of Henle, the filtrate enters the distal convoluted tubule (DCT), which is responsible for the reabsorption of other ions / important nutrients.

•Note the “scientific kiss” that occurs here, where the DCT comes back towards the glomerulus. This produces the juxtaglomerular apparatus, responsible for controlling blood pressure.

•After leaving the distal convoluted tubule, this more concentrated filtrate gathers in the collecting duct.

•Note that there are many DCTs which feed into a single collecting duct.•The collecting duct also descends into the renal medulla, and allows for further reabsorption of H2O and urea. Urea is one of the main waste products we pee away, but sometimes kidneys like to hold onto it (by reabsorption) to increase the osmolarity in the medulla to help drive water reabsorption in the loop of Henle. From here, it goes into urea recycling.

•From the collecting duct, this filtrate (now urine!) enters renal calyces and is sent off to be peed out.

•After reabsorption, the efferent arteriole collects, via small peritubular capillaries (purple) across the nephron, all the nutrients that have been reabsorbed! These capillaries then feed into the renal vein.

Details of Countercurrent Multiplication in the Loop of Henle•The 3 segments of the loop of Henle have different characteristics that enable countercurrent mult:

• Thin descending limb — passively permeable to both water & small solutes (ions, urea, etc.).

•Water and solutes move down their concentration gradients until their concentrations within the descending tubule and the interstitial space have equilibrated.

ORGAN SYSTEMS 84•As such, water moves out and solutes to move in. This means the tubular fluid becomes steadily more concentrated or hyperosmotic (compared to blood) as it travels down.

• Thin ascending limb — passively permeable to small solutes, but impermeable to water, which means water cannot escape from this part of the loop.

•As a result, solutes move out of the tubular fluid, but water is retained and the tubular fluid becomes steadily more dilute or hyposmotic as it moves up the ascending limb of the tubule.

• Thick ascending limb (sometimes called “diluting segment” actively reabsorbs Na+, K+ and Cl+.

•This segment is also impermeable to water, which again means H2O cannot leave.

•Countercurrent multiplication moves sodium chloride from the tubular fluid into the interstitial space deep within the kidneys. Although it’s really a continual process, the way countercurrent multiplication process builds up an osmotic gradient in the interstitial fluid can be thought of in two steps:

1. The single effect. The single effect is driven by active transport of sodium chloride out of the tubular fluid in the thick ascending limb into the interstitial fluid, which becomes hyperosmotic. — As a result, water moves passively down its concentration gradient out of the tubular fluid in the descending limb into the interstitial space, until it reaches equilibrium.

2. Fluid flow. As urine is continually being produced, new tubular fluid enters the descending limb, which pushes the fluid at higher osmolarity down the tube. An osmotic gradient begins to develop.

•As the fluid continues to move through the loop of Henle, these two steps are repeated over and over, causing the osmotic gradient to steadily multiply until it reaches a steady state. The length of the loop of Henle determines the size of the gradient - the longer the loop, the greater the osmotic gradient.

•Although the loops of Henle are essential for concentrating urine, they don’t work alone. The specialized blood capillary network (the vasa recta) that surrounds the loop is equally important for countercurrent exchange:

•The vasa recta returns absorbed water to the circulatory system.•Consists of long, hairpin-shaped capillaries that run parallel to the loop. •These hairpin turns slow the rate of blood flow, so any solutes that are reabsorbed into bloodstream have time to diffuse back into interstitial fluid, maintaining the hyperosmotic medulla for H2O reabsorption.

•The concentration of urine is controlled by ADH, which can increase water permeability in the late distal tubule and collecting ducts. This increases active transport of NaCl in the thick ascending limb, and enhances countercurrent mult. and urea recycling, thus increasing H2O reabsorption.

• Urea recycling in the inner medulla also contributes to the osmotic gradient generated by the loop of Henle. ADH increases water permeability, but not urea permeability, in the cortical and outer medullary collecting ducts, causing urea to concentrate in the tubular fluid in this segment.

ORGAN SYSTEMS 85•In the inner medullary collecting ducts, ADH increases both water and urea permeability, which allows urea to flow passively down its concentration gradient into the interstitial fluid, also adding to the osmotic gradient that helps drive water reabsorption.

SECONDARY ACTIVE TRANSPORT IN THE NEPHRON •The proximal tubule has a brush border, with the glomerular filtrate entering the lumen of the nephron. This lumen/tube is surrounded by cells.

• note: membrane of cell side facing the lumen is apical, while that facing the capillary is basolateral.

•Adjacent to proximal tubule is the peritubular capillary, where reabsorbed nutrients re-enter the blood.

•On the basolateral side of the proximal convoluted tubule is a sodium/potassium pump! Sends 3 Na+ out (using ATP) and takes in 2 K+.

•This active pumping out of Na+ means we’ll have a lower Na+ concentration inside the cells of the tubule wall than inside the lumen. Na+ wants to leave the lumen, then, to go into the cell.

•A co-transporter symporter on the apical membrane takes advantage of this concentration gradient. As Na+ leaves the lumen to enter the cell(s) of tubule wall, moving down its concentration gradient, a glucose molecule is simultaneously transported up its concentration gradient without using ATP.

•This same process happens in the loop of Henle with other ions… the basolateral cell wall of the ascending limb of the loop has a Na+/K+ pump, which reduces Na+ concentration in the cell(s) of the tube’s wall. Na+ then wants to move from the lumen to those cells, down its concentration gradient, and with it (via the Na+/K+/Cl– cotransporter) takes another ion up its concentration gradient.

•Use of cotransporters after Na+ has already been pumped out is called secondary active transport.

•In the distal convoluted tubule, Na+ is again pumped out via a Na+/K+ pump in the basolateral cell wall of the tubule, lowering Na+ concentration in the cell(s) of DCT’s wall. In this case, it drives reabsorption of Ca2+ through an antiporter. (The apical membrane of the cells of the tubule wall is porous to Ca2+)

•Recall that the peritubular capillaries run parallel to these tubules.. Thanks to the Na+/K+ pump, the concentration of Na+ in the capillary blood is higher than in the cell, so Na+ will want to go back in. When Na+ moves in, the Ca2+ is simultaneously moved up its gradient (in opposite direction).

URINATION •After we concentrate urine in our nephrons, it flows through the collecting duct to the renal calyx at the tip of the medulla. Several renal calyces come together to make the renal pelvis, and from there our urine flows out of the ureter into the bladder.

•Ureters attach to the back of the bladder. They have valves that prevent backflow of urine up the ureter towards the kidneys.

•The ureters spray urine into the bladder with the ureter jet, one at a time (recall ultrasound video)

•Looking at the bladder from the side, the anterior (front) has a sort of point and both interior and posterior sides funnel down.

ORGAN SYSTEMS 86•The bladder is lined with transitional epithelium, which is structurally somewhere in between the flat squaemous epithelium and taller columnar epithelium. These types of cell allows the bladder to expand!

•The bladder then funnels into the urethra, controlled (at the top of the urethra / bottom of the bladdar) by the internal urethral sphincter (IUS). This sphincter is involuntary & thus made of smooth muscle.

• In women , after the IUS, we have the external urethra sphincter (EUS), a membranous part surrounding the urethra. This is in our control (unlike IUS) and thus it’s made of skeletal muscle. This is the muscle we learn to control in potty training. After the EUS, the urethra is fairly short (much shorter than in men), and it leads to the outside world.

• In men , after the IUS there is the prostatic urethra (named because it passes through the prostate, which circumscribes the urethra), and then the EUS. After the EUS, the urine will travel through a urethra section called the spongey urethra, which is in the penis. After this, the urine leaves the world.

•Note: If our ureter valves (which are normally one-way and prevent backflow) malfunction, we can get what’s called stasis, where the urine basically sits in the ureter. This can be a problem, and even cause infection, if there’s any bacteria there, which is not unlikely seeing as our urethra is connected to the outside world. [Women are much more susceptible to these UTIs bc their urethra is so much shorter.]

—————————————Renal Regulation of Blood Pressure—————————————

OVERVIEW OF THE RAAS SYSTEM AND RENIN PRODUCTION •RAAS = Renin Angiotensin Aldosterone System. It begins with a set of cells that releases messengers.

•The key cell is the juxtaglomerular cells, which are in the blood vessels of the kidney. They’re made of smooth muscle, and release renin: an endocrine peptide hormone that helps raise blood pressure.

•Recall that in the kidney, the afferent arteriole leads in to the glomerulus, and the efferent arteriole leaves. In between these arterioles, the distal convoluted tubule crosses over. ———>

•The distal convoluted tubules are partly made of some special macula densa cells.

•The arterioles are made of the inner layer (aka the tunica intima) of endothelial cells, then a layer of smooth muscle cells (tunica media).

•On the afferent arteriole side (well, both sides, but mostly afferent), the tunica media also has clusters of juxtaglomerular cells - also called granular cells because they all have little granules in them. After this layer is the tunica externa layer, which is home to many nerve endings for a nearby sympathetic nerve (will be important later)

•In the arterioles are also mesangial cells, which are mostly there for structural support.

ORGAN SYSTEMS 87•Together, this is all called the juxtaglomerular apparatus, whose goal is to release renin.

•The granules of the JG cells are filled with renin. When released, renin enters afferent arteriole, goes through the glomerulus, and exits through the efferent arteriole. But how / why is renin released?

•Triggers for JG cells to release renin include:• (1) Low blood pressure

•JG cells directly sense low blood pressure in the afferent arteriole• (2) Sympathetic (fight or flight) nerve cell stimulation

•Major stressor events cause this nerve cell to fire on the afferent arteriole, which in turn causes the release of renin from JG cells

• (3) Low Na+ concentration in the distal convoluted tubule, sensed by macula densa cells.

• Macula densa cells sense concentration of sodium ion in glomerular filtrate.• Macula densa cells (which form the lining of the distal convoluted tubule) are part of the

juxtaglomerular apparatus, which regulates blood pressure.

• A component of blood pressure is blood volume: higher blood volume means higher blood pressure.• A decrease in sodium ion in the distal convoluted tubule implies low blood pressure.• Macula densa cells send local, short-range signals to juxtaglomerular cells via release of prostaglandins.• Prostaglandins are molecules that send short-range signals between cells; unlike hormones, they are not produced by specific organs, but rather throughout the body.• Renin is released in response to signals that represent low mean arterial pressure.• The sympathetic nervous system innervates the juxtaglomerular apparatus and can signal in response to low blood pressure.• Macula densa cells detect low blood pressure by sensing sodium concentration in the glomerular filtrate, not in the blood plasma.• Renin is not released in response to detection of low plasma electrolyte levels by macula densa cells.•

•If BP is low, not a lot of blood is moving through the glomerulus, so not a lot of fluid is moving through the nephron, and thus a lot of salt is being reabsorbed. Macula Densa cells “taste” the fluid going by and sense that there’s not much salt in it (bc blood pressure is low), so they signal JG cells to release renin through paracrine (short-ish distance) prostaglandins.

ANGIOTENSINOGEN — > ANGIOTENSIN 1 — > ANGIOTENSIN 2 — > INCREASED BLOOD PRESSURE •In addition to the kidney, with its juxtaglomerular apparatus (and sympathetic nerves), the liver is also involved in raising blood pressure.

•Liver cells release angiotensinogen, a large (~450 AA) hormone precursor, or inactive hormone.

ORGAN SYSTEMS 88•When angiotensinogen meets up with renin in blood vessels (all over body), renin cleaves that long AA chain into just about 10 AA, effectively converting angiotensinogen into its active form: angiotensin 1

•Angiotensin 1 now floats through capillaries, tiny blood vessels that are so small they’re basically just made of a layer of endothelial cells. In these endothelial cells is ACE: Angiotensin Converting Enzyme.

•ACE cuts another 2 amino acids off angiotensin 1 making it into the 8 AA hormone, angiotensin 2.

•Note: It used to be thought that ACE was only present in the lung capillaries, but is now widely recognized that ACE is in a lot of different vessels / organs, including the kidneys.

•Angiotensin 2 ultimately raises blood pressure through four different cell types:(1) Vasoconstriction — causes smooth muscle cells of blood vessels to constrict and increase resistance

•Angiotensin = “blood vessel” “tension”•Recall, blood pressure can be measured with ∆P = Q x R ———> PA - PV = (SV x HR) x R, so it makes sense that if you increase resistance, arteriole blood pressure will also be increased (because venous blood pressure doesn’t really change). — note: SV = stroke volume = mL of blood pumped out of the heart with each beat

(2) Increases Na+ reabsorption in the kidneys — by reabsorbing Na+, the kidneys also end up absorbing and retaining more water with it.

•When your blood has this increased Na+ and increased water, it will cause the stroke volume to go up and, as we saw above in PA - PV = (SV x HR) x R, by increasing stroke volume (SV), blood pressure will be increased

(3) Causes pituitary gland to secrete antidiuretic hormone — ADH also accomplishes (1), making blood vessels constrict. And it sort of accomplishes (2), making kidneys retain H2O instead of Na+. [Water retention also makes SV increase, and thus pressure.](4) Causes adrenal gland (on top of kidney) to secrete aldosterone, which also accomplishes (2) - increases reabsorption of Na+ in the kidneys (and thus increases SV).

•What’s the difference between salt and water reabsorption?•When Na+ is reabsorbed, the medulla gets salty, so H2O absorption will follow… as long as the tube is permeable to H2O. [Where

•If the tube is impermeable to H2O, though, obviously this will not work. Instead, the tube uses a bunch of special channels to allow H2O through.

•The area of the nephron where angiotensin 2 and aldosterone affect reabsorption is permeable to water, so causing Na+ reabsorption works to retain water, too.

•But the area where ADH affects the nephron is impermeable to water, so it must directly cause H2O reabsorption through channels.

DETAILS OF ALDOSTERONE FUNCTION IN RAISING BP: •Aldosterone is released by the adrenal gland, which has two parts: cortex (outer) and medulla (inner).

ORGAN SYSTEMS 89•Adrenal cortex cells are provided nutrients / oxygen by small capillaries, and they’re filled with cholesterol. The cholesterol is very useful in making the hormone aldosterone.

•Triggers for adrenal cortex to make aldosterone:(1) Angiotensin 2(2) Increase in K+ concentration

•Aldosterone affects the late distal convoluted tubules and the collecting ducts of nephrons.

•These tubules are lined with principal cells, which are adjacent to the peritubular capillary. (the side of peripheral cells facing the capillary is the basolateral surface; that facing the lumen is the apical surface)

•There are lots of K+ ions inside the principal cell, and lots of Na+ in the blood flowing through the capillaries. These two ions are exchanged through the sodium-potassium pump on the basolateral surface — 3 Na+ ions move out of the cell as 2 K+ ions are pumped in.

•Aldosterone works by:1. Making the sodium-potassium pump in the basolateral surface of the tubule /

duct work harder.2. Opening potassium channels on the apical surface, so K+ flows out of the

principal cells into the fluid (soon to be urine) flowing through the tubule. This increases drive to get K+ into the cell.

3. Opening Na+ channels, moving Na+ into the principal cell from the urine, which again makes the Na+/K+ pump work even harder to pump Na+ out of the principal cells (where concentration is increasing) into the capillaries. When Na+ enters the capillaries, water follows.

•TL:DR — Aldosterone works on the principal cell and causes blood to lose K+ and gain Na+ (and thus gain water)… this leads to increased stroke volume and thus increased blood pressure

ALDOSTERONE ALSO REMOVES ACID FROM THE BLOOD: •Aldosterone also works on α-intercalated cells, whose main job is to get rid of protons (and thus acid).

•Alpha intercalated cells are in the collecting duct; they secrete hydronium ion (acid) and absorb bicarbonate.[The ß-intercalated cell, by contrast, tries to hold onto acid.]

•The α-intercalated cell is also bordered by a peritubular capillary on the basolateral side.

•Recall: all cells make CO2 and H2O through glycolysis, and are then turned into H+ and HCO3- by carbonic anhydrase.

•Let’s say the blood is getting a bit too acidic and H+ starts building up. What happens?

•In the α-intercalated cell’s basolateral side, there is a channel that allows HCO3- to travel from the cell into the capillary and simultaneously brings a Cl- into the cell. In the blood, the HCO3- combines with H+ to make CO2 and H2O.

ORGAN SYSTEMS 90•In the α-intercalated cell, that Cl- that entered when HCO3- left can leave the cell through a channel on the basolateral side.

•But we’re still left with the H+ from the initial rxn with carbonic anhydrase… For every H+ we remove from the blood, we have one in the cell, and these start to build up.

How do we get rid of the acid from α-intercalated cells? 4 main transporters•On the apical side, there’s an active transporter (requires ATP) that will send the H+ from the α-intercalated cell into the urine, and it can just be peed out. Aldosterone makes this transporter work super well.

•A second transporter on the apical side can send out H+ without using energy; instead it uses the Na+ concentration gradient. Aldosterone also makes this transporter work super well.

•Recall that cells have a lot of K+, but not a lot of Na+. (Most of the Na+ is in the blood.) The entrance of Na+ down its gradient fuels the movement of H+ against its gradient.

•A third type of transporter on the apical side also requires energy (is “active” transporter) to allow H+ out. As H+ leaves the cell, K+ is driven back in, against its gradient (which is why energy is required).

•In α-intercalated cells, there are also (like all cells) sodium-potassium pumps on the basolateral side that bring 2 K+ in and force our 3 Na+; this also takes energy.

•TL;DR — Acid is removed from the blood by bringing in HCO3- from α-intercalated cells to neutralize it, but that leaves H+ (from the same rxn) in the α-intercalated cells. H+ is then removed from those cells by several transporters, two of which are driven by aldosterone.

ANTI-DIURETIC HORMONE (ADH) SECRETION: •ADH is sometimes called vasopressin.•Consider the pituitary/hypothalamus structure: There is the hypothalamus (at the top), the infundibulum in the middle, and then the two lobes of the pituitary: anterior and posterior.

•On this structure is also a little nodule called the optic chiasm, above which sits the supraoptic nucleus (recall that a nucleus is a collection of cell bodies / somas).

•The nerve cells in the supraoptic nucleus start there and travel all the way down to the posterior pituitary; this is how the hypothalamus and pituitary are connected.

•There are lots of tiny capillaries and venules in the posterior pituitary, as well.• ADH is a peptide hormone made in the nerve cells of the supraoptic nerve cells.

•When there’s a trigger, these nerve cells fire off ADH and signal the capillaries to release ADH hormone into the body.

•What are the triggers for ADH release?• *High blood concentration (aka high osmolarity, meaning level of solutes in the blood) — this is most important trigger

ORGAN SYSTEMS 91•Body likes to stay in the 280 - 300 mOsm/L range. If it gets above 300, it’s a little salty / too osmotic and ADH is triggered to be released (by osmoreceptors in unknown locations)

• Low blood volume•This is sensed by nerve endings in the walls of the vena cava blood vessels and the right atrium (because, recall, the venous system is very large volume.. If the cells of those walls sense that they are less stretched, they know blood volume is low and they trigger ADH release.

• Low Blood Pressure•This is sensed by arteriole baroreceptors in the aortic arch and the carotid sinuses on both sides.

• Angiotensin 2 also triggers release of ADH.

ANTI-DIURETIC HORMONE (ADH) EFFECTS ON INCREASING BLOOD PRESSURE: •ADH signals all arteriole vessels of the body, with their smooth muscle, to constrict. This increases resistance, which in turn increases blood pressure. PA - PV = (SV x HR) x R

•It also causes the kidneys to retain / reabsorb water by affecting the collecting duct, specifically, which causes stroke volume to increase.

•As you go deeper in the medulla (from bowman’s capsule down the loop of Henle), there is an increasing gradient of mOsm concentration. It gets salty

•In the collecting duct cells, there are little vesicles called aquaporins, which do not allow water to go through, except through their aquaporin channels.

•Note, though, that they are not close to the wall, so H2O cannot enter the collecting ducts.

•ADH will float through the blood (which flows in opposite direction to the urine in the collecting duct that the capillary is next to), and signals the collecting duct cells to merge aquaporin vesicles with the apical wall of the cell, so channels allow water in and out.

•After opening the aquaporin channels, lots of H2O flows into the cell and then basically straight into the adjacent peritubular capillary, significantly increasing blood volume and thus stroke volume, and thus blood pressure.

ALDOSTERONE AND ADH: •Aldosterone: uses an osmole to pull H2O into the blood

•The tubules it affects are water permeable. It pulls Na+ into the capillary and sends in K+ through an active transport pump.

•Recall, Na+ is not able to cross membranes; which means it is a big contributor to tonicity; it can’t leave the blood vessel. By comparison, K+ can slightly cross membranes, but net tonicity still increases. This increase in tonicity pulls in water.

•Increases osmolarity and also increases volume.•Because they both increase proportionally, we don’t think of osmolarity really being affect.

•ADH: uses channels to pull H2O into the blood•The tubules it affects are not water permeable, so it opens aquaporin channels that allow H2O across.

ORGAN SYSTEMS 92•Increases volume, but not osmols, so overall osmolarity (fraction of osmole / vol.) decreases.

•Given this information and the changes the hormones make, think about a situation where you want to

•increase volume but maintain osmolarity: increase ADH•increase volume, regardless of osmolarity: increase aldosterone and ADH•decrease osmolarity, regardless of volume: ADH •decrease osmolarity, maintain volume: increase ADH, decrease aldosterone

——————————————Gastrointestinal System————————————————

OVERVIEW OF THE GASTROINTESTINAL TRACT •Mouth: chewing + hydrolysis (enzymatic breakdown) = bolus.•Esophagus: propela bolus•Stomach: churning (like chewing, but more dimensions) + hydrolysis + storage = chyme.

•Small Intestine: hydrolysis + absorption•Large intestine (colon): absorption (not of nutrients, but ions, water, vitamin K, etc.)

•Rectum: storage of processed food until we expel it•Anus: expulsionMOUTH (ORAL / BUCCAL CAVITY) •Goal of the mouth is to convert food into bolus, which we do in two steps:(1) Chewing (mastication) — accomplished by teeth and the tongue.

•The tongue is made of extrinsic and intrinsic muscles. • Extrinsic tongue muscles cause elevation, depression, protrusion, retraction

• Intrinsic tongue muscles (only inside the tongue) shorten & widen (run A/P), and lengthen & narrow (R/L)

(2) Breakdown of food particles by hydrolysis. The enzymes in our mouth that do this come from glands.

•Glands release: Serous content (for enzymes) - breakdown / cut food by hydrolysis, and mucinous (musin) content - wet the food to make it easier to form bolus)

• Parotid glands (mainly serous) release about 25% of saliva content• Submandibular (also mainly serous) - 70% of saliva• Sublingual gland (mainly releases mucin) - 5% of saliva• Von Ebner’s gland (mainly at the tip of the tongue, also serous) - less than 5% of saliva

•Von Ebner’s gland is important in that is releases lingual lipase, which breaks down triglycerides into free fatty acids, diglycerides, and monoglycerides.

•The other three glands (parotid, submandibular, and sublingual) release α-amylase, which breaks down starch into smaller carbs

•Note that the amount of hydrolysis and breakdown that occurs in the mouth is very insufficient for digestion; it’s basically just so we can taste things (e.g. enjoy the sugars in our soda)

ORGAN SYSTEMS 93•The mouth normally is at a pH of ~7, but if we eat a lot of sugar (which, recall, has a lot of hydroxyl groups), it can actually lower the pH of your mouth to as low as 5.5! This acidity will start to break down your teeth.

TEETH • mandible = lower jaw; maxilla = upper jaw. There is symmetry both on the left/right sides, as well as between the mandible and maxilla.

•The textbook picture to the right – with 4 central incisors,4 lateral incisors, 8 premolar, and 12 molar teeth –is actually only what 28% of people’s teeth look like.

•Why? Your 3rd molars are your wisdom teeth, and most people (72%) have them removed.

•Wisdom teeth are often removed because teeth come up through little holes in your gums (aka gingiva). In most people, the hole for the 3rd molar is very small — too small for the 3rd molar to get through. So the tooth ends up twisting and trying to “erupt” through the gingiva in a such bad way that it can cause inflammation and tearing.

ESOPHAGUS •There are sphincters — circular localizations of muscle — at the very top and very bottom of the esophagus. These keep food moving in one direction.

•The upper esophageal sphincter only opens when we tell it to, and is thus made of skeletal muscle.

•The lower esophageal sphincter doesn’t really look like a sphincter, because it’s not a ring of muscle that opens and closes when we want. Instead it’s really the diaphragm — a sheet of muscle that lines the connection between the thoracic cavity (lungs, heart, etc), and the abdominal cavity, and helps our lungs expand to breathe.

•This diaphragm forms a ring around the base of the esophagus and holds it in place.

•Over time, humans can get a hernia where the esophagus moves up through the diaphragm (aka lower esophageal sphincter) and causes acid reflux.

•The esophagus works as a passageway for food, and doesn’t do much except peristalsis — the wavelike propulsion of food. Contraction of the muscle above + simultaneous relaxation of muscle below.

•Esophageal tract is not made of 100% skeletal or 100% smooth muscle; instead it’s split into thirds.

•top-third: all skeletal muscle, which is completely in our control•middle-third: combination of skeletal and smooth•last-third: all smooth muscle, 100% not in our control.

STOMACH •Stomach is primarily responsible for 3 steps:

•(1) receives bolus of food•(2) churns the bolus / food to break down the food even more•(3) hydrolysis (enzyme assisted breakdown) of the bolus

ORGAN SYSTEMS 94•These steps end with making chyme, which just sort of sits there for a little bit (the stomach also stores food, up to 4 L at a time!) before moving on to the small intestine.

•The stomach is lined with many infoldings of the gastric wall that help to increase surface area. The folds are lined with cells that secrete enzymes. Three main types of cells:

• Parietal cells — release HCl• Chief cells — release pepsinogen (inactive form of pepsin. HCl turns pepsinogen into pepsin)

•Pepsin break down proteins by cleaving peptide bonds; thus, peptin is the only type of molecule broken down in the stomach.

•Note: with just these two secretions, HCl and pepsin, your stomach would basically eat itself! This is what is happening when we get gastric ulcers.

• Mucous cells — make mucous to line the stomach wall and protect it from pepsin and HCl.

SMALL INTESTINE •The small intestine has three different parts to it:

•(1) Duodenum — receives chyme from the stomach. Most of the digestion occurs here.

•(2) Jejunum — most absorption happens here•(3) Ileum — absorbs important things like vitamins

•The Duodenum is very busy with four key processes:•Receives chyme and HCl from the stomach•Liver and gallbladder send bile to the duodenum•Pancreas also delivers some important enzymes•The duodenum itself has brush border enzymes, which are important for absorption and for enzymatic activity.

• The brush border is basically in-foldings on the wall of the duodenum (bumps face in), called villi.

•Within each villus is even more in-foldings, microscopic projections of tiny bumps called microvilli

•All these increase surface area for absorption and digestions, because the projections have enzymes.

Digestion (in the duodenum):•Protein is broken down by several enzymes in the small intestine into constituent amino acids

• Peptidase is found on the brush border. •The pancreas sends trypsinogen and chymotrypsinogen, which an enzyme called enteropeptidase turn into their active forms of trypsin and chymotrypsin.

•Carbohydrates are broken down by: amylase (sent by the pancreas) and lactidase (can only break apart lactose — this is found on the brush border).

•When you get a stomach bug, it can inflame the duodenum and actually knock off some of the lactidase enzymes. Thus, you may be temporarily lactose intolerant.

• Eventually you’re left with just monosacharides.

ORGAN SYSTEMS 95• Nucleotides are broken down by nucleosidases on the brush border, which cleaves base–pentose bond.

• Fat is broken down by lipase, which is released by the pancreas and cleaves triglycerides into the glycerol backbone and 3 fatty acids.

• Bile released by the liver / gall bladder to organize the fatty acids.Absorption (mostly in the jejunum)• After digestion, we have all out monomers (AA, monosaccharides, nucleobases, fatty acids, etc.)

• Amino acids are funneled into intestinal cells with primary active transport (uses ATP) —> eventually enters a blood capillary.

• Sugar monosaccharides are funneled into and eventually out of the intestinal cells with secondary active transport — This is when an ion like Na+ flows down its concentration gradient into the cell from the lumen (or out of the cell into the capillary), which allows the monosaccharide to also enter (or exit)

• The P-pentose and nitrogenous base also enter/exit the cell with primary active transport and eventually end up in the blood capillary.

• Because of their nonpolar tail, fatty acids can just diffuse across the membrane into the enterocyte (intestinal cell). There, they are organized into chylomicrons, which are too big to go to the blood capillary. Instead, chylomicrons are absorbed into the lymphatic capillary (aka lacteal), where they are further digested into smaller bits and can then get into the veins and eventually the blood capillaries.

LIVER •The liver is responsible for for main things:

•(1) Metabolism — involves catabolism and anabolism•(2) Storage

•Carbs are stored as glycogen, while fats can be stored as lipoprotein and triglycerides.

•Proteins are also seen in the liver, but aren’t really stored.. instead they’re turned into molecules like albumin and sent off into the bloodstream until they need to be retrieved back to the liver

•(3) Detoxification — achieved mainly by cytochrome P450. Unlike other enzymes, they can take many different kinds of substrates and react with them.

•This detoxification process causes a problem when we take medications, it decreases the drug efficacy.

•(4) Bile production — needed for fat absorption•Uniquely, the liver has two separate blood supplies going to it, and one that leaves it. These three vessels make up the portal triad.

•The portal vein supplies the liver with nutrient rich blood (The nutrients come from food absorbed in the intestinal track, which go through circulation to end up in the portal vein.)

•The proper hepatic artery supplies the liver with arteriole, oxygen-rich blood.

•The hepatic vein carries away nutrient- & oxygen-poor blood. This blood then travels to the heart to be oxygenated, goes past intestines to gain nutrients, then re-enters liver through portal vein.

ORGAN SYSTEMS 96•The other output from the liver is bile, which leaves through the common hepatic duct.

Hepatic lobule•The portal triad is important to identify in surgery, and is easy to identify when we look at pieces of the liver called hepatic lobules.

•In the hepatic lobule, there are many lot of liver cells, or hepatocytes, and around them three distinct branches that make up the portal triad. There’s actually bunches of portal triads surrounding hepatocytes — this leads to 6 distinct sides of the hepatic lobule.

•The portal vein is how we get nutrient rich blood to enter the hepatic lobule (portal vein branches are called sinusoids), where hepatocytes then break those nutrients down for storage or whatever is needed. The proper hepatic artery brings in oxygen to the hepatic lobule.

•Once those have been extracted, we need to send the blood out to be oxygenated and get nutrients again.. so the blood collects in the center of the hepatic lobule, into the central vein, which then becomes the hepatic vein. (which sends blood back to the heart —> intestines, etc)

Biliary tree•Bile is composed of bile pigments (make the color and aren’t really important for function) and bile salts (very important, help us emulsify fat into miscelles, which can then be absorbed in the ileum).

•Bile that’s made in the liver travels through the common hepatic duct into the cystic duct, which then leads it to be (temporarily) stored in the gall bladder, a blind pouch..

•The singular purpose of the gall bladder is to store the bile.•The hormone that causes bile to be released from the gall bladder is cholecystokinin (CCK); it causes the gall bladder to contract, and in doing so all the bile is squeezed back through the cystic duct and then into the common bile duct.

•The common bile duct travels to the duodenum of the small intestine and releases its bile there. In the duodenum, fats are emulsified.

•Note, though, that fat is not absorbed in the duodenum. Instead, the bile salts with the emulsified fat travel along to the ileum (last part of the small intestine) for absorption.

•What happens to bile salts after they’re absorbed in the ileum? They circulate back to the liver to repeat the process.

EXOCRINE PANCREAS •The pancreas sits below and behind the stomach, and sort of hugs the duodenum of the small intestine.

•Some say it’s in a completely different section of the body, not in the peritoneum (abdominal cavity with the stomach, intestine, etc.), but is instead is in the retroperitoneum (along with some big blood vessels)

•The pancreas releases powerful enzymes that digest lots of macromolecules — things we eat as well as some that make up parts of our body. It also is unique in that it’s un-encapsulated; it’s just a slurry of cells (which makes it difficult especially for surgeons operating nearby).

ORGAN SYSTEMS 97•Many consider the pancreas to be the “lion” of the abdomen because of it’s importance and power.

•There are two main components to the pancreas:•Exocrine pancreas takes salts and enzymes and releases them in the duodenum.

•Endocrine pancreas releases hormones.•The exocrine pancreas releases four main things:

•(1) Bicarbonate — neutralizes gastric acid (HCl with chyme from the stomach)

•(2) Amylase — breaks down starch into monosaccharides.•(3) Lipase — breaks down triglycerides into free FAs, monoglycerides, diglycerides, and glycerol.

•(4) Proteolytic enzymes — includes trypsinogen and chymotrypsinogen. •Trypsinogen is turned into its active form trypsin by anteropeptidase enzyme in the duodenum. Chymotryspinogen is then turned into its active form chymotrypsin by trypsin!

•What happens when the bonds of trypsinogen are broken while its still in the pancreas? — e.g. if you get hit in the abdomen really hard and trypsinogen ends up turning into trypsin? Well, because the pancreas is un-encapsulated, that trypsin would just travel around and digest all sorts of proteins (in membranes, in our food, in other organs, etc)… not good.

•The endocrine pancreas is more famous — it releases hormones rather than enzymes and salts. Those hormones enter the blood stream and move all over the body.

•The endocrine pancreas is composed of many islet cells that sit in “islands.”•Three main types of islet cells (all are present to some extent in each island):

(1) α-islet cells: release glucagon [breaks down many macromolecules, e.g. glycogen —> glucose]

(2) ß-islet cells: release insulin [builds up / stores macromolecules, e.g. glucose ——> glycogen.

•It’s also the hormone responsible for diabetes, aka “eye nerve & kidney disease, which is caused by too much glucose in the body bc insulin isn’t working.

•Type I diabetes: no insulin•Type II diabetes: insulin receptors are broken

(3) ∂-islet cells: release somatostatin [stops the effect of other hormones in the GI tract]

COLON, RECTUM, AND ANUS •After food is absorbed in the small intestine, it travels to the large intestine (which is bigger in diameter, but actually much shorter).

•At the end of the small intestine / beginning of the large intestine is the ileocecal valve.

•The first main part of the large intestine is the cecum (with appendix “tail” hanging off). It then goes up through the ascending colon, then goes across through the transverse colon, and then down the descending colon. The last part of the large intestine is the sigmoid colon (has an S shape to it).

•The large intestine is most responsible for absorbing:

ORGAN SYSTEMS 98• Water

•If we absorb too little water, the output of our body would be a little watery. This is diarrhea.

•If we absorb too much water, we’ll get constipated.•The disease cholera attacks certain proteins / receptors in the intestinal lining that cause you to lose tremendous amounts of fluid and eventually lead to death by dehydration. If, however, you can keep a person very hydrated throughout the whole disease manifestation, they’ll end up passing the bacteria and be okay.

• Inorganic Ions — includes Na+, K+•Like other organs (the small intestine and, more notably, the kidney), Na+ and K+ are absorbed with transport mechanisms. The kidney is much more important for inorganic ion absorption than the large intestine, so even if you have to have a colonectomy, you’ll be okay.

•The large intestine is also home to lots of micro-organisms that assist in digestion of things like carbohydrates, making byproducts of methane (CH4) and dihydrogen sulfide (H2S)

•After the sigmoid colon is the rectum, whose main function is storage. It holds onto stool until it’s an appropriate time to go to the bathroom.

•The anus comes next, and is composed of two sphincters: • Internal anal sphincter is made of smooth muscle that is involuntary.• External anal sphincter is made of skeletal muscle; it’s under our control.•When it’s time to release stool, the internal anal sphincter will relax and the stool will move forward to push on our external anal sphincter, so we know it’s time to go. But we can wait until we get to a bathroom b/c the external sphincter is under own own control.

CONTROL OF THE GI TRACT •The GI tract has sort of its own brain! It’s called the enteric nervous system, because it can act on its own without having to send neuronal signals to the brain or spinal cord to regulate its action.

•ex: When we consume a meal, we initiate the gastrocolic reflex. The presence of food in your stomach is signal 1 — tells your colon it’s time to make way for food that’s coming down; so it pushes the food/stool that’s currently in there out.

•The GI tract is also under hormonal control. Important hormones include:• Gastrin: released from mucosal cells when we notice there’s food in the stomach. It’s initially released into bloodstream, then comes back into stomach to stimulate secretion of digestive juices.

•Gastrin causes secretion of HCl from the stomach’s parietal cells and pepsinogen from chief cells. Gastrin also increases stomach motility (churning power of the stomach to produce chyme).

•Gastrin is checked by low pH (~3) — this decreases gastrin release.•When chyme is delivered to the duodenum, it causes release of secretin hormone into the bloodstream.

•Secretin first goes to the pancreas and cause the release of bicarbonate rich solution (involves pancreatic enzymes and bicarbonate, which will neutralize the acid of chyme.

ORGAN SYSTEMS 99•Secretin also goes back to the stomach to inhibit stomach motility and acid / pepsinogen release (it counters gastrin)

•Because of the acidic chyme, we also see the release of cholosystokinin (CCK) from our intestinal mucousa into our bloodstream where it travels to:

(1) The pancreas, to stimulate release of pancreatic enzymes, such as lipase.

(2) The gall bladder, to cause it to contract, sending bile back into the cystic duct and down and out of the common bile duct into the duodenum. There it helps emulsify fat

(3) Cholosystokinin also goes into the stomach and decreases stomach motility to slow the release of chyme.•Note: It’s not just chyme as a whole that requires CCK to be released, it’s the fat in our chyme that specifically causes the release of CCK.

•Similarly, it’s not a macromolecule that causes secretin to be released, but the HCl that comes in along with chyme.

•The pancreas also is a big player of hormones, causes glycogen build up and break down.

————————————————Muscular System——————————————————

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MYOSIN AND ACTIN •Myosins comprise a family of ATP-dependent motor proteins. They’re known for their role in muscle contraction and their involvement in a wide range of other motility processes.

• Myosin 2 (has two heads) is an ATPase involved in actin-based motility (muscle contraction)

•Contraction of muscle:. (1) Myosin is bound to the actin filament. ATP then binds to myosin “head” & myosin releases actin.(2) ATP hydrolyzes (—> ADP + Pi + energy). This “cocks” the myosin protein to high energy conformation (“loads the spring”)(3) Phosphate group is released from myosin, which releases the energy of the cocked position and causes it to push on the actin filament, it “releases the spring” as a power stroke that creates mechanical energy.(4) ADP released, and myosin is still bound to the actin… so we’re where we were in step 1, but one stroke further along the actin filament. Chemical energy (ATP) has turned into mechanical energy.•This action contracts the muscle cell, and through the synchronous process in many muscle cells, contracts the entire muscle.

ORGAN SYSTEMS 100TROPOMYOSIN AND TROPONIN AND THEIR ROLE IN REGULATING MUSCLE CONTRACTION: •When the myosin releases the actin after ATP binds, why wouldn’t the actin just go back to where it was before, because of the tension? How does myosin keep pulling it along when it’s not on the actin filament 100% of the time?

•You have many myosins working on one actin filament at once! So when one pair of heads is off the actin, others might be in the process of pulling it; they all work together.

•How do we stop this movement of myosin along actin when we don’t want to contract our muscle? — Tropomyosin and Troponin!

• Tropomyosin protein coils around the actin, and it’s attached by the protein complex troponin.

•When a muscle is contracting, tropomyosin keeps the myosin from crawling up the actin.

•Blocks the myosin from being able to attach to the actin in its usual place OR if myosin is already bound, tropomyosin keeps it from moving and walking up the actin.

•The only way to make the troponin unblock myosin is for the troponin to change its shape; this only happens with a high concentration of calcium ions in the cell.

•Ca2+ binds to troponin and changes its conformation enough that the tropomyosin is moved out of the way and myosin can bind and walk up the actin. [contraction]

•If Ca2+ concentration gets low, the troponin will go back to standard conformation and that makes the tropomyosin block the myosin again, so contraction does not happen. [relaxation]

SARCOPLASMIC RETICULUM: •How does the nervous system tell the cells to make its Ca2+ concentration high and contract muscle, or make the Ca2+ concentration low and relax muscle? The sarcoplasmic reticulum

•The membrane of the muscle cell is the sarcolemma, and in it is a fold called the T-tubule.

•Inside of the muscle cell is an organelle called the sarcoplasmic reticulum, whose function is purely storage. ATP-fueled channels on the SR pump in lot of Ca2+, so in a resting muscle, you have a very high concentration of Ca2+

concentration within the SR.•A protein complex connects the T-tubule to the sarcoplasmic reticulum.•When a muscle is contracting, the SR will release the Ca2+ into the cell (where actin/myosin/etc. are)

•How does the sarcoplasmic reticulum know when to release the Ca2+? Motor neuron synapse!

•A motor neuron synapses on the muscle cell. Recall that for a neuron to be synapsed, it sends an action potential down its axon. Na+ voltage gated channel open and depolarizes membrane in one place, which causes Na+ voltage gated channels to open up further along and depolarize the membrane there . . . etc. Eventually at the axon terminal, Ca2+ gates are opened and Ca2+ floods into the axon terminal body. The Ca2+ binds to vesicles that are holding neurotransmitters,

ORGAN SYSTEMS 101the vesicles bind to the membrane of the neuron, and neurotransmitters are released into the synaptic cleft.

•In motor neurons, the neurotransmitter released is acetylcholine.•Acetylcholine binds to receptors on the muscle cell, which opens gated channels that allow Na+ inside the muscle cell, which causes membrane depolarization and action potential in that cell!

•The action potential travels along the membrane as subsequent channels are opened, and eventually reaches the T-tubule.

• When the action potential gets far enough down the T-tubule, the protein complex triggers all the Ca2+ ions to be dumped from the sarcoplasmic reticulum into the cell.

•Of course, this Ca2+ in the cell then binds to troponin, which changes conformation to release tropomyosin, and myosin can start “walking” along the actin filament to contract the muscle cell.

•Once the signal goes away, the “door” releasing Ca2+ closes & SR gains back all Ca2+ in just 30 millisec!

ANATOMY OF A MUSCLE CELL: • Tendons on either side of the muscle anchor it to bone. The tendon is just a type of connective tissue, and it’s somewhat continuous with the connective tissue that forms the outer layer of the muscle, the epimysium. The epimysium protects the muscles.

•A second layer of connective tissue, called the perimysium, is right under this protective layer. The perimysium covers subunits of muscle, including the fascicle (aka fassiculus).

•Within each fasicle there’s another layer of connective tissue called the endomysium, which covers individual muscle cells (aka myofibers)

•The myofiber has bumps on the outside, which are where nuclei sit — on the periphery of the cell.

•The cytoplasm of the myofiber is called the sarcoplasm. (myo = muscle; sarco = flesh)

•Within the myofiber is a further division called a myofibril — this is where contraction actually occurs.

• If you look at a myofiber under the microscope, you’ll see striations (another name for skeletal muscle is “striated skeletal muscle”). These striations are the z-lines, or z-disks, and the space between two z-lines is called the sarcomere — it’s the most basic unit of muscle contraction.

•Actin filaments are anchored to the z-line, and myosin is attached to the actin. (Myosin is anchored in the sarcomere by the protein titin.

•The sarcomere has 2 different parts: A-bands & I-bands.•The part that’s myosin and actin is the A-band.•The part that is solely actin is the I-band.

•In contraction, it’s the actin filaments that move. So the Z-lines move closer together, towards the center of the sarcomere, and the I band is shortened but the A-band remains the same length.

ORGAN SYSTEMS 102THREE TYPES OF MUSCLE: •There are three types of muscle — smooth, skeletal, & cardiac — which are involved in basically all movement of the body.

• Skeletal muscle: most are attached to tendon and bone, but not all are (e.g. external oblique muscles are not attached to a tendon, or the “tendon” is just a sheet of fibrous tissue called aponeurosis).

•Skeletal muscles are voluntary, and are the fastest type of muscle•They’re also straight, and have many nuclei that show up as bumps (they’re on the periphery rather than in the middle) on the cell.

• Cardiac muscle is in the heart; this is only where you can find these special cells. — involuntary

•Cardiac muscles are branched (which makes them easy to spot), and have 1-2 nuclei, also in the middle of the cell.

• Smooth muscle: largely found in the walls of hollow organs (e.g. stomach, bowels, etc) & blood vessels

•Involuntary; slowest muscle•Often described as “spindle-shaped;” smooth muscle cells have just one nucleus in the middle

•Ex: Involuntary processes like vasodilation take a lot longer than than the active, voluntary process of using skeletal muscles to jump, e.g.

• Skeletal and cardiac muscle is striated; smooth muscle is not.A general rule of thumb is that smooth muscle is often found in hollow organs, like stomach and intestine. (esophagus etc) + helps dilate blood vessels. MOTOR NEURONS: •Upper motor neurons (in the brain) send a signal to lower motor neurons (in the PNS).

•UMNs tell the LMNs when to start and when to stop contracting. LMNs directly signal muscle cells.

•The soma is the body of the lower motor neuron. Dendrites of the LMN receive signals from the UMN; then the LMN then sends out the signal through the axon.

•If you have a lower motor neuron injury, your muscle(s) experience weakness because they can’t contract like they’re supposed to. If you have an upper motor neuron injury, you would also experience weakness in the muscle(s), but this time because your muscle never receives the signal to contract.

•The key thing we look for with UMN injury, though, is not a weakness due to muscles not receiving start signal; it’s a constant spasticity because the muscles don’t receive the stop signal.

•To make sure that signals aren’t dissipated and instead stay in the axon going down, some neurons are insulated with a fatty myelin sheath. Action potential jumps down those axons along nodes of Ranvier.

•In the CNS, myelin is produced by oligodendrocytes. In the PNS, it’s produced by Schwann cells.

NEUROMUSCULAR JUNCTION, MOTOR END-PLATE: •The neuromuscular junction is where motor neurons talk to muscle cells.

•Involves the axon terminal and the receiving muscle cell. In the receiving portion of the muscle cell there are many folds, which increase the surface area available for Na+ and Ca2+ channels.

ORGAN SYSTEMS 103•The axon terminal receives action potential in the opening of Na+ channels so sodium floods into the cell and depolarizes the membrane. At the same time (and only in the terminal), Ca2+ channels open so Ca2+ floods into the axon terminal body.

•The Ca2+ then binds to vesicles that are holding neurotransmitter, acetylcholine the vesicles bind to the membrane of the neuron, and lots of acetylcholine is released into the synaptic cleft.

• On the receiving muscle cell are nicotinic acetyl-choline receptors; when ACh binds, it opens the Na+ channels so Na+ floods the cell and depolarizes. After the cell is sufficiently depolarized, the sarcoplasmic reticulum is triggered to open it’s floodgate and send lots of Ca2+ into the cell.

•Note: In cardiac muscle, intracellular Ca2+ is a trigger for the release of even more calcium from the SR. This mechanism doesn’t occur in skeletal muscle, though.

•Gap junctions connect adjacent muscle cells, and allow for “synergy” between muscle fibers — when one muscle cell contracts, many groups of muscle cells are triggered to contract.

TYPE 1 AND TYPE 2 MUSCLE FIBERS: • Golden rule : mitochondria are more prevalent in type 1 muscle than type 2

• Color: Type 1 muscle fibers are red, because their increased mitochondria means they produce more energy from oxygen (in oxidative phosphorylation) than type 2 fibers, which are white.

• Contraction Speed: Because type 1 muscle fibers rely on mitochondria, they have a very involved energy making process (glycolysis, krebs, electron transport, etc.) & thus have slower contraction speed

• Conduction Velocity: This is also slow in type 1 (“slow twitch”), compared to type 2’s fast twitch.

• Activity: Type 1 fibers (bc mitochondria) undergo aerobic respiration. Type 2 use anaerobic respiration.

• Duration of contraction: Type 1 fibers, bc they can make a lot of ATP, will have a long duration contraction. Type 2 can’t make as much ATP, so they have shorter duration contractions.

•Long duration contractions are used in places like your back or thigh muscles, which are used to stand for long periods of time and to walk at an even pace.

•Short duration fibers are found in places like the arms, so you can quickly shake someone’s hand; or in the fingers used to flick something — if you do those things all day long you’ll get very tired!

• Fatigue: Because type 1 muscle fibers have a lot of energy, they are resistant to fatigue. In contrast, type 2 muscle fibers don’t have as much mitochondria or energy so they are easily fatigued.

• Power: Type 2 fibers generate more instantaneous force than type 1 fibers. Type 1 fibers have more energy overall, though, and more fibers contracting for longer durations, so type 1 is more powerful.

• Storage: Both fast twitch (type 2) and slow twitch (type 1) use ATP to contract, but they use different mechanisms to produce it. ATP is a very reactive molecule — if we have it we expect it to be used right away… So type 2 muscle

ORGAN SYSTEMS 104fibers, with their faster contractions, use ATP as the main energy storage, in addition to creatine phosphate. In type 1 muscle fibers, triglycerides are the main energy storage.

CALCIUM PUTS MYOSIN TO WORK: •Let’s zoom into the heart wall. You see cardiac cells, with branches and 1-2 nuclei. Inside that heart cell, there are many proteins, most notably actin fibers and - in the middle of that actin - myosin.

•The z-lines (or z-disks) are pulled towards each other when muscle cell contracts.

•Binding sites for myosin are cover up with tropomyosin, bound to the actin fiber by troponin (which is really a protein complex, with subunits C, I, and T).

•When troponin-C binds Ca2+, it moves the whole complex out of the way and myosin can then bind to the actin.

•TL;DR — myosin likes when Ca2+ is around because then it can do work•How do we increase inotropy, i.e. increase muscle contraction

•(1) Increase Ca2+ in the cell•(2) Get troponin-C to be more sensitive, and bind Ca2+ more easily

MUSCLE INNERVATION: •Voluntary contractions are those of the skeletal muscle.

•These are controlled by me, so I use the cerebral cortex or the spinal cord.•Involuntary contractions include those of cardiac and smooth muscles. We don’t need to think about when to beat our heart, or when to vasoconstrict our capillaries in our hand when it’s cold.

•These are beyond me, so I use the brainstem or ganglia beside the spinal cord.

•The brainstem is responsible for involuntary contractions through sympathetic or parasympathetic mechanisms. The sympathetic ganglia (i.e. cell body/soma of neurons) that sit outside the brain and spinal cord) are also involved in involuntary contractions.

AUTONOMIC VS. SOMATIC, DIVISIONS OF THE PERIPHERAL NERVOUS SYSTEM: •The autonomic system is under involuntary control; the somatic is under voluntary control

•Somatic nervous systems use acetylcholine as neurotransmitters.

Type 1 Type 2

color red white

contraction speed slow fastconduction velocity slow twitch fast twitchactivity aerobic respiration anaerobic respirationduration long shortfatigue resistant to fatigue easily fatiguedpower strong power less powerstorage triglycerides ATP and creatine

ORGAN SYSTEMS 105•There are two subdivisions to the autonomic nervous system: sympathetic and parasympathetic.

• Sympathetic = “fight or flight” response•The pre-ganglionic nerves of the SNS use acetylcholine still, but the post-ganglionic nerves use epinephrine (aka adrenaline) as an endocrine hormone, with norepinephrine as neurotransmitters

• Parasympathetic = “rest and digest” response•Also uses acetylcholine.

THERMOREGULATION: •When the skin perceives that it’s hot outside (or wherever you are), it will send a neuronal signal to the hypothalamus in the brain.

•The anterior (front) part of the hypothalamus responds to hot temperatures.•The posterior (back) part of the hypothalamus responds to cold temperatures.

•The brain then sends a signal back to smooth muscles (which line our blood vessels) and skeletal muscles (particularly in our core) as needed to help us maintain our core body temperature.

•In a hot environment, smooth muscle relaxes and vasodilates the arterioles. This allows the blood flow to the skin to increase which allows us to dissapate heat.

•In a cold environment, smooth muscle will contract and vasoconstrict the arterioles. This shrinks the heat filled blood vessels away from the skin so less heat is lost.

•Our skeletal muscles (particularly those in the core) shiver when we’re cold. This is because when skeletal muscle contracts, ATP —> ADP + energy.. so our body shivers to increase this exothermic reaction and release energy into the cells as heat.

————————————————Skeletal System——————————————————

SKELETAL STRUCTURE AND FUNCTION: •Arthropods have exoskeletons. Humans, and all vertebrates, have endoskeletons!

•Our skeleton provides a variety of functions:•Supports / structures the body, and provides a framework for movement•Protects vital organs•Performs a variety of physiological functions (most notably, storage of Ca2+ and hematopoiesis, or the production of cellular components of our blood — RBCs, WBCs, and platelets).

•The axial skeletal is our skull, ribcage, and vertebral column — down the midline of our body.

•The appendicular skeleton is everything else — limbs, hip / pelvic area, metatarsals, etc.

Another classification of our skeletal system is between flat bones and long bones.• Flat bones = skull, rubs, and bones in the pelvis

•Made of an inner spongey / cancellous bone, and an outer shell of compact bone

•Protect organs and serve as site of hematopoiesis.

ORGAN SYSTEMS 106• Long Bones = humerus, femur

• The long middle portion of long bones is the diaphysis; the ends are called epiphysis.

• In between the diaphysis and epiphysis (or where they connect) is the metaphysis, which is where the growth plate is found.

•Long bones are also made of same inner spongey bone, and an outer shell of compact bone

• These provide the framework for movement, and also serve as a site of hematopoiesis.

•There are two types of bone marrow: red and yellow.• Red bone marrow serves as site of hematopoiesis. (red = blood) — found in flat bones and in the epiphysis of long bones

• Yellow bone marrow is the site of fat storage — found in diaphyses of long bones.

MICROSCOPIC STRUCTURE OF BONE — THE HAVERSIAN SYSTEM: •The innermost part of a bone is made of spongey bone, which is filled with cavities called trabeculae.

•Surface area of spongey bone is 10x that of outer compact bone. Its purpose is to make bone light.

•Compact bone has fewer gaps and spaces than spongey bone, but what really makes it different is that it has a specific type of organization made of osteon functional units (aka the Haversian system).

•Each osteon looks sort of like a cylinder, and it has multiple concentric layers of bone (sheets) that wrap around to form the osteon. Each of these layers is called a lamellae.

•In the center of the lamellae layers is the Haversian canal, or central canal. Blood and lymph vessels, as well as nerves, travel through this canal.

•In between the sheets of lamellae are tiny channels called canaliculli. They branch out from the central canal to empty spaces called lacunae. Each lacunae is just an empty space for osteocytes, or bone cells.

•The osteocytes have long cellular processes that branch through the canalliculi to contact other osteocytes via gap junctions, which allow the cells to communicate and exchange nutrients / signals.

• Volkmann’s canals run perpendicular to the Haversian canals, and they connect osteons to one another. They also carry their own set of small blood vessels.

•The outermost superficial layer of bone is called the periosteum.

CELLULAR STRUCTURE OF BONE: •Bone is mostly made up of the bone matrix, and then the cells that help to form this bony matrix.

•The bone matrix consists of two principal building blocks:• Osteoid forms the organic portion of the matrix

ORGAN SYSTEMS 107• Hydroxyapatite forms the inorganic portion of the matrix

•Osteoid consists of a soft but highly ordered structure of proteins and type 1 collagen fibers. Together, this gives bone its tensile strength.

•Tensile strength refers to how much an object can be stretched before breaking. This is different from compressive strength, which is how much the object can be compressed before breaking.

• Hydroxyapatite is made of calcium phosphate crystals. These make up the mineral content of bones, and give them their rigid strength and density.

•There are four different types of cells we should know in bone:•(1) Osteoprogenitor

•These cells are basically an immature version, or the precursor to, osteoblasts. They differentiate into osteoblasts under certain growth factors

•(2) Osteoblasts•These are responsible for synthesizing collagen and proteins (specifically, osteocalcin and osteopontin, which together make up osteoid, the organic part of bone matrix).

•Osteoblasts also synthesize alkalaine phosphatase, which is responsible for forming hydroxyapatite.

•Once osteoblasts have synthesized enough collagen, proteins, and alkaline phosphatase to form the organic and inorganic portions of the bony matrix around them, they mature into the osteocyte.

•(3) Osteocytes •The spaces osteocytes occupy are called lacunae (“lakes” of empty space in bone)

•They have little branched projections that reach out to communicate with other osteocytes or osteoblasts, which give them a star-like appearance.

•(4) Oxteoclasts•Derived from monocytes•These are responsible for bone resorption; they break bone back down (using an enzyme called tartrate resistant acid phosphotase).

•Bone is constantly being remodeled — it’s built up with osteoblasts (using alkaline phosphatase), and broken down by osteoclasts (using tartrate resistant phosphotase).

•As osteoclasts are resorbing bone, they start to form empty spaces. Recall, empty spaces are lacunae; osteoclasts form a special type of lacunae called Howship’s lacunae.

SKELETAL ENDOCRINE CONTROL: •One of the main functions that bone performs is storage of calcium.•Calcium homeostasis (the flow of calcium between the bloodstream and bone) is under endocrine hormone control. These hormones alter the ratio of osteoclast activity to osteoblast activity.

•As osteoclast activity increases (more bone resorption / break down) relative to osteoblast activity, there’s an increase in the liberation of calcium and phosphate into the bloodstream from bone.

•The opposite happens with an increase in osteoblast activity - Ca2+ & PO43– levels in blood decrease.

ORGAN SYSTEMS 108•Main hormones responsible for maintaining calcium homeostasis are: parathyroid (PTH), calcitonin, and calcitriol (which is basically the active form of vitamin D).

•These hormones help to regulate the amount of calcium absorbed from the gut or reabsorbed from the kidneys. They also help regulate osteoblast / osteoclast activity in bone.

• Calcitonin decreases the amount of calcium and phosphate in the blood. (calcitonin tones down blood)

• Parathyroid hormone (PTH) and calcitrol both increase calcium in the blood; but PTH decreases phosphate levels, while calcitrol increases them.

•General themes of calcium homeostasis:(1) Each time calcium increases in the blood, you have a concurrent increase in phosphate. Same thing if Ca2+ decreases, phosphate will decrease.(2) If calcium + phosphate increases in the blood, it decreases in bone; and vice versa.

•Why does the concentration of free Ca2+ in the blood matter so much? Why the elaborate system?

•Too much free Ca2+ ions in the blood leads to hyper-excitable cell membranes. Can cause lethargy, fatigue, and memory loss.

•Too little calcium in the blood leads to muscle cramps and convulsions.

CARTILAGE: • Cartilage is, at the most basic level, an extracellular connective tissue found throughout the body. It’s created by cells called chondrocytes, which derive from the same precursor cells as bone (fibroblasts).

•Chondrocytes secrete collagen (fibrous protein) and elastin (elastic protein)•These two proteins give cartilage strength and flexibility.

•Cartilage is not innervated (no nerve cells) and it’s avascular (doesn’t have arteries, veins, or blood vessels). Instead, cartilage receives its nutrition and immune protection from the surrounding fluid.

•There are three main types of cartilage in the body: (1) Hyalin (articular) cartilage — found in the larynx, trachea, all the joints (where the surfaces of bones are articulating each other).

•Its main purpose is to reduce friction and absorb shock. (2) Elastic cartilage — found in the shape of the outer ear and in the epiglottis (which protects your airway when you’re swallowing food.)

•Its main purpose is to provide shape and support

PTH increase Calcitonin increase Calcitriol increase

osteoblast activity decreases increases decreases

osteoclast activity increases decreases increases

intestinal / renal Ca2+ absorption

increases decreases increases

ORGAN SYSTEMS 109 (3) Fibrous cartilage — found in the intervertebral discs of the spine, and where the two halves of your pelvic bone come together to form a joint (pubic symphysis)

• Main purpose is to provide rigidity and absorb the shock transmitted between these joints.

LIGAMENTS, TENDONS, AND JOINTS: •Ligaments and tendons are types of extra strong and dense connective tissue

•Ligaments connect bone to bone; tendons connect muscle to bone.•A joint is the point where one bone meets up with another — there are different joint types in the body:

• Synarthroses joints — immovable; where two bones are fused together (ex: in the skull)

• Antiarthroses joints — both stiff, but slightly moveable (ex: vertebral joints)

• Synovial joints (aka diarthroses) — includes ball and sockets joints (ex: shoulders and hips) which have many degrees of motion, and hinge joints (ex: elbow or knee) which have one plane of movement.

•These are lubricated by synovial fluid, contained within synovial capsule that surrounds the joint.

•The surfaces of bones that meet up in a joint are lined by a special kind of smooth cartilage: articular (aka hyalin) cartilage. Like all cartilage, it’s avascular and not innervated — so it has a hard time getting the nutrients it needs to heal and recover if it were to become damaged by overuse or infection.

•Overuse of joints over time can lead to inflammation, which causes arthritis. (This can cause permanent destruction of articular cartilage, which leads to the pain and stiffness).

•Ossification is the process in which cartilage is transformed into bone. Bone grows in three stages: first, tissue forms a mesh of collagen fibers, then the body creates a polysaccharide that acts like cement to hold the tissues together. Finally, calcium crystals salts are deposited to form bone.

———————————————Integumentary System—————————————————

SKIN OVERVIEW The integumentary system comprises the skin and appendages. The

appendages include nails, hair, and sweat glands. The skin is the largest organ of your body, weighing approximately 21

pounds. The skin has several functions: it serves as an impermeable surface to the

outside, serves as a structural barrier, serves as an immunological barrier against pathogens such as viruses, can perceive stimuli from the environment via receptors, conducts sensation, and cools the body via sweating (thermoregulation) by evaporative cooling

WHAT IS SKIN? (Epidermis)

ORGAN SYSTEMS 110 There are three distinct layers to the skin. In order from outermost to

innermost, the order is: epidermis, dermis, and hypodermis (subcutaneous tissue).

The epidermis is composed of five strata (latyers). The stratum basale is the most inferior strata of the epidermis and is composed of keratinocytes, which secrete cytokeratin, giving skin its toughness to protect skin. The stratum basale also is known for rapid cell division, and where we get our skin color. The cells that give skin color are called melanocytes. The melanocytes secrete melanin, which causes skin color.

The amount of melanin determines the darkness of skin. The layer on top of the stratum basale is called the stratum spinosum, or

the spiny layer. It is composed of desmosomes, which permit water loss. This layer also includes Langerhans cells, which are part of the immune system.

Above the stratum spinosum is called the stratum granulosum. This is composed of granules called keratohyalin granules. These granules hold proteins which help handle keratin. They move cytokeratin around the cells. These cells also release lamellar bodies, which secrete lipids that give skin its water-tight capability.

The layer above is the stratum lucidum, or the clear layer. This layer is composed of dead keratinocytes, which are clear. These cells have lost their nuclei and organelles.

The outermost layer is the stratum corneum, composed of stacked layers of dead keratinocytes. 15-20 layers of these cells which randomly and continuously slough off.

WHAT LIES BENEATH THE EPIDERMIS (Dermis and Hypodermis) The dermis is composed of two strata and sits below the epidermis. The

bottomost layer of the epidermis is the stratum basale. Immediately underneath that is the first layer of the dermis, or the papillary dermis. Underneath that is the bottomost layer of the dermis is the reticular dermis.

While the epidermis is composed of epithelial tissue, the dermis and hypodermis is composed of connective tissue. Connective tissue contains

ORGAN SYSTEMS 111proteins like actin, collagen, and structural proteins. Its primary purpose is to hold things together.

In the papillary dermis, there is thin, loose connective tissue. In the reticular dermis, there is thicker and denser connective tissue to anchor things down.

The thin connective tissue of the papillary dermis allows for movement of structures like blood vessels and diffusion of oxygen. This layer must be flexible to allow for this.

The papillary dermis also contains nerve endings. The reticular dermis contains thick dense tissue for anchoring structures

down. This layer also anchors glands, which extend outward toward the epidermis, and also anchors follicles form which hairs protrude. The hair follicle is anchored within the reticular dermis.

The reticular dermis also contains an arrector pili muscle, which allows for hair to stand on end when you are cold.

The hypodermis is the bottommost layer of skin. It is also known as subcutaneous fat. This layer is composed of many layers of fat. Fat is used to absorb shock and insulates tissue.

WHERE DO OUR HAIR AND NAILS COME FROM? Nails and hair are part of our appendages, the second component of the

integument. The nail root is attached to the epidermis. Cells emerge from the stratum basale and other layers of the epidermis and extend to form the nail.

The nail is therefore considered a part of the epidermis. It is made up of keratin packed into dead cells. This is what keeps the nail strong. The fingernails grow 4x faster than the toenails.

The hair is another appendage. Hair grows from the dermis, the middle layer between the epidermis and the hypodermis. The dermis has two layers (papillary and reticular layer).

The follicle originates in the reticular dermis, and the shaft of the hair emerges outwards through the other layers.

ORGAN SYSTEMS 112 The hair also is composed of keratin. There is a band of muscle in the

papillary dermis called the arrector pili muscle, a smooth muscle which causes hair to stand on end when it contracts. This is what causes goosebumps as well.

Hair standing on end creates a bed of warm, insulating air to protect polar bears from the cold. In humans, the hair is not long enough so this phenomenon does not occur, so the hair can be considered a vestigial structure.

WHAT’S IN SWEAT? (HOLOCRINE, APOCRINE, MEROCRINE GLANDS) There are three kinds of glands in the reticular dermis. Ducts lead out from

the reticular dermis to aid in secretions. There are three kinds of glands in the reticular dermis: the holocrine gland,

apocrine gland, and merocrine gland. The holocrine gland disintegrates an entire cell to release sebum. These

glands are also known as sebaceous gland. Apocrine glands release secretions form the apex (top) of the cell. These

glands release proteins, lipids, and steroids. The merocrine glands release watery sweat via exocytosis. Holocrine glands are found on the face, chest on the back. Apocrine glands

are concentrated in the armpits, groin, and around the nipples. Apocrine sweat glands release secretions right into the hair follicle, in

contrast to the other glands. Merocrine glands are concentrated in the palms and soles. Sebum from the holocrine gland is used to lubricate the skin and to slow

bacterial growth. Apocrine glands do not start to release secretions until puberty starts. These

glands are implicated in emotional sweating. Merocrine glands are considered the most important, as they hope to cool

down during evaporative cooling, and allow the disposal of salts and nitrogenous wastes. Lysozyme and antibodies are also released by the merocrine glands.

WHY DOES SWEATING COOL YOU DOWN?

ORGAN SYSTEMS 113 Sweat is mostly composed of water. A rephrasing of the titular question is: why does water

sitting on the surface of the skin cool us down? When the body temperature rises, the temperature of our epidermis also rises. This epidermis is

in contact with water, therefore heat is transferred from the skin to the water molecules of sweat sitting on the skin.

When the water of the sweat has enough energy, it evaporates. This cools down the entire system of water and skin, as only the highest energy molecules of water are those that evaporate. Therefore, the departure of high energy water molecules decreases the total kinetic energy of the system, and therefore the temperature.

OVERVIEW OF SENSATION AND MEISSNER’S CORPUSCLE Our skin helps us perceive the environment and plays a role in sensation. Mechanoreceptors

and other receptors generate signals in respond to stimuli to help us perceive the environment. This sensation takes place via afferent nerve fibers which take a stimulus and create a signal for processing in our CNS. Efferent nerve fibers are used to communicate from the CNS to muscle fibers.

A-delta fibers are afferent fibers which perceive pain and temperature. A-beta fibers perceive everything, and include mechanoreceptors.

The structure of the mechanoreceptor determine the function, and the function will help us determine the location of the receptor.

The Meissner’s corpuscle is a type of mechanoreceptor, located in the papillary dermis for perception of external stimuli. In the corpuscle are layers of disks composed of many nuclei. These disks are known as epithelial or laminar disks. When a force perturbs a disk, the disks are nudged past each other. Sodium ions then enter an afferent fiber, causing an action potential and sensation.

Meissner’s corpuscle is used to perceive light touch in glaborous skin, or non-hairy skin. For example, this mechanoreceptor would perceive the feeling of putting on a smooth cotton T-shirt.

In Messiner’s corpuscle, a constantly changing stimulus is needed to perceive the stimulus. Therefore, after the cotton T-shirt is on our skin and no longer moving, it will not be felt and Meissner’s corpuscle will not be activated.

PACNIAN’S CORPUSCLE AND MERKEL’S DISK Pacnian’s corpuscle is another mechanoreceptor. It is also known as the onion-layered

corpuscle or the lamellar corpuscular. When a significant force touches one of the lamella, or one of the concentric rings of the

corpuscle, an action potential in an efferent nerve cell is activated. This type of corpuscle responds to a deep touch in hairy and non-hairy skin. For example, a poke

or push would activate this corpuscle. This type of mechanoreceptor also requires a constantly changing stimulus. It is located in the

hypodermis.

ORGAN SYSTEMS 114

Merkel’s disk is a single disk. It is a specialized keratinocyte which holds many vesicles. These vesicles hold many neuropeptides, and the disk is attached to a receptor.

When the disk is stimulated, the peptides are released and stimulate a receptor, causing sodium to enter the disk.

This stimulates an afferent neuron. It is located in the stratum basale or the papillary dermis. It responds to light touch that is sustained. The stimulus does not need to change for us to notice

it.RUFFINI’S ENDING AND HAIR FOLLICLE RECEPTOR

Ruffini’s ending is another corpuscle. It is called Ruffini’s ending or Ruffini’s corpuscle. This mechanoreceptor has no disks or rings, but rather a afferent nerve fiber. It is a A-beta fiber which branches into the corpuscle.

There are many afferent branch receptors in the corpuscle, as well as collagen, a structural fiber. When the skin is stretched, a force is generated which hits the Ruffini corpuscle. This causes the collagen to be perturbed. Because this collagen shifts, ion channels within the A-beta fiber opens causing an action potential to be generated.

This type of mechanoreceptor responds to sustained touch and is located deep within the skin in the dermis, specifically the reticular dermis.

The last mechanoreceptor discussed is the hair follicle receptor. When a stimulus touches a hair, there is a nerve fiber that surrounds the follicle.

The impetus for this action potential is due to the deflection of the hair (a light touch on hairy skin). This type of receptor is located in the reticular dermis. A constantly changing stimulus is needed, else collagen will fill in the receptor.

PAIN AND TEMPERATURE The perception of pain is called nociception while the perception of heat is called

thermoception. We sense pain and temperature using a specialized receptor. To sense temperature, we rely on the TrpV1 receptor, which is also sensitive to pain. TrpV1 is a

receptor located in the cell membrane. When there is a change in temperature, a conformational change occurs in this protein.

When heat or pain are applied, this conformational change occurs. Each cell with TrpV1 receptor has nerve fibers which send signals to the brain.

Pain, such as poking, causes cells to break up and release molecules, which bind to TrpV1 receptors, causing the same conformational change a change in temperature causes, sending a signal to the brain.

There are three types of nerve fibers: fast, medium, and slow. Fast nerve fibers are fat and contain a lot of myelin, allowing the signal to travel quickly. The large diameter of the nerve fiber also causes less resistance. These types of fibers are also known as A-beta fibers.

Medium nerve fibers are smaller in diameter and have less myelin, causing a slower signal. These are known as A-delta fibers.

Slow nerve fibers are very small in diameter and are unmyelinated. Signals through these fibers are sent to the brain slowly. They are also known as c fibers.

ORGAN SYSTEMS 115 When we touch a stove, all fibers would act. A-beta fibers will act fast causing us to recoil our

hand, A-delta fibers will carry the sensation of pain, and c-fibers will cause a lingering sense of pain hours after we have touched the stove.

Similarly, when we eat spicy foods containing capsaicin, the capsaicin binds to nerve fibers, causing the signaling pathway as a change in temperature.

THERMOREGULATION BY MUSCLES We shiver and use our muscles to maintain our body temperature, a process called

thermoregulation. When we perceive it is hot, our brain senses it is hot in the hypothalamus. The hypothalamus is split into the anterior and posterior hypothalamus, each of which

responding to different temperature. When it is hot, we use the front (anterior) hypothalamus (mnemonic – think Front=Fire). If it is

cold, we use the posterior part of our hypothalamus. Smooth muscle lines our arterioles, while skeletal muscle works on our biceps, etc. When blood cells move around in arterioles, they carry energy. When it is hot, we aim to

dissipate this energy/heat. Vasodilation therefore occurs when it is hot to dilate the arterioles of the skin. This allows more blood flow to flow near the skin, allowing us to cool off by diverting blood flow to our skin.

Skeletal muscles do nothing when it is hot. Vasoconstriction occurs when it is cold, causing arterioles near the skin to become narrower to

retain more heat carried by the blood. Skeletal muscle contract when it is cold and take ATP to make ADP and energy. This is an exothermic reaction, which can be used to heat up in cold environments (shivering).

Reproductive System:

A secondary spermatocyte is formed after completion of meiosis I; it has 46 chromatids and 23 chromosomes.

Reproductive System: Ejaculatory duct is not one of the first structure to conduct sperm during ejaculationVas Deferens is not one of the first structure to conduct sperm during ejaculationAmpulla of vas deferens is the expansion of the vas deferens closer to ejaculatory duct.Epididymis, vas deferens, ampulla of vas deferens, ejaculatory duct, urethra is the correct order.Prostatic cancer may lead to inhibition of secretions of prostate that are essential for sperm activationBulbourethral glands produce pre ejaculatory fluid that aids in lubrication, thus its obstruction does not interfer with sperm production, maturation or activation (acronym: think of an imaginary BULBO lubricant brand)During spermiogenesis, maturation of the sperm, unnecessary cytoplasm is shed off.The pliable tissues are not responsible for secretion of seminal fluidCorpus spongiosum remains pliable during an erection.During an erection the corpus spongiosum remains pliable, corpora cavernosa becomes firm, and the pliable tissues maintain the urethra open.Clitoris is very distant from cervixFimbriae is connected with ovaries, thus distant from cervixFornix is immediately adjacent to cervical canal, thus likely to be infected.

ORGAN SYSTEMS 116

Oxytocin is responsible for labor contractions and kept at low levels during pregnancyLevels of estrogen are kept high during pregnancyProgesterone secretion has to be kept high during pregnancy. Progesterone is initially secreted by corpus luteum, so early degeneration of corpus luteum may lead to misscarriage.

The ovaries hold the corpus luteum that secrete estrogen earlier in the pregnancy and the placenta is responsible for estrogen production later in the pregnancyLow estrogen/progesterone = menses

Estrogen levels peak twice during the uterine cycle, and changes do not consistently correlate with changes in the endometrium.Luteinizing hormone levels peak prior to thickening of the endometrium.Follicle-stimulating hormone levels peak prior to thickening of the endometrium.Progesterone is a progestational hormone whose peak is correlated with thickening of the endometrium.

Estrogen levels must rise before ovulationFollicle stimulating hormone levels must rise before ovulationLuteinizing hormone levels must rise before ovulation.Progesterone levels rise after ovulation already occurred.

Order of Sperm Leaving:  straight tubules, rete testis, efferent ductules, epididymis ductus, vas deferens, ejaculatory duct, prostatic urethra, membranous urethra

Second polar body is haploidHint #2Secondary oocyte is halpoidHint #3Spermatid is haploidHint #4Primary spermatocyte, primary oocyte, and zygote are examples of diploid cells

Sertoli cells' tight junction create the blood testis barrier prevent antibodies from binding to spermCredits: reddit.com/u/magstarr

Other: Stratified layers of epithelial cells line tissues and glands that require layers of protection.Simple, single layer epithelia allow for the passage of small particles.Simple cuboidal epithelial cells line secretory ducts.The lining of lymphatic vessels is composed of simple squamous epithelium.

ORGAN SYSTEMS 117

ORGAN SYSTEMS 118