NEUROPHYSIOLOGY (HPHY 305)

Rabiu AbduSSALAM Magaji, Ph.D.

E-mails: ramagaji@abu.edu.ng; rabiumagaji@yahoo.co.uk

AHMADU BELLO UNIVERSITY, ZARIA - NIGERIAFACULTY OF MEDICINE

DEPARTMENT OF HUMAN PHYSIOLOGY

Learning ObjectivesAt the end of this lecture, it is expected that the studentwould be able to:

List and describe the parts of the nervous system and theircomponents

List the various types of glia and their functions.

Name the parts of a neuron and their functions.

Describe the role of myelin in nerve conduction.

List the types of nerve fibers found in the mammaliannervous system.

Need for Review Excitable Tissues

Nerves (Structures and functions)

Muscles (Structures and functions)

Organization of the Nervous System in general

Organization of the Central Nervous System (CNS)specifically

Anatomy of the different parts of the brain

Organization of the Nervous System - Origin

In the developing embryo, the Nervous system (NS) developsfrom ectoderm, that forms the neural plate.

The neural plate differentiates into neural tube and a neuralcrest.

The neural tube then differentiates into the Central NervousSystem (CNS), which consists of the Brain and the Spinalcord.

The neural crest gives rise to most of the Peripheral NervousSystem (PNS), which consists of 12 pairs of cranial nervesand 31 pairs of spinal nerves.

The Central Nervous System

The brain develops at the cranial end of the embryonic neural tube.

By the end of the first month of development, three (3) Primaryvesicles are formed: Forebrain (Prosencephalon), the Midbrain(Mesencephalon), and the Hindbrain (Rhombencephalon).

A week later, the forebrain gives rise to the Telencephalon and theDiencephalon, and the hindbrain gives rise to the Metencephalonand the Myelencephalon resulting in a total of five (5) secondaryvesicles.

In adults:

Telencephalon develops intoCerebral hemispheres.

Diencephalon gives rise tothe Thalamus and theHypothalamus and otherstructures.

Mesencephalon becomesthe Midbrain.

Metencephalon gives rise tothe Pons and theCerebellum.

Mylencephalon becomesMedulla oblongata. Themedulla oblongata, pons andthe midbrain form the adultBrain stem.

Subdivisions of the Central Nervous System

The central nervous system (defined as the brain and spinalcord) is usually considered to have seven basic parts:

spinal cord,

medulla,

pons,

cerebellum,

midbrain,

diencephalon, and

cerebral hemispheres

Running through all of these subdivisions are fluid-filledspaces called ventricles

These ventricles are the remnants of the continuous lumeninitially enclosed by the neural plate as it rounded to becomethe neural tube during early development.

Variations in the shape and size of the mature ventricularspace are characteristic of each adult brain region.

The brainstem surrounds the 4th ventricle (medullaand pons) and cerebral aqueduct (midbrain).

The forebrain encloses the 3rd and lateral ventricles.

The diencephalon and cerebral hemispheres(telencephalon) are collectively called the forebrain, andthey enclose the 3rd and lateral ventricles, respectively.

Within the brainstem are the cranial nerve nuclei thateither receive input from the cranial sensory ganglia via thecranial sensory nerves, or give rise to axons that constitutethe cranial motor nerves.

OVERVIEW OF NEUROPHYSIOLOGYThe nervous system can be divided into two parts:

the central nervous system (CNS), which is composed ofthe brain and spinal cord, and

the peripheral nervous system, which is composed ofnerves that connect the CNS to muscles, glands, and senseorgans.

Neurons are the basic building blocks of the nervoussystem. The human brain contains about 100 billion neurons.

It also contains 10–50 times this number of glial cells orglia.

Organization of the Nervous System

Structure and location of the three functional classes of neurons. *Efferent autonomic nerve pathways consist of a two-neuron chain between the CNS and the effector organ.

The CNS is a complex organ; it has been calculated that40% of the human genes participate, at least to a degree, inits formation.

Glia Cells

The word glia is Greek for glue; for many years, glia werethought to function merely as connective tissue.

However, these cells are now recognized for their role incommunication within the CNS in partnership with neurons.

Unlike neurons, glial cells continue to undergo cell divisionin adulthood and their ability to proliferate is particularlynoticeable after brain injury.

There are two major types of glia, microglia andmacroglia.

Microglia arise from macrophages outside of the CNS and arephysiologically and embryologically unrelated to other neural celltypes.

Microglia are scavenger cells that resemble tissue macrophagesand remove debris resulting from injury, infection, and disease.

There are three types of macroglia: oligodendrocytes, Schwanncells, and astrocytes.

Oligodendrocytes and Schwann cells are involved in myelinformation around axons in the CNS and peripheral nervous system,respectively.

Astrocytes, which are found throughout the brain, are of twosubtypes:

Fibrous astrocytes, which contain many intermediatefilaments are found primarily in white matter; and the

Protoplasmic astrocytes are found in gray matter and havea granular cytoplasm.

• Both types of astrocytes send processes to blood vessels,where they induce capillaries to form the tight junctionsmaking up the blood–brain barrier.

• The blood–brain barrier prevents the diffusion of large orhydrophilic molecules (e.g., proteins) into the cerebrospinalfluid and brain, while allowing diffusion of small molecules.

The astrocytes also send processes that envelop synapsesand the surface of nerve cells.

Principal types of glial cells in the nervous system (Adapted from Medical Physiology: a Systems Approach byHershel and Michael. McGraw-Hill Company, 2011).

Functions of the NeurogliaAstrocytes Physically support neurons in proper spatial relationships Serve as a scaffold during fetal brain development Induce formation of blood–brain barrier Help transfer nutrients to neurons Form neural scar tissue Take up and degrade released neurotransmitters Take up excess K to help maintain proper brain-ECF ion

concentration and normal neural excitability Enhance synapse formation and strengthen synaptic

transmission via chemical signaling with neurons Communicate by chemical means with neurons and among

themselves

Oligodendrocytes Form myelin sheaths in CNS

Microglia Play a role in defense of brain as phagocytic scavengers Release nerve growth factor

Ependymal Cells Line internal cavities of brain and spinal cord Contribute to formation of cerebrospinal fl uid Serve as neural stem cells with the potential to form new

neurons and glial cells

Glial cells of the central nervous system. The glial cells include the astrocytes, oligodendrocytes, microglia, and ependymalcells

The peripheral nervous system transmits information from theCNS to the effector organs throughout the body.

It contains 12 pairs of cranial nerves and 31 pairs of spinalnerves.

The cranial nerves have rather well-defined sensory andmotor functions.

Spinal nerves are named on the basis of the vertebral levelfrom which the nerve exits (cervical, thoracic, lumbar,sacral, and coccygeal).

These nerves include motor and sensory fibers of muscles,skin, and glands throughout the body.

Food for Thought“A basic principle to remember when studyingthe brain is that one function, even anapparently simple one such as bending yourfinger, will involve multiple brain regions (aswell as the spinal cord). Conversely, onebrain region may be involved in severalfunctions at the same time. In other words,understanding the brain is not simple andstraightforward”.

THE SPINAL CORDThe spinal cord is the major pathway for information owing

back and forth between the brain and the skin, joints, andmuscles of the body.

In addition, the spinal cord contains neural networksresponsible for locomotion.

If the spinal cord is severed, there is loss of sensation fromthe skin and muscles as well as paralysis, loss of the ability tovoluntarily control muscles.

The spinal cord is divided into four regions (cervical,thoracic, lumbar, and sacral), named to correspond to theadjacent vertebrae.

Each spinal region is subdivided into segments, and eachsegment gives rise to a bilateral pair of spinal nerves.

Just before a spinal nerve joins the spinal cord, it divides intotwo branches called roots.

The dorsal root of each spinal nerve is specialized to carryincoming sensory information.

The dorsal root ganglia, swellings found on the dorsal rootsjust before they enter the cord, contain cell bodies of sensoryneurons.

The ventral root carries information from the CNS tomuscles and glands.

In cross section, the spinal cord has a butter y- or H-shapedcore of gray matter and a surrounding rim of white matter.

Sensory fibers from the dorsal roots synapse withinterneurons in the dorsal horns of the gray matter.

The dorsal horn cell bodies are organized into two distinctnuclei, one for somatic information and one for visceralinformation.

The ventral horns of the gray matter contain cell bodies ofmotor neurons that carry efferent signals to muscles andglands.

The ventral horns are organized into somatic motor andautonomic nuclei.

Efferent fibers leave the spinal cord via the ventral root.

The white matter of the spinal cord is the biological equivalentof fiber-optic cables that telephone companies use to carry ourcommunications systems.

White matter can be divided into a number of columnscomposed of tracts of axons that transfer information up anddown the cord.

Ascending tracts take sensory information to the brain. Theyoccupy the dorsal and external lateral portions of the spinal cord.

Descending tracts carry mostly efferent (motor) signals fromthe brain to the cord. They occupy the ventral and interior lateralportions of the white matter.

Propriospinal tracts (proprius, one’s own) are those thatremain within the cord.

The spinal cord can function as a self-contained integratingcenter for simple spinal re exes, with signals passing from asensory neuron through the gray matter to an efferent neuron.

In addition, spinal interneurons may route sensoryinformation to the brain through ascending tracts or bringcommands from the brain to motor neurons.

In many cases, the interneurons also modify information as itpasses through them.

Reflexes play a critical role in the coordination of movement.

Neural Growth and RegenerationThe elaborate networks of nerve-cell processes that

characterize the nervous system are remarkably similar in allhuman beings and depend upon the outgrowth of specificaxons to specific targets.

Development of the nervous system in the embryo beginswith a series of divisions of precursor cells that can developinto neurons or glia.

After the last cell division, each neuronal daughter celldifferentiates, migrates to its final location, and sends outprocesses that will become its axon and dendrites.

A specialized enlargement, called the growth cone, formsthe tip of each extending axon and is involved in finding thecorrect route and final target for the process.

As the axon grows, it is guided along the surfaces of othercells, most commonly glial cells.

Which particular route is followed depends largely onattracting, supporting, deflecting, or inhibiting influencesexerted by several types of molecules.

Some of these molecules, such as cell adhesionmolecules, reside on the membranes of the glia andembryonic neurons.

Others are soluble neurotropic factors (growth factors forneural tissue) in the extracellular fluid surrounding the growthcone or its distant target.

Once the target of the advancing growth cone is reached,synapses are formed.

The synapses are active, however, before their finalmaturation occurs, and this early activity, in part, determinestheir final use.

During these intricate early stages of neural development,which occur during all trimesters of pregnancy and into infancy,alcohol and other drugs, radiation, malnutrition, and virusescan exert effects that cause permanent damage to thedeveloping fetal nervous system.

A normal, although unexpected, aspect of development of thenervous system occurs after growth and projection of the axons.

Many of the newly formed neurons and synapses degenerate.

In fact, as many as 50 to 70 percent of neurons die byapoptosis in some regions of the developing nervous system!

Exactly why this seemingly wasteful process occurs isunknown although neuroscientists speculate that in this wayconnectivity in the nervous system is refined, or “fine tuned.”

Although the basic shape and location of existing neurons inthe mature central nervous system do not change, the creationand removal of synaptic contacts begun during fetal developmentcontinue, albeit at a slower pace, throughout life as part ofnormal growth, learning, and aging.

Division of neuron precursors is largely complete beforebirth, and after early infancy new neurons are formed at aslower pace to replace those that die.

Severed axons can repair themselves, however, andsignificant function regained, provided that the damage occursoutside the central nervous system and does not affect theneuron’s cell body.

After repairable injury, the axon segment now separatedfrom the cell body degenerates.

The proximal part of the axon (the stump still attached to thecell body) then gives rise to a growth cone, which grows out tothe effector organ so that in some cases function is restored.

In contrast, severed axons within the central nervous systemattempt sprouting, but no significant regeneration of the axonoccurs across the damaged site, and there are no well-documented reports of significant function return.

Either some basic difference of central nervous systemneurons or some property of their environment, such asinhibitory factors associated with nearby glia, prevents theirfunctional regeneration.

In humans, however, spinal injuries typically crush ratherthan cut the tissue, leaving the axons intact.

In this case, a primary problem is self-destruction (apoptosis)of the nearby oligodendroglia, because when these cells dieand their associated axons lose their myelin coat, the axonscannot transmit information effectively.

PROTECTION AND NOURISHMENT OF THE BRAINDue to the very delicate nature of the CNS tissue and the fact

that its damaged nerve cells cannot be replaced, makes itimperative that this fragile, irreplaceable tissue be wellprotected

Four (4) major features help protect the CNS from injury:

1. It is enclosed by hard, bony structures. The cranium (skull)encases the brain, and the vertebral column surrounds thespinal cord.

2. Three protective and nourishing membranes called themeninges,lie between the bony covering and the nervoustissue.

3. The brain “floats” in a special cushioning fluid known as thecerebrospinal fluid (CSF).

4. A highly selective blood–brain barrier limits access of bloodborne materials into the vulnerable brain tissue.

The role of the first of these protective devices, the bonycovering, is self-evident while the latter three protectivemechanisms warrant further discussion.

Meninges

The three meningeal membranes wrap, protect, and nourishthe central nervous system.

From the outermost to the innermost layer they are the duramater, the arachnoid mater, and the pia mater (Mater means“mother,” indicative of these membranes’ protective andsupportive role).

The dura mater is a tough, inelastic covering that consistsof two layers (dura means “tough”).

Usually, these layers adhere closely, but in some regionsthey are separated to form blood filled cavities, dural sinuses,or in the case of the larger cavities, venous sinuses.

Venous blood draining from the brain empties into thesesinuses to be returned to the heart.

Cerebrospinal fluid also reenters the blood at one of thesesinus sites.

The arachnoid mater is a delicate, richly vascularized layerwith a “cobwebby” appearance (arachnoid means “spiderlike”).

The space between the arachnoid layer and the underlyingpia mater, the subarachnoid space, is filled with CSF.

Protrusions of arachnoid tissue, the arachnoid villi,penetrate through gaps in the overlying dura and project intothe dural sinuses.

CSF is reabsorbed across the surfaces of these villi into theblood circulating within the sinuses.

The innermost meningeal layer, the pia mater, is the mostfragile (pia means “gentle”).

It is highly vascular and closely adheres to the surfaces of thebrain and spinal cord, following every ridge and valley.

In certain areas it dips deeply into the brain to bring a richblood supply into close contact with the ependymal cells lining theventricles.

This relationship is important in the formation of CSF, a topic towhich we now turn our attention.

Cerebrospinal fluid is formed primarily by the choroidplexuses found in particular regions of the ventricles.

Choroid plexuses consist of richly vascularized, cauliflower-like masses of pia mater tissue that dip into pockets formed byependymal cells.

Cerebrospinal fluid forms as a result of selective transportmechanisms across the membranes of the choroid plexuses.

The composition of CSF differs from that of blood.

Cerebrospinal fluid (CSF) surrounds and cushions the brainand spinal cord.

Cerebro-Spinal Fluid (CSF)

Cerebrospinal Fluid (CSF) Composition

Composition CSF Blood Plasma

Na+ (mEq/L) 140 – 145 135 – 147

K+ (mEq/L) 3 3.5 – 5

Cl- (mEq/L) 115 – 120 95 – 105

HCO3- (mEq/L) 20 22 – 28

Glucose (mg/ml) 50 – 75 70 – 110

Protein (g/dL) 0.05 – 0.07 6 – 7.8

pH 7.3 7.35 – 7.45

Frank et al. (2002). Atlas of Neuroanatomy and Neurophysiology. Icons Custom Communications, USA, p 61

The CSF has about the same density as the brain itself, sothe brain essentially floats or is suspended in this special fluidenvironment.

The major function of CSF is to serve as a shock-absorbingfluid to prevent the brain from bumping against the interior ofthe hard skull when the head is subjected to sudden, jarringmovements.

In addition to protecting the delicate brain from mechanicaltrauma, the CSF plays an important role in the exchange ofmaterials between the neural cells and the interstitial fluidsurrounding the brain.

Only the brain interstitial fluid but not the blood or CSF comesinto direct contact with the neurons and glial cells.

Because the brain interstitial fluid directly bathes the neuralcells, its composition is critical.

The composition of the brain interstitial fluid is influencedmore by changes in the composition of the CSF than byalterations in the blood.

Materials are exchanged fairly freely between the CSF andbrain interstitial fluid, whereas only limited exchange occursbetween the blood and brain interstitial fluid.

Thus, the composition of the CSF must be carefullyregulated.

For example, CSF is lower in K and slightly higher in Na,making the brain interstitial fluid an ideal environment formovement of these ions down concentration gradients, a processessential for conduction of nerve impulses.

The biggest difference is the presence of plasma proteins inthe blood but almost no proteins normally present in the CSF.

Plasma proteins cannot exit the brain capillaries to leave theblood during formation of CSF.

Once CSF is formed, it flows through the four interconnectedventricles of the brain and through the spinal cord’s narrowcentral canal, which is continuous with the last ventricle.

• Cerebrospinal fluid also escapes through small openings fromthe fourth ventricle at the base of the brain to enter thesubarachnoid space and subsequently flows between themeningeal layers over the entire surface of the brain and spinalcord.

• When the CSF reaches the upper regions of the brain, it isreabsorbed from the subarachnoid space into the venous bloodthrough the arachnoid villi.

• Flow of CSF through this system is facilitated by ciliary beatingalong with circulatory and postural factors that result in a CSFpressure of about 10 mm Hg.

Reduction of this pressure by removal of even a few milliliters(ml) of CSF during a spinal tap for laboratory analysis mayproduce severe headaches.

Through the ongoing processes of formation, circulation, andreabsorption, the entire CSF volume of about 125 to 150 ml isreplaced more than three times a day.

If any one of these processes is defective so that excessCSF accumulates causing hydrocephalus (“water on thebrain”) occurs.

The resulting increase in CSF pressure can lead to braindamage and mental retardation if untreated. Treatment consistsof surgically shunting the excess CSF to veins elsewhere in thebody.

Blood Brain BarrierThe brain is carefully shielded from harmful changes in the

blood by a highly selective blood–brain barrier (BBB).

Throughout the body, materials can be exchanged betweenthe blood and interstitial fluid only across the walls of capillaries,the smallest blood vessels.

Unlike the rather free exchange across capillaries elsewhere,only selected, carefully regulated exchanges can be madeacross the BBB.

For example, even if the K+ level in the blood is doubled, littlechange occurs in the K+ concentration of the fluid bathing thecentral neurons.

This is beneficial because alterations in interstitial fluid K+

would be detrimental to neuronal function.

The BBB has both anatomic and physiologic features.

Capillary walls throughout the body are formed by a singlelayer of cells.

Usually, all blood plasma components (except the largeplasma proteins) can be freely exchanged between the bloodand the interstitial fluid through holes or pores between the cellsof the capillary wall.

In brain capillaries, however, the cells are joined by tightjunctions, which completely seal the capillary wall so thatnothing can be exchanged across the wall by passing betweenthe cells.

The only possible exchanges are through the capillary cellsthemselves.

Lipid-soluble substances such as O2, CO2, alcohol, and steroidhormones penetrate these cells easily by dissolving in their lipidplasma membrane.

Small water molecules also diff use through readily, by passingbetween the phospholipid molecules of the plasma membrane orthrough aquaporins (water channels).

All other substances exchanged between the blood and braininterstitial fluid, including such essential materials as glucose,amino acids, and ions, are transported by highly selectivemembrane-bound carriers.

Thus, transport across brain capillary walls between the wall-forming cells is prevented anatomically and transport through thecells is restricted physiologically.

Together, these mechanisms constitute the BBB.

By strictly limiting exchange between the blood and brain,the BBB protects the delicate brain:

from chemical fluctuations in the blood;

minimizes the possibility that potentially harmful blood-bornesubstances might reach the central neural tissue; and

it further prevents certain circulating hormones that couldalso act as neurotransmitters from reaching the brain, wherethey could produce uncontrolled nervous activity.

On the negative side, the BBB limits the use of drugs for thetreatment of brain and spinal cord disorders because manydrugs are unable to penetrate this barrier.

Certain areas of the brain, most notably a portion of thehypothalamus, are not subject to the BBB.

Functioning of the hypothalamus depends on its “sampling”the blood and adjusting its controlling output accordingly tomaintain homeostasis.

Part of this output is in the form of water-soluble hormonesthat must enter hypothalamic capillaries to be transported totheir sites of action.

Appropriately, these hypothalamic capillaries are not sealedby tight junctions.

Brain Oxygen and Glucose DeliveryEven though many substances in the blood never actually come

in contact with the brain tissue, the brain is more dependent thanany other tissue on a constant blood supply.

Unlike most tissues, which can resort to anaerobic metabolismto produce ATP in the absence of O2 for at least short periods, thebrain cannot produce ATP without O2.

Scientists recently discovered an O2-binding protein,neuroglobin, in the brain.

This molecule, which is similar to hemoglobin, the O2-carryingprotein in red blood cells, is thought to play a key role in O2handling in the brain, although its exact function remains to bedetermined.

Also in contrast to most tissues, which can use other sourcesof fuel for energy production in lieu of glucose, the brain normallyuses only glucose but does not store any of this nutrient.

Because of its high rate of demand for ATP, under restingconditions the brain uses 20% of the O2 and 50% of the glucoseconsumed in the body.

Therefore, the brain depends on a continuous, adequate bloodsupply of O2 and glucose.

Although it constitutes only 2% of body weight, the brainreceives 15% of the blood pumped out by the heart.

Instead of using glucose during starvation, the brain can resortto using ketone bodies produced by the liver, but this alternatenutrient source also must be delivered by the blood to the brain.

Brain damage results if this organ is deprived of its critical O2supply for more than 4 to 5 minutes or if its glucose supply is cutoff for more than 10 to 15 minutes.

The most common cause of inadequate blood supply to thebrain is a stroke.

INTRODUCTORY NOTESThe term “autonomic” implies independent, self-controlling

function without conscious effort.

The ANS therefore helps to regulate our internal environment(visceral functions).

The ANS is activated mainly by centers that are located in thespinal cord, brain stem and the hypothalamus.

It comprises of the Sympathetic and parasympathetic nervoussystem but Enteric Nervous System (ENS) can also be consideredas part of the ANS.

Portions of cerebral cortex, especially the limbic cortex cantransmit impulses to the lower centers thereby influencingautonomic control.

The ANS also operates via visceral reflexes.

INTRODUCTORY NOTES

THE AUTONOMIC NERVOUSSYSTEM

The autonomic nervoussystem (ANS) regulatesphysiologic processes withoutconscious control.

The ANS consists of twosets of nerve bodies:preganglionic andpostganglionic fibers.

The two major divisions ofthe ANS are the sympatheticand parasympatheticsystems.

Anatomy of the Autonomic Nervous SystemSympathetic:

The preganglionic cell bodiesof the sympathetic system arelocated in the intermediolateralhorn of the spinal cord betweenT1 and L2 or L3.

The sympathetic ganglia areadjacent to the spine andconsist of the vertebral(sympathetic chain) andprevertebral ganglia

Long fibers run from theseganglia to effector organs,including the smooth muscle ofblood vessels, viscera, lungs,scalp (piloerector muscles), andpupils; the heart; and glands(sweat, salivary, and digestive).

Parasympathetic

The preganglionic cell bodies ofthe parasympathetic system arelocated in the nuclei of the brainstem and sacral portion of thespinal cord (S2-S4).

These preganglionic fibers exitthe brain stem with the 3rd, 7th,9th, and 10th cranial nerves.

Parasympathetic ganglia arelocated in the blood vessels of thehead, neck, and thoracoabdominalviscera; lacrimal and salivaryglands; smooth muscle of visceraand glands.

Postganglionic parasympatheticfibers are relatively short (onlyabout 1 or 2 mm long) therebyproducing specific, localizedresponses in the effector organs.

Inputs to the Autonomic Nervous System

The ANS receives input fromparts of the CNS thatprocess and integrate stimulifrom the body and externalenvironment.

These parts include thehypothalamus, nucleus of thesolitary tract, reticularformation, amygdala,hippocampus, and olfactorycortex.

Neurotransmitters of the ANS

Two most common neurotransmitters released by neurons ofthe ANS are acetylcholine (cholinergic) andnorepinephrine/noradrenaline (adrenergic).

Acetylcholine:All preganglionic nerve fibersAll postganglionic fibers of the parasympathetic systemSympathetic postganglionic fibers innervating sweat glands

Adrenaline:In most sympathetic postganglionic fibers

Receptors of the ANS Neurotransmitters Cholinergic receptors: nicotinic or muscarinic.

Adrenergic receptors: alpha (α) and beta (β), with α beingmore abundant.The adrenergic receptors are further divided into (α1, α2,

β1 and β2) according to some factors.

Functions of the ANS

The two divisions of the ANS are dominant under differentconditions.

The sympathetic system is activated during emergency“fight-or-flight” reactions and during exercise.

The parasympathetic system is predominant during quietconditions (“rest and digest”). As such, the physiologicaleffects caused by each system are quite predictable.

In other words, all of the changes in organ and tissuefunction induced by the sympathetic system work together tosupport strenuous physical activity and the changes inducedby the parasympathetic system are appropriate for when thebody is resting.

AUTONOMIC GANGLIA These are small swellings along the course of the autonomicnerves that contain a collection of nerve cells.

Efferent autonomic fibers that arise from the lateral horn cellsare called the preganglionic fibers which are thick, white andmyelinated fibers.

The preganglionic fibers enter the autonomic ganglia wherethey take either of two courses:

i) terminate into several nerve terminals in the ganglion that relayimpulses into the ganglionic nerve cells.

Postganlionic fibers emerge from these ganglionic fibers andproceed to supply the effector organs. These are thin, gray andunmyelinated fibers.

ii) Pass via the ganglion uninterrupted without relay andemerge on the other side still as preganglionic fibers toproceed to the adrenal medulla or to another ganglion wherethey terminate and relay

The postganglionic nerve fibers emerge from the laterganglion to supply the effector organs.

Types of the Autonomic Ganglia

a) Lateral or Paravertebral Ganglia: Form sympatheticchain on both sides of the vertebral column with each chainforming 23 ganglia (3 cervical – superior, middle and inferiorganglia; 12 thoracic; 4 lumbar and 4 sacral) connected toeach other by nerve fibers.

b) Collateral or Prevertebral ganglia: These are celiac, thesuperior and inferior mesenteric ganglia. They are found along the

course of sympathetic nerves, midway between the spinal cord and

the viscera. These are sympathetic ganglia i.e. sites of relay for

sympathetic nerves only.

c) Terminal Ganglia: These are present near or inside the effector

organ e.g. the eye, heart and the stomach. They are parasympathetic

ganglia i.e. sites of relay for parasympathetic nerves only.

The Autonomic ganglia serve as: relay stations, expansion as well

as distribution centers.

REGULATORY SYSTEMS OF THE ANS Autonomic reflexes represent the

simplest level of ANS control

The ANS involvement with the

limbic system, hypothalamus,

solitary nucleus of the medulla and

other brain stem nuclei has

explained the ANS regulation.

In fact, the limbic system has

been termed the “cerebral cortex of

the ANS”. So the limbic system

represents one of the highest levels

of the hierarchy of normal control of

the ANS.

Stimulation of the limbicsystem areas can evoke a broadrange of feelings and behaviors,including rage, anger, fear, andaggression.

In addition, stimulation of the limbic system, either directly or by input

from the senses, can evoke ANS-mediated physiological changes such as

increased heart rate, sexual arousal, and nausea.

Autonomic Functions of the Hypothalamus Hypothalamus is known as the main ganglion of the ANS and the

activation of its different parts produces a variety of coordinated autonomic

responses:

Activation of the dorsal hypothalamus, for e.g. increases blood pressure,

intestinal motility, and intestinal blood supply but decreases supply to the

skeletal muscles. These are associated with feeding behavior.

However, activation of ventral hypothalamus increases blood pressure

and the blood supply to the skeletal muscles but decreases intestinal motility

and blood flow to the intestines. These are associated with flight or flightresponses.

CHEMICAL TRANSMISSION• Chemical transmissions (synapses) enable cell-to-cell

communication via the secretion of neurotransmitters by activatingspecific receptor molecules.

•• A synapse is a junctional area between a neuronal terminal and

another cell that could be another neuron, muscle cell or a gland.

• If the second cell is a neuron, the synapse is called a neuronalsynapse.

• The neuron that conducts the signals is the presynaptic neuronhaving a presynaptic membrane at the synapse. However, theneuron that receives the signals and its membrane are postsynapticneuron and postsynaptic membrane respectively.

• The space between the presynaptic and postsynaptic membranes iscalled synaptic cleft and measures about 30-50 nm.

A key feature of all chemical synapses is the presence of small,

membrane-bounded organelles called the synaptic vesicles within the

presynaptic terminal

Neurotransmitters

There are more than 100 types of neurotransmitters and they

virtually undergo a similar cycle of use:

synthesis and packaging into synaptic vesicles

Release from the presynaptic cell

Binding to postsynaptic receptor

Rapid removal and degradation

The secretion of the neurotransmitters is triggered by the influx of Ca2+

through the voltage-gated channels that give rise to transient increase inCa2+ concentration within the presynaptic terminal.

Sequence of Events involved in Transmission at a TypicalChemical Synapse

The rise in the Ca2+ causes synaptic vesicles to fuse with presynaptic

plasma membrane and release their contents into the space between the

pre- and postsynaptic cells.

Neurotransmitters released therefore evoke postsynaptic electrical

responses by binding to members of a diverse group of

neurotransmitter receptors.

There are two major classes of receptors: those in which the receptor

molecule is also an ion channel and those in which the receptor and the

ion channel are two separate molecules.

These receptors give rise to electrical signals by transmitter-induced

opening or closing of the ion channels.

CHEMICAL TRANSMISSION – Cont’d Whether the postsynaptic actions of a particular neurotransmitterare excitatory or inhibitory is determined by:

The ionic permeability of the ion channel affected by the neurotransmitterand

By the concentration of the permanent ions inside and outside thecell

Criteria that Define NeurotransmittersThere are 3 primary criteria been used to confirm that a molecule actsas a neurotransmitter at a given chemical synapse:

1) The substance must be present within the presynaptic neuron. Moreso,when enzymes and precursors required to synthesize the substance providemore evidence. However, presence of glutamate, glycine and aspartate is nota sufficient evidence.

(1) Neurotransmitter presence (2) Neurotransmitter release (3) Postsynaptic presence of specific receptors

Requirements of identifying a neurotransmitter

2) The substance must be released in response to presynaptic

depolarization, and the release must be Ca2+-dependent. This is quite

challenging not only because it may be difficult to selectively stimulate the

presynaptic neuron, but also because enzymes and transporters efficiently

remove the secreted neurotransmitters.

3) Specific receptors for the substance must be present on the postsynaptic

cell/membrane. One way to demonstrate receptors is to show that application

of exogenous transmitter mimics the postsynaptic effect of presynaptic

stimulation.

A more rigorous demonstration is to show that agonists and antagonists that

alter the normal postsynaptic response have the same effect when the substance

in question is applied exogenously. High resolution histological techniques can

also be used to show that specific receptors are present in the postsynaptic

membrane (by detection of radioactively labeled receptor antibodies).

Categories of Neurotransmitters More than 100 different agents are known to serve as

neurotransmitters that allow for diverse chemical signaling between

neurons.

These neurotransmitters are broadly divided into two based on size:

i) Neuropeptides: These are relatively large transmitter molecules

composed of 3 to 36 amino acids.

ii) Small-molecule neurotransmitters: individual amino acids, such as

Glutamate, GABA, Ach, serotonin and histamine are examples.

Within this category, the biogenic amines such as dopamine,

norepinephrine, epinephrine, serotonin and histamine are often discussed

separately because of their similar properties and postsynaptic actions.

NORADRENERGIC TRANSMISSIONSynthesis of Norepinephrine/Epinephrine

The adrenal medulla that secretes epinephrine/adrenaline andnorepinephrine/noradrenaline, is an important component of thesympathetic nervous system. As a result, the sympathetic nervoussystem and adrenal medulla are often referred to as thesympathoadrenal system.

Norepinephrine is one of the five well-established biogenic amineneurotransmitters: 3 catecholamines (dopamine, norepinephrineand epinephrine), histamine and serotonin.

Noradrenaline like the other 2 catecholamines are derived fromtyrosine (which is a product of phenylalanine).

Synthesis of Norepinephrine/Epinephrine

This reaction is catalyzed by phenylalanine hydroxylase in theliver) in a reaction catalyzed by tyrosine hydroxylase (in theneuron) requiring O2 as a co-substrate and tetrahydrobiopterin as acofactor to form DihydrOxyPhenylAlanine (DOPA).

Norepinephrine synthesis requires dopamine β-hydroxylasethat catalyzes the production of noradrenaline from Dopamine.

In the central adrenergic fibers (neurons of the thalamus,hypothalamus and midbrain) and in the adrenal medulla,noradrenaline is converted to adrenaline by Phenylethanolamine-N-methyl Transferase (PNMT).

This enzyme is not found in the peripheral adrenergic fibers.

Synthesis of Norepinephrine/Epinephrine

Fate / Degradation of Norepinephrine/epinephrine Noradrenaline is the loaded into synaptic vesicles via the Vesicular

MonoAmine Transporter (VMAT) same as with dopamine.

Norepinephrine is cleared from the synaptic cleft byNorepinephrine Transporter (NET) mainly in the nerve terminalswhich is also capable of taking up dopamine to be recirculated.

Small amount of Noradrenaline like dopamine is oxidized byMonoAmine Oxidase (MAO) to inactive products. MAO is foundin nerve terminals and other organs like liver and kidney.

Some small amount is methylated to inactive products by CatecholO-Methyl-Transferase (COMT) enzymes found in the manytissues such as kidney and brain but not in the nerve terminals.

Epinephrine is mainly methylated in various organs by COMT.

Adrenergic Receptors/Adrenoceptors Norepinephrine as well as epinephrine, acts on α- and β-adrenergicreceptors that are both G-protein coupled.

There are two types of α-adrenergic receptors (α1 and α2) andthree β-adrenergic receptors (though 2 are the well known becauseof their expression in many types of neurons, β1 and β2).

Norepinephrine for example excites mainly α receptors but excitesβ receptors to a slight extent; while epinephrine excites both types ofreceptors almost equally.

Isoproterenol (a synthetic catecholamine) has strong action on β-receptors but essentially no action on α-receptors

AdrenergicDrugs/Agonists/Protagonists/Symphatomimietic Drugs These are drugs that mimic the actions of norepinephrine or epinephrinethrough the following mechanisms:

i) Stimulating the release of the transmitter. Example of these include Amphetamineand Ephedrine

ii) Inhibiting the action of MAO enzyme. Example, Ephedrine and Hydrazine

iii) Direct stimulation of receptors. Example norepinephrine and epinephrine (αand β), phenylephrine (α1), clonidine (α2), Dobutamine (β1), Salbutamol (β2) andisoproterenol (β1 and β2)

Agonists and antagonists of adrenergic receptors, such as the β blockerpropanolol are used clinically for a variety of conditions ranging from cardiacarrhythmias to migraine headaches.

However, most of the actions of these drugs are on smooth muscle receptorsparticularly on cardiovascular and respiratory systems.

Anti-Adrenergic Drugs/AdrenergicBlockers/Antagonists/Symphatolytic Drugs

• These are drugs that block the actions of norepinephrine and

epinephrine and they produce their actions via the following

mechanisms:

i) Inhibiting the synthesis of norepinephrine. Example is Aldomet(that inhibits β-hydroxylase leading to the formation of a false

transmitter).

ii) Preventing the release of the transmitter. Example is Guanethidine

iii) Direct blocking of the receptors. Examples are: Prazosin (α1),Yohimbine (α2), Phentolamine (α1 and α2), Atenolol (β1),Butaxamine (β2) and Propranolol (β1 and β2)

CHOLINERGIC TRANSMISSION Ach is synthesized in nerve terminals from the precursors acetyl

coA and choline in the recation catalyzed by choline acetyltransferase (CAT)

Choline is present in plasma at a high concentration (about 10 mM)and is taken up into cholinergic neurons by a high - affinityNa+/choline transporter.

After synthesis in the neuroplasm a vesicular Ach transporter loadsapprox 10, 000 molecules of Ach into each cholinergic vesicle.

In contrast to most other small-molecular neurotransmitters, thepostsynaptic actions of Ach at many cholinergic synapses (theNMJ in particular) is not terminated by reuptake but by a powerfulhydrolytic enzyme, Acetylcholinesterase (AchE)

Electrical synapse Chemical synapse

(a) Chemically gatedreceptor-channel

(b) Receptor Enzyme (c) G-Protein coupledReceptor

Functions of Cranial Nerves

Classification of Mammalian Nerve Fibers

NB: A and B fibers are myelinated while the C fibers are unmyelinated

Relative susceptibility of mammalian A, B, and C nerve fibers to conduction block produced byvarious agents

Neurotrophins: Trophic Support of NeuronsProteins necessary for survival and growth of neurons are

called neurotrophins.

Many are products of the muscles or other structures that theneurons innervate, but others are produced by astrocytes.

These proteins bind to receptors at the endings of a neuron.

They are internalized and then transported by retrogradetransport to the neuronal cell body, where they foster theproduction of proteins associated with neuronal development,growth, and survival.

Other neurotrophins are produced in neurons and transportedin an anterograde fashion to the nerve ending, where theymaintain the integrity of the postsynaptic neuron.

The first neurotrophin to be characterized was nerve growthfactor (NGF), a protein that is necessary for the growth andmaintenance of sympathetic neurons and some sensoryneuron.

It is found in many different tissues. NGF is picked up byneurons and transported in retrograde fashion from the endingsof the neurons to their cell bodies.

It is also present in the brain and appears to be responsiblefor the growth and maintenance of cholinergic neurons in thebasal forebrain and striatum.

NEUROTRANSMITTERSMostly, neurons in the human brain communicate with one

another by releasing chemical messengers called neurotransmitters.

A large number of neurotransmitters are now known and moreremain to be discovered.

Neurotransmitters evoke postsynaptic electrical responses bybinding to members of a diverse group of proteins calledneurotransmitter receptors.

There are two major classes of receptors:

those in which the receptor molecule is also an ion channel,which are called ionotropic receptors or ligand gated ionchannels, and give rise to fast postsynaptic responses thattypically last only a few milliseconds; and

those in which the receptor and ion channel are separatemolecules called metabotropic receptors, that produce slowerpostsynaptic effects that may endure much longer.

Abnormalities in the function of neurotransmitter systemscontribute to a wide range of neurological and psychiatric disorders.

As a result, many neuropharmacological therapies are based ondrugs that affect neurotransmitter release, binding, and/or removal.

Categories of NeurotransmittersMore than 100 different agents are known to serve as

neurotransmitters.

This large number of transmitters allows for tremendous diversityin chemical signaling between neurons and are divided into twobroad categories based on size.

i) neuropeptides are relatively large transmitter moleculescomposed of 3 to 36 amino acids.

ii) small-molecule neurotransmitters are Individual aminoacids, such as glutamate, GABA, acetylcholine, serotonin,and histamine, are much smaller than neuropeptides

Within the category of small-molecule neurotransmitters, thebiogenic amines (dopamine, norepinephrine, epinephrine,serotonin, and histamine) are often discussed separatelybecause of their similar chemical properties and postsynapticactions.

The particulars of synthesis, packaging, release, andremoval differ for each neurotransmitter.

AcetylcholineAcetylcholine (ACh) was the first

substance identified as aneurotransmitter.

Acetylcholine is synthesized innerve terminals from the precursorsacetyl coenzyme A (acetyl CoA,which is synthesized from glucose)and choline, in a reaction catalyzedby choline acetyltransferase(CAT).

Choline is present in plasma at ahigh concentration and is taken upinto cholinergic neurons by a high-affinity Na+/choline transporter.

After synthesis in the cytoplasmof the neuron, a vesicular Achtransporter loads approximately10,000 molecules of ACh intoeach cholinergic vesicle.

In contrast to most other small-molecule neurotransmitters,the postsynaptic actions of ACh at many cholinergic synapses(the neuromuscular junction in particular) is not terminated byreuptake but by a powerful hydrolytic enzyme,acetylcholinesterase (AChE).

This enzyme is concentrated in the synaptic cleft, ensuring arapid decrease in ACh concentration after its release from thepresynaptic terminal.

The AChE has a very high catalytic activity (about 5000molecules of ACh per AChE molecule per second) andhydrolyzes Ach into acetate and choline.

The choline produced by ACh hydrolysis is transported backinto nerve terminals and used to re-synthesize ACh.

Among the many interesting drugs that interact with cholinergicenzymes are the organophosphates that include some potentchemical warfare agents.

One such compound is the nerve gas “Sarin,” which was madenotorious after a group of terrorists released this gas in Tokyo’sunderground rail system.

Organophosphates can be lethal because they inhibit AChE,causing Ach to accumulate at cholinergic synapses.

This build-up of ACh depolarizes the postsynaptic cell andrenders it refractory to subsequent ACh release, causingneuromuscular paralysis and other effects.

The high sensitivity of insects to these AChE inhibitors hasmade organophosphates popular insecticides.

Acetylcholine Receptors

There are two types of cholinergic receptors:

Muscarinic

Nicotinic

Glutamate

• Glutamate is the most important transmitter in normal brainfunction.

• Nearly all excitatory neurons in the central nervous system areglutamatergic, and it is estimated that over half of all brainsynapses release this agent.

• Glutamate plays an especially important role in clinicalneurology because elevated concentrations of extracellularglutamate, released as a result of neural injury, are toxic toneurons.

• Glutamate is a nonessential amino acid that does not cross theblood-brain barrier and therefore must be synthesized in neuronsfrom local precursors.

The most prevalent precursorfor glutamate synthesis isglutamine, which is released byglial cells.

Once released, glutamine istaken up into presynaptic terminalsand metabolized to glutamate bythe mitochondrial enzymeglutaminase.

Glutamate can also besynthesized by transaminationof 2-oxoglutarate, an intermediateof the tricarboxylic acid cycle.

Hence, some of the glucosemetabolized by neurons can alsobe used for glutamate synthesis.

The glutamate synthesized inthe presynaptic cytoplasm ispackaged into synapticvesicles by transporters,termed VGLUT.

The glutamate synthesized in the presynaptic cytoplasm ispackaged into synaptic vesicles by transporters, termedVGLUT.

At least three different VGLUT genes have been identified.

Once released, glutamate is removed from the synaptic cleftby the excitatory amino acid transporters (EAATs).

Glutamate taken up by glial cells is converted into glutamineby the enzyme glutamine synthetase; glutamine is thentransported out of the glial cells and into nerve terminals.

In this way, synaptic terminals cooperate with glial cells tomaintain an adequate supply of the neurotransmitter.

This overall sequence of events is referred to as theglutamate-glutamine cycle.

Glutamate ReceptorsSeveral types of glutamate receptors have been identified.

Three of these are ionotropic receptors and are called:

NMDA (N-methyl-D-aspartate)receptors, AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate),

receptors, and kainate receptors

These glutamate receptors are named after the agonists thatactivate them.

All of the ionotropic glutamate receptors are nonselectivecation channels similar to the nAChR, allowing the passage ofNa+ and K+, and in some cases small amounts of Ca2+.

Hence AMPA, kainate, and NMDA receptor activation alwaysproduces excitatory postsynaptic responses.

Like other ionotropic receptors, AMPA/kainate and NMDAreceptors are also formed from the association of several proteinsubunits that can combine in many ways to produce a largenumber of receptor isoforms.

GABA and Glycine

Most inhibitory synapses in the brain and spinal cord useeither γ-Aminobutyric acid (GABA) or glycine asneurotransmitters.

Like glutamate, GABA was identified in brain tissue during the1950s.

It is now known that as many as a third of the synapses in thebrain use GABA as their inhibitory neurotransmitter.

GABA is most commonly found in local circuit interneurons,although cerebellar Purkinje cells provide an example of aGABAergic projection neuron.

The predominant precursor for GABA synthesis is glucose,which is metabolized to glutamate by the tricarboxylic acid cycleenzymes (pyruvate and glutamine can also act as precursors).

The predominant precursor forGABA synthesis is glucose, whichis metabolized to glutamate by thetricarboxylic acid cycle enzymes(pyruvate and glutamine can alsoact as precursors).

The enzyme glutamic aciddecarboxylase (GAD), which isfound almost exclusively inGABAergic neurons, catalyzes theconversion of glutamate to GABA.

GAD requires a cofactor,pyridoxal phosphate, for activity.

Because pyridoxalphosphate is derived fromvitamin B6, a B6 deficiencycan lead to diminishedGABA synthesis.

The significance of thisbecame clear after a disastrousseries of infant deaths was linkedto the omission of vitamin B6from infant formula.

This lack of B6 resulted in alarge reduction in the GABAcontent of the brain, and thesubsequent loss of synapticinhibition caused seizures that insome cases were fatal.

Once GABA is synthesized, itis transported into synapticvesicles via a vesicularinhibitory amino acidtransporter (VIATT).

The mechanism of GABA removal is similar to that forglutamate: Both neurons and glia contain high-affinitytransporters for GABA, termed GATs (several forms of GAThave been identified).

Most GABA is eventually converted to succinate, which ismetabolized further in the tricarboxylic acid cycle that mediatescellular ATP synthesis.

The enzymes required for this degradation, GABAtransaminase and succinic semialdehyde dehydrogenase,are mitochondrial enzymes.

Inhibition of GABA breakdown causes a rise in tissue GABAcontent and an increase in the activity of inhibitory neurons.

There are also other pathways for degradation of GABA.

The most noteworthy of these results in the production of γ-hydroxybutyrate, a GABA derivitive that has been abused as a“date rape” drug.

Oral adminis-tration of γ-hydroxybutyrate can causeeuphoria, memory deficits, and unconsciousness.

Presumably these effects arise from actions on GABAergicsynapses in the CNS.

Inhibitory synapses employing GABA as their transmitter canexhibit three types of postsynaptic receptors, called GABAA,GABAB, and GABAC.

GABAA and GABAC receptors are ionotropic receptors,while GABAB receptors are metabotropic.

Drugs that act as agonists or modulators of postsynapticGABA receptors, such as benzodiazepines and barbiturates,are used clinically to treat epilepsy and are effective sedativesand anesthetics.

Learning Objectives

At the end of this lesson, the students are expected to:

List common senses and their receptors;

Explain the terms hyperalgesia and allodynia;

Explain sensory coding;

Compare the pathway that mediates sensory input from touch,proprioceptive, and vibratory senses to that mediating informationfrom pain and thermoreceptors; and

Describe mechanisms to modulate transmission in painpathways.

SENSORY SYSTEMS: TOUCH, PAIN, AND TEMPERATURE

Information about the internal and external environmentactivates the central nervous system (CNS) via sensoryreceptors.

These receptors are transducers that convert various formsof energy into action potentials in neurons.

The somatic sensory system has two major components:

a subsystem for the detection of mechanical stimuli (e.g.,light touch, vibration, pressure and cutaneous tension); and

a subsystem for the detection of painful stimuli andtemperature.

Together, these two subsystems give humans and otheranimals the ability to:

identify the shapes and textures of objects;

monitor the internal and external forces acting on the body atany moment; and

Detect potentially harmful circumstances.

Types of Somatic Sensory Receptors

Cutaneous (superficial) receptors for touch and pressure aremechanoreceptors.

Potentially harmful stimuli such as pain, extreme heat, andextreme cold are mediated by nociceptors.

Chemoreceptors are stimulated by a change in the chemicalcomposition of the environment in which they are located.

These include receptors for taste and smell as well asvisceral receptors such as those sensitive to changes in theplasma level of O2, pH, and osmolality.

Photoreceptors are those in the rods and cones in the retinathat respond to light.

Cutaneous Mechanoreceptors

Sensory receptors can be specialized dendritic endings ofafferent nerve fibers and are often associated with non-neuralcells that surround them, forming a sense organ.

Touch and pressure are sensed by four types of mechanoreceptors:

i. Meissner’s corpuscles respond to changes in texture andslow vibrations.

ii. Merkel cells respond to sustained pressure and touch.

iii. Ruffini corpuscles respond to sustained pressure.

iv. Pacinian corpuscles respond to deep pressure and fastvibration.

Nociceptors and ThermoreceptorsPain and temperature sensations arise from unmyelinated

dendrites of sensory neurons located around hair folliclesthroughout the smooth and hairy skin, as well as in deep tissue.

Impulses from nociceptors (pain) are transmitted via two fibertypes:

i. One system comprises thinly myelinated Aδ fibers thatconduct at rates of 12–30 m/s.

ii. The other is unmyelinated C fibers that conduct at low rates of0.5–2 m/s.

Thermoreceptors also span the following two fiber types:

i. cold receptors are on dendritic endings of Aδ fibers and Cfibers; and

ii. warm receptors are on C fibers.

On the other hand, the nociceptors could be categorizedbased on stimuli they respond to into:

Mechanical nociceptors respond to strong pressure.

Thermal nociceptors are activated by skin temperaturesabove 45°C or by severe cold.

Chemically sensitive nociceptors respond to various agentssuch as bradykinin, histamine, high acidity, andenvironmental irritants.

Polymodal nociceptors respond to combinations of thesestimuli.

The Major Classes of Somatic Sensory Receptors

The Major Afferent Pathway for MechanosensoryInformation: The Dorsal Column–Medial Lemniscus System

The action potentials generated by tactile and othermechanosensory stimuli are transmitted to the spinal cord byafferent sensory axons traveling in the peripheral nerves.

The neuronal cell bodies that give rise to these first-orderaxons are located in the dorsal root (or sensory) gangliaassociated with each segmental spinal nerve.

The dorsal horn in the spinal cord is divided on the basis ofhistologic characteristics into laminae I–VII, with lamina I beingthe most superficial and lamina VII the deepest.

Lamina II and part of lamina III make up the substantiagelatinosa, the area near the top of each dorsal horn.

Schematic representation of the terminations of the three types of primary afferent neurons in thevarious layers of the dorsal horn of the spinal cord

Dorsal root ganglion cells are also known as first-orderneurons because they initiate the sensory process.

Depending on whether they belong to the mechanosensorysystem or to the pain and temperature system, the first-orderaxons carrying information from somatic receptors have:

different patterns of termination in the spinal cord; and

define distinct somatic sensory pathways within the centralnervous.

These differences provide for different pathways as follows:

the dorsal column–medial lemniscus pathway that carriesthe majority of information from the mechanoreceptors thatmediate tactile discrimination and proprioception; and

the spinothalamic (anterolateral) pathway mediates painand temperature sensation.

The difference(s) in the afferent pathways of these modalitiesis one of the reasons of treating the sensations separately.

DORSAL COLUMN (MEDIAL LEMNISCAL) PATHWAYThis is the principal direct

pathway to the cerebralcortex for touch, vibratorysense, and proprioception(position sense).

Upon entering the spinalcord, the major branch of theincoming axons called thefirst-order axons carryinginformation from peripheralmechanoreceptors ascendsipsilaterally through thedorsal columns (posteriorfuniculi) of the cord.

In this column, it goes allthe way to the lower medulla,where it terminates bysynapsing with the second-order neurons in the gracileand cuneate nuclei (togetherreferred to as the dorsalcolumn nuclei).

Axons in the dorsal columnsare topographically organizedsuch that:

the fibers that conveyinformation from lower limbsthat are in the medialsubdivision of the dorsalcolumns, called the graciletract; and

The lateral subdivision,called the cuneate tract,which contains axonsconveying information fromthe upper limbs, trunk, andneck.

In a cross-section through themedulla, the medial lemniscalaxons carrying information fromthe lower limbs are locatedventrally, whereas the axonsrelated to the upper limbs arelocated dorsally (again, a fact ofsome clinical importance).

The second-order neuronsfrom these nuclei ascendcontralaterally ascend in themedial lemniscus to end in thecontralateral ventral posteriorlateral (VPL) nucleus andrelated specific sensory relaynuclei of the thalamus.

These axons of the medial lemniscus that reach the ventralposterior lateral (VPL) nucleus of the thalamus are the third-order neurons of the dorsal column–medial lemniscus system.

The Trigeminal Portion of the Mechanosensory SystemAs noted, the dorsal column–medial lemniscus pathway

described in the preceding section carries somatic informationfrom only the upper and lower body and from the posterior thirdof the head.

Tactile and proprioceptive information from the face isconveyed from the periphery to the thalamus by a different routecalled trigeminal somatic sensory system.

Low-threshold mechanoreception in the face is mediated byfirst order neurons in the trigeminal (cranial nerve V) ganglion.

The peripheral processes ofthese neurons form the threemain subdivisions of thetrigeminal nerve:

the ophthalmic; Maxillary; and mandibular branches,

• Each of these innervates awell-defined territory on theface and head, including theteeth and the mucosa of theoral and nasal cavities.

10 SomaticSensory Cortex

The central processes oftrigeminal ganglion cells formthe sensory roots of thetrigeminal nerve.

They enter the brainstem atthe level of the pons toterminate on neurons in thesubdivisions of the trigeminalbrainstem complex.

The trigeminal complex hastwo major components:

the principal nucleus(responsible for processingmechanosensory stimuli); and

10 SomaticSensory Cortex

the spinal nucleus(responsible for processingpainful and thermal stimuli).

Thus, most of the axonscarrying information from low-threshold cutaneousmechanoreceptors in the faceterminate in the principal nucleus.

In effect, this nucleuscorresponds to the dorsal columnnuclei that relay mechanosensoryinformation from the rest of thebody.

The spinal nucleus correspondsto a portion of the spinal cord thatcontains the second-order neuronsin the pain and temperature systemfor the rest of the body.

10 SomaticSensory Cortex10 SomaticSensory Cortex

The second order neurons of thetrigeminal brainstem nuclei give offaxons that cross the midline andascend to the ventral posterior medial(VPM) nucleus of the thalamus via thetrigeminothalamic tract (also calledthe trigeminal lemniscus).

The Somatic Sensory Components of the Thalamus

Each of the several ascendingsomatic sensory pathwaysoriginating in the spinal cord andbrainstem converge on the thalamus.

The ventral posterior complex(VPL and VPM) of the thalamus,which comprises a lateral and amedial nucleus, is the main target ofthese ascending pathways.

The VPL nucleus receivesprojections from the mediallemniscuscarrying all somatosensoryinformation from the body andposterior head.

The VPM nucleus receivesaxons from the trigeminallemniscus (that is,mechanosensory and nociceptiveinformation from the face).

The Somatic Sensory Cortex

The axons arising fromneurons in the ventral posteriorcomplex of the thalamus projectto cortical neurons locatedprimarily in layer IV of thesomatic sensory cortex.

The primary somatic sensorycortex in humans (also called SI),which is located in thepostcentral gyrus of theparietal lobe, comprises fourdistinct regions, or fields, knownas Brodmann’s areas 3a, 3b, 1,and 2.

Experiments carried out innon-human primates indicatethat neurons in areas 3b and 1respond primarily to cutaneousstimuli.

The axons arising fromneurons in the ventral posteriorcomplex of the thalamus projectto cortical neurons locatedprimarily in layer IV of thesomatic sensory cortex.

The primary somatic sensorycortex in humans (also called SI),which is located in thepostcentral gyrus of theparietal lobe, comprises fourdistinct regions, or fields, knownas Brodmann’s areas 3a, 3b, 1,and 2.

Experiments carried out innon-human primates indicatethat neurons in areas 3b and 1respond primarily to cutaneousstimuli.

Neurons in 3a respond mainlyto stimulation of proprioceptors;area 2 neurons process bothtactile and proprioceptive stimuli.

Mapping studies in humansand other primates show furtherthat each of these four corticalareas contains a separate andcomplete representation of thebody.

In these somatotopic maps,the foot, leg, trunk, forelimbs, andface are represented in a medialto lateral arrangement.

Ventrolateralspinothalamic TractFibers from nociceptors and

thermoreceptors synapse onneurons in the dorsal horn.

The axons from these neuronscross the midline and ascend in theventrolateral quadrant of the spinalcord, where they form the lateralspinothalamic tract.

Fibers within this tract synapse inthe VPL nuclei.

Other dorsal horn neurons thatreceive nociceptive input synapse inthe reticular formation of the brainstem (spinoreticular pathway).

From this pathway,fibers then project to thecentrolateral nucleus ofthe thalamus.

Positron emission tomographic (PET) and functionalmagnetic resonance imaging (fMRI) studies in normalhumans indicate that pain activates cortical areas SI, SII, andthe cingulate gyrus on the side opposite the stimulus.

Also,the mediofrontal cortex and insular cortex are activated.These technologies were important in distinguishingtwo components of pain pathways.

From VPL nuclei in the thalamus, fibers project to SI and SII.

This is called the neospinothalamic tract, and it isresponsible for the immediate awareness of the painfulsensation and the awareness of the location of the noxiousstimulus.

The pathway that includes synapses in the brain stem reticularformation and centrolateral thalamic nucleus projects to thefrontal lobe, limbic system, and insula.

This is called the paleospinothalamic tract, and it mediatesthe emotional response to pain.

In the CNS, visceral sensation travels along the samepathways as somatic sensation in the spinothalamic tracts andthalamic radiations, and the cortical receiving areas for visceralsensation are intermixed with the somatic receiving areas.

This likely contributes to the phenomenon called referredpain.

Dorsal Column Medial Lemniscal Pathway Spinothalamic (anterolateral) Pathway

PHYSIOLOGY OF PAINPain is defined by the International Association for the

Study of Pain (IASP) as “an unpleasant sensory and emotionalexperience associated with actual or potential tissue damage….”

This is different from nociception, which the IASP defines asthe unconscious activity induced by a harmful stimulus applied tosense receptors.

Pain can be classified mainly into two as:

A) Physiological (or acute) painAcute pain typically has a sudden onset and recedes during

the healing process.

It can be considered “good pain” because it serves animportant protective mechanism.

The withdrawal reflex is an example of this protective roleof pain.

B) Pathological (Chronic) PainChronic pain can be considered “bad pain” because it

persists long after recovery from an injury and is often refractoryto common analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates.

It can result from nerve injury including diabeticneuropathy, toxin-induced nerve damage, and ischemia.

Pathological pain can be subdivided into:

i) Inflammatory pain; andii) neuropathic pain

Hyperalgesia and Allodynia

Pain that is often accompanied by, an exaggerated responseto a noxious stimulus is called hyperalgesia.

Allodynia is a sensation of pain in response to an innocuousstimulus.

An example of allodynia is the painful sensation from a warmshower when the skin is damaged by sunburn.

Hyperalgesia and allodynia signify increased sensitivity ofnociceptive afferent fibers.

Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.

Injured cells releasechemicals such as K+ thatdepolarize nerve terminals,making nociceptors moreresponsive.

Injured cells also releasebradykinin and substance P,which can further sensitizenociceptive terminals.

Other Chemicals include:

histamine is released frommast cells;

serotonin (5-HT) fromplatelets;

In response to tissue injurychemical mediators cansensitize and activatenociceptors therebycontributing to hyperalgesiaand allodynia.

Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.

Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.

All these chemicalscontribute to theinflammatory process andactivating or sensitizing thenociceptors.

Substance P acts on mastcells to cause degranulationand release of histamine,which activates nociceptorsand plasma extravasation

CGRP dilates bloodvessels that together with theplasma extravasation resultin edema formation.

calcitonin gene-related peptide(CGRP) from nerve terminals; and

prostaglandins from cellmembranes.

Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.

Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.

Some releasedsubstances act by releasinganother one (e.g., bradykininactivates both Aδ and Cfibers and increasessynthesis and release ofprostaglandins).

Prostaglandin E2 (acyclooxygenase metaboliteof arachidonic acid) isreleased from damaged cellsand produces hyperalgesia.

This is why aspirin andother NSAIDs (inhibitors ofcyclooxygenase) alleviatePain.

The resulting edema causesadditional release of bradykinin.

Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:Principles of Neural Science. McGraw-Hill, 2000.

Sensory CodingConverting a receptor stimulus to a recognizable sensation is

termed sensory coding.

All sensory systems code for four elementary attributes of astimulus: modality, location, intensity, and duration.

Modality is the type of energy transmitted by the stimulus.

The particular form of energy to which a receptor is mostsensitive is called its adequate stimulus.

Location is the site on the body or space where the stimulusoriginated.

A sensory unit is a single sensory axon and all its peripheralbranches while the receptive field of a sensory unit is the spatialdistribution from which a stimulus produces a response in thatunit.

One of the most important mechanisms that enablelocalization of a stimulus site is lateral inhibition.

Activity arising from sensory neurons whose receptors are atthe peripheral edge of the stimulus is inhibited compared to thatfrom the sensory neurons at the center of the stimulus.

Thus, lateral inhibition enhances the contrast between thecenter and periphery of a stimulated area and increases theability of the brain to localize a sensory input.

Lateral inhibition underlies the neurological assessmentcalled the two-point discrimination test, which is used to testthe integrity of the dorsal column (medial lemniscus) system.

Intensity is signaled by the response amplitude or frequencyof action potential generation.

Duration refers to the time from start to end of a response inthe receptor.

If a stimulus of constant strength is applied to a receptor, thefrequency of the action potentials in its sensory nerve declinesover time.

This phenomenon is known as adaptation or desensitization;the degree to which it occurs varies from one sense to another.

Based on this phenomenon, receptors can be classified into:

rapidly adapting (phasic) receptors; and slowly adapting (tonic) receptors.

Central Pain PathwaysThe pathways that carry information about noxious stimuli to

the brain, as might be expected for such an important andmultifaceted system, are also complex.

It helps in understanding this complexity to distinguish twocomponents of pain:

the sensory discriminative component, which signals thelocation, intensity, and quality of the noxious stimululation,

the affective-motivational component of pain—which signalsthe unpleasant quality of the experience, and enables theautonomic activation that follows a noxious stimulus.

The discriminative component is thought to depend onpathways that target the traditional somatosensory areas ofcortex, while the affective- motivational component is thought todepend on additional cortical and brainstem pathways.

Pathways responsible for the discriminative component of painoriginate with other sensory neurons, in dorsal root ganglia and,like other sensory nerve cells the central axons of nociceptivenerve cells enter the spinal cord via the dorsal roots.

When these centrally projecting axons reach the dorsal horn ofthe spinal cord, they branch into ascending and descendingcollaterals, forming the dorsolateral tract of Lissauer.

Axons in Lissauer’s tract typically run up and down for one ortwo spinal cord segments before they penetrate the gray matterof the dorsal horn.

Once within the dorsal horn, the axons give off branches thatcontact neurons located in several of Rexed’s laminae (theselaminae are the descriptive divisions of the spinal gray matter incross section).

The axons of these second-order neurons in the dorsal horn ofthe spinal cord cross the midline and ascend all the way to thebrainstem and thalamus in the anterolateral (also calledventrolateral) quadrant of the contralateral half of the spinal cord.

These fibers form the spinothalamic tract, the majorascending pathway for information about pain and temperature.

This overall pathway is also referred to as the anterolateralsystem, much as the mechanosensory pathway is referred to asthe dorsal column–medial lemniscus system.

The location of the spinothalamic tract is particularly importantclinically because of the characteristic sensory deficits that followcertain spinal cord injuries.

Since the mechanosensory pathway ascends ipsilaterally in thecord, a unilateral spinal lesion will produce sensory loss of touch,pressure, vibration, and proprioception below the lesion on thesame side.

The pathways for pain and temperature, however, cross themidline to ascend on the opposite side of the cord.

Therefore, diminished sensation of pain below the lesion will beobserved on the side opposite the mechanosensory loss (and thelesion).

This pattern is referred to as a dissociated sensory loss and(together with local dermatomal signs) helps define the level of thelesion.

As is the case of the mechanosensory pathway, informationabout noxious and thermal stimulation of the face follows a separateroute to the thalamus.

First-order axons originating from the trigeminal ganglion cellsand from ganglia associated with nerves VII, IX, and X carryinformation from facial nociceptors and thermoreceptors into thebrainstem.

After entering the pons, these small myelinated and unmyelinatedtrigeminal fibers descend to the medulla, forming the spinaltrigeminal tract (or spinal tract of cranial nerve V), and terminate intwo subdivisions of the spinal trigeminal complex:

the pars interpolari; and pars caudalis.

Axons from the second-order neurons in these two trigeminalnuclei, like their counterparts in the spinal cord, cross the midlineand ascend to the contralateral thalamus in the trigeminothalamictract.

The principal target of the spinothalamic and trigeminothalamicpathway is the ventral posterior nucleus of the thalamus.

Similar to the organization of the mechanosensory pathways,information from the body terminates in the VPL, while informationfrom the face terminate in the VPM.

These nuclei send their axons to primary and secondarysomatosensory cortex.

The nociceptive information transmitted to these cortical areasis thought to be responsible for the discriminative component of pain:

identifying the location;

the intensity; and

quality of the stimulation.

Consistent with this interpretation, electrophysiologicalrecordings from nociceptive neurons in S1, show that theseneurons have small localized receptive fields, propertiescommensurate with behavioral measures of pain localization.

The affective–motivational aspect of pain is evidently mediatedby separate projections of the anterolateral system to thereticular formation of the midbrain (in particular the parabrachialnucleus), and to thalamic nuclei that lie medial to the ventralposterior nucleus (including the so-called intralaminar nuclei).

Studies in rodents show that neurons in the parabrachialnucleus respond to most types of noxious stimuli, and have largereceptive fields that can include the whole surface of the body.

Neurons in the parabrachial nucleus project in turn to thehypothalamus and the amygdala, thus providing nociceptiveinformation to circuits known to be concerned with motivation andaffect.

These parabrachial targets are also the source of projections tothe periaqueductal grey of the midbrain, a structure that plays animportant role in the descending control of activity in the painpathway.

Nociceptive inputs to the parabrachial nucleus and to theventral posterior nucleus arise from separate populations ofneurons in the dorsal horn of the spinal cord.

Parabrachial inputs arise from neurons in the most superficialpart of the dorsal horn (lamina I), while ventral posterior inputsarise from deeper parts of the dorsal horn (e.g., lamina V).

By taking advantage of the unique molecular signature of thesetwo sets of neurons, it has been possible to selectively eliminatethe nociceptive inputs to the parabrachial nucleus in rodents.

In these animals, the behavioral responses to the presentationof noxious stimulation (capsaicin, for example) are substantiallyattenuated.

Projections from the anterolateral system to the medial thalamicnuclei provide nociceptive signals to areas in the frontal lobe, theinsula and the cingulate cortex.

In accord with this anatomy, functional imaging studies inhumans have shown a strong correlation between activity in theanterior cingulate cortex and the experience of a painful stimulus.

Moreover, experiments using hypnosis have been able to teaseapart the neural response to changes in the intensity of a painfulstimulus from changes in its unpleasantness.

Changes in intensity are accompanied by changes in theactivity of neurons in somatosensory cortex, with little change inthe activity of cingulate cortex, whereas changes inunpleasantness are correlated with changes in the activity ofneurons in cingulate cortex.

The cortical representation of pain is the least well documentedaspect of the central pathways for nociception, and further studieswill be needed to elucidate the contribution of regions outside thesomatosensory areas of the parietal lobe.

Nevertheless, a prominent role for these areas in the perceptionof pain is suggested by the fact that ablations of the relevantregions of the parietal cortex do not generally alleviate chronicpain (although they impair contralateral mechanosensoryperception, as expected).

Some Disorders of Sensory System1. Referred Pain

• There are few, if any, neurons in the dorsal horn of the spinalcord that are specialized solely for the transmission of visceralpain.

• The visceral pain is conveyed centrally via dorsal hornneurons that are also concerned with cutaneous pain.

• As a result of this arrangement, disorder of an internal organis sometimes perceived as cutaneous pain.

• This phenomenon is called referred pain.

• The most common clinical example is anginal pain which isreferred to the upper chest wall, with radiation into the left armand hand.

Other important examples are:

gallbladder pain referred to the scapular region;

esophogeal pain referred to the chest wall;

ureteral pain (e.g., from passing a kidney stone) referred to thelower abdominal wall;

bladder pain referred to the perineum; and

the pain from an inflamed appendix referred to the anteriorabdominal wall around the umbilicus.

Understanding referred pain can lead to an astute diagnosisthat might otherwise be missed.

2. Phantom Limbs and Phantom PainFollowing the amputation of an extremity, nearly all patients

have an illusion that the missing limb is still present.

Although this illusion usually diminishes over time, it persists insome degree throughout the amputee’s life and can often bereactivated by injury to the stump or other perturbations.

Such phantom sensations are not limited to amputated limbsbut there could also be:

phantom breasts following mastectomy;

phantom genitalia following castration; and

phantoms of the entire lower body following spinal cordtransection.

Phantoms are also common after local nerve block forsurgery and sometimes during recovery from brachial plexusanesthesia.

These sensory phantoms demonstrate that the centralmachinery for processing somatic sensory information is not idlein the absence of peripheral stimuli.

Apparently, the central sensory processing apparatuscontinues to operate independently of the periphery, giving riseto these bizarre sensations.

The resulting condition is refered to as, a chronic, intenselypainful experience that is difficult to treat with conventionalanalgesic medications.

Neurogenic Quote

……..from this description, it should be evident that

the full experience of sensory sensations (including

mechanosensation, pain and temperature) involve the

cooperative action of an extensive network of brain

regions whose properties are only beginning to be

understood…….

MOVEMENT AND ITS CENTRAL CONTROL

Movements, whether voluntary or involuntary, are producedby muscular contractions orchestrated by the brain and spinalcord.

Analysis of these circuits is fundamental to an understandingof both normal behavior and the etiology of a variety ofneurological disorders.

Ultimately, all movements produced by the skeletalmusculature are initiated by “lower” motor neurons in the spinalcord and brainstem that directly innervate skeletal muscles.

The innervation of visceral smooth muscles is separatelyorganized by the autonomic divisions of the visceral motorsystem.

The lower motor neurons are controlled:

directly by local circuits within the spinal cord and brainstemthat coordinate individual muscle groups; and

indirectly by “upper” motor neurons in higher centers thatregulate those local circuits, thus enabling and coordinatingcomplex sequences of movements.

Especially important of the circuits are in the basal gangliaand cerebellum that regulate the upper motor neurons, ensuringthat movements are performed with spatial and temporalprecision.

Specific disorders of movement often signify damage to aparticular brain region.

Some clinically important and intensively studiedneurodegenerative disorders such as Parkinson’s disease,Huntington’s disease, and amyotrophic lateral sclerosisresult from pathological changes in different parts of the motorsystem.

Knowledge of the various levels of motor control is essentialfor understanding, diagnosing, and treating these diseases.

Overall organization of neural structures involved in the control of movement

Lower and Upper Motor Neurons

• Skeletal (striated) muscle contraction is initiated by “lower”motor neurons in the spinal cord and brainstem.

• The cell bodies of the lower neurons are located in theventral horn of the spinal cord gray matter and in the motornuclei of the cranial nerves in the brainstem.

• The cell bodies of upper motor neurons are located either inthe cortex or in brainstem centers, such as the vestibularnucleus, the superior colliculus, and the reticular formation.

• The axons of the upper motor neurons typically contact thelocal circuit neurons in the brainstem and spinal cord, which,via relatively short axons, contact in turn the appropriatecombinations of lower motor neurons.

These neurons (also called α motor neurons) send axonsdirectly to skeletal muscles via the ventral roots and spinalperipheral nerves, or via cranial nerves in the case of thebrainstem nuclei.

The spatial and temporal patterns of activation of lower motorneurons are determined primarily by local circuits locatedwithin the spinal cord and brainstem.

Descending pathways from higher centers comprise theaxons of “upper” motor neurons and modulate the activity oflower motor neurons by influencing this local circuitry.

The local circuit neurons also receive direct input fromsensory neurons, thus mediating important sensory motorreflexes that operate at the level of the brainstem and spinalcord.

Lower motor neurons, therefore, are the final commonpathway for transmitting neural information from a variety ofsources to the skeletal muscles.

Neural Centers Responsible for Movement

The neural circuits responsible for the control of movementcan be divided into four distinct but highly interactivesubsystems, each of which makes a unique contribution tomotor control.

The first of these subsystems is the local circuitry within thegray matter of the spinal cord and the analogous circuitry in thebrainstem.

The relevant cells of this subsystem include:

the lower motor neurons (which send their axons out of thebrainstem and spinal cord to innervate the skeletal muscles ofthe head and body, respectively); and

the local circuit neurons (which are the major source ofsynaptic input to the lower motor neurons).

All commands for movement, whether reflexive or voluntary,are ultimately conveyed to the muscles by the activity of the lowermotor neurons.

Thus these neurons comprise, the “final common path” formovement.

The second motor subsystem consists of the upper motorneurons whose cell bodies lie in the brainstem or cerebral cortex

Axons of the upper motor neurons descend to synapse with the localcircuit neurons or, more rarely, with the lower motor neurons directly.

The upper motor neuron pathways that arise in the cortex areessential for the initiation of voluntary movements and for complexspatiotemporal sequences of skilled movements.

In particular, descending projections from cortical areas in the frontallobe, including:

Brodmann’s area 4 (the primary motor cortex); the lateral part of area 6 (the lateral premotor cortex); and the medial part of area 6 (the medial premotor cortex)

• Are essential for planning, initiating, and directing sequences ofvoluntary movements.

Upper motor neurons originating in the brainstem areresponsible for regulating muscle tone and for orienting the eyes,head, and body with respect to vestibular, somatic, auditory, andvisual sensory information.

Their contributions are thus critical for basic navigationalmovements, and for the control of posture.

The third and larger of these subsystems, the cerebellum, islocated on the dorsal surface of the pons.

The cerebellum acts via its efferent pathways to the uppermotor neurons as a servomechanism, detecting the difference,or “motor error,” between an intended movement and themovement actually performed.

The cerebellum uses this information about discrepancies tomediate both real-time and long-term reductions in these motorerrors (the latter being a form of motor learning).

As might be expected from this account, patients withcerebellar damage exhibit persistent errors in movement.

The fourth subsystem, embedded in the depths of theforebrain, consists of a group of structures collectively referred toas the basal ganglia.

The basal ganglia suppress unwanted movements andprepare (or “prime”) upper motor neuron circuits for the initiationof movements.

The problems associated with disorders of basal ganglia, such asParkinson’s disease and Huntington’s disease, attest to theimportance of this complex in the initiation of voluntary movements.

Despite much effort, the sequence of events that leads fromvolitional thought to movement is still poorly understood.

The picture is clearest, however, at the level of control of themuscles themselves.

It therefore makes sense to begin an account of motor behaviorby considering the anatomical and physiological relationshipsbetween lower motor neurons and the muscle fibers they innervate.

The third and fourth subsystems are complex circuits with outputpathways that have no direct access to either the local circuitneurons or the lower motor neurons; instead, they controlmovement by regulating the activity of the upper motor neurons.

Upper motor neuron and their control of theBrainstem and the spinal cord

The axons of upper motor neurons descend from highercenters to influence the local circuits in the brainstem andspinal cord

This is done by coordinating the activity of lower motorneurons.

The sources of these upper motor neuron pathways include:

several brainstem centers; and

a number of cortical areas in the frontal lobe.

Upper motor neurons in the Brain Stem

The motor control centers in the brainstem are especiallyimportant in postural control each having a distinct influence:

i) the vestibular nuclear complex; and

ii) the reticular formation

The above two have widespread effects on body position.

iii) the red nucleus controls movements of the arms;

iv) the superior colliculus contains upper motor neurons thatinitiate orienting movements of the head and eyes.

Upper motor neurons in the Frontal Lobe

Upper motor neurons in the frontal cortex are located in:i) the motor; and

ii) premotor areas

The motor and premotor areas of the frontal lobe areresponsible for the planning and precise control of complexsequences of voluntary movements.

Most upper motor neurons, regardless of their source,influence the generation of movements by directly affecting theactivity of the local circuits in the brainstem and spinal cord.

Upper motor neurons in the cortex also control movementindirectly, via pathways that project to the brainstem motorcontrol centers, which, in turn, project to the local organizingcircuits in the brainstem and cord.

A major function of these indirect pathways is to maintain thebody’s posture during cortically initiated voluntary movements.

The efferent cells of thecerebellum do not projectdirectly either to the localcircuits of the brainstem andspinal cord that organizemovement, or to the lower motorneurons that innervate muscles.

The cerebellum (like the basalganglia) influences movementsby modifying the activitypatterns of the upper motorneurons.

In fact, the cerebellum sendsprominent projections to virtuallyall upper motor neurons.

Modulation of Movement by the Cerebellum

Structurally, the cerebellumhas two main components:

a laminated cerebellar cortex;and

a subcortical cluster of cellsreferred to collectively as thedeep cerebellar nuclei.

Pathways that reach thecerebellum (afferent pathways)from other brain regions (inhumans, predominantly thecerebral cortex) project to bothcomponents.

The output cells of the cerebellar cortex project to the deepcerebellar nuclei, which give rise to the main efferent pathways thatleave the cerebellum to regulate upper motor neurons in thecerebral cortex and brainstem.

Thus, much like the basal ganglia, the cerebellum is part of a vastloop that receives projections from and sends projections back tothe cerebral cortex and brainstem.

The primary function of the cerebellum is evidently to detect thedifference, or “motor error,” between an intended movement andthe actual movement, and, through its projections to the uppermotor neurons, to reduce the error.

These corrections can be made both during the course of themovement and as a form of motor learning when the correction isstored.

When this feedback loop is damaged, as occurs in manycerebellar diseases, the afflicted individuals make persistentmovement errors whose specific character depends on the locationof the damage.

The cerebellum can besubdivided into three mainparts based on differencesin their sources of input:

1) Cerebrocerebellum, thelargest subdivision in humans.

It occupies most of thelateral cerebellarhemisphere and receivesinput from many areas ofthe cerebral cortex.

This region of the cerebellumis especially well developedin primates.

Organization of the Cerebellum

The cerebrocerebellum isconcerned with theregulation of highly skilledmovements, especially theplanning and execution ofcomplex spatial and temporalsequences of movement(including speech).

2) Vestibulocerebellum, thephylogenetically oldest part ofthe cerebellum.

This portion comprises thecaudal lobes of thecerebellum that includes:

the flocculus; and the nodulus.

As its name suggests, thevestibulocerebellum receivesinput from the vestibular nucleiin the brainstem and is primarilyconcerned with the regulation ofmovements underlying postureand equilibrium.

3) Spinocerebellum is the last ofthe major subdivisions of thecerebellum.

The spinocerebellum occupiesthe median and paramedianzone of the cerebellarhemispheres and is the only partthat receives input directly fromthe spinal cord.

The lateral part of thespinocerebellum is primarilyconcerned with movements ofdistal muscles, such as therelatively gross movements ofthe limbs in walking.

The central part, called thevermis, is primarily concernedwith movements of proximalmuscles, and also regulates eyemovements in response tovestibular inputs.

The connections between the cerebellum and other parts of thenervous system occur via three large pathways called cerebellarpeduncles.

i) The superior cerebellar peduncle (or brachium conjunctivum)is almost entirely an efferent pathway.

Connections between Cerebellum and other NS Regions

The neurons that give rise to this pathway are in the deepcerebellar nuclei, and their axons project to upper motorneurons in the red nucleus, the deep layers of the superiorcolliculus, and, after a relay in the dorsal thalamus, the primarymotor and premotor areas of the cortex.

ii) The middle cerebellarpeduncle (or brachium pontis)is an afferent pathway to thecerebellum.

Most of the cell bodies thatgive rise to this pathway are inthe base of the pons, where theyform the pontine nuclei.

The pontine nuclei receiveinput from a wide variety ofsources, including almost allareas of the cerebral cortex andthe superior colliculus.

The axons of the pontinenuclei, called transversepontine fibers, cross themidline and enter the cerebellumvia the middle cerebellarpeduncle.

The pontine nuclei receiveinput from a wide variety ofsources, including almost allareas of the cerebral cortexand the superior colliculus.

The axons of the pontinenuclei, called transversepontine fibers, cross themidline and enter thecerebellum via the middlecerebellar peduncle.

Each of the two middlecerebellar peduncles containover 20 million axons,making this one of the largestpathways in the brain.

Most of these pontine axonsrelay information from thecortex to the cerebellum.

iii) The inferior cerebellarpeduncle (or restiform body)is the smallest but mostcomplex of the cerebellarpeduncles.

It contains multiple afferentand efferent pathways:

Efferent pathways in thispeduncle project to thevestibular nuclei and thereticular formation;

the afferent pathwaysinclude axons from thevestibular nuclei, the spinalcord, and several regions ofthe brainstem tegmentum.

1. The central processingcomponent, thecerebrocerebellar cortex,receives massive input fromthe cerebral cortex.

2. It then generates signals thatadjust the responses ofupper motor neurons toregulate the course of amovement.

3. Note that modulatory inputsalso influence the processingof information within thecerebellar cortex.

Summary diagram of motor modulation by thecerebrocerebellum

4. The output signals from thecerebellar cortex are relayedindirectly to the thalamus andthen back to the motorcortex, where they modulatethe motor commands.

BASAL GANGLIAThe term “basal ganglia”

refers to the collection of grey

matter made of cell bodies lying

deep inside the white matter of

the cerebrum, and makes up part

of the midbrain.

It consists of a large and

functionally diverse set of nuclei

that lie deep within the cerebral

hemispheres.

Anatomy of the Basal Ganglia

The subset of these nuclei

relevant to motor function

includes:

the caudate;

putamen; and

the globus pallidus.

Two additional structures are:

the substantia nigra in the

base of the midbrain; and

the subthalamic nucleus in the

ventral thalamus.

Components of the Basal GangliaComponents of the Basal Ganglia

These additional structures are closely associated with the

motor functions of these basal ganglia nuclei.

The components of the basal ganglia, effectively make a

subcortical loop that links most areas of the cortex with upper

motor neurons in the primary motor and premotor cortex and in

the brainstem.

The neurons in this loop respond in anticipation of and during

movements, and their effects on upper motor neurons are

required for the normal course of voluntary movements.

On the overall, the basal ganglia receive large amount of inputfrom the cerebral cortex and after processing send it back to thecerebral cortex via the thalamus.

This major pathway led to the creation of the popular conceptof cortico-basal ganglia- cortical loops.

When one of these components of the basal ganglia orassociated structures is compromised, the patient cannot switchsmoothly between commands that initiate a movement and thosethat terminate the movement.

The disordered movements that result can be understood as aconsequence of abnormal upper motor neuron activity in theabsence of the supervisory control normally provided by thebasal ganglia.

The globus pallidus is divided into external and internalsegments (GPe and GPi).

The substantia nigra is divided into pars compacta and parsreticulata.

The caudate nucleus and putamen are collectively called the(corpus) striatum.

The putamen and globus pallidus form the lenticular nucleus.

The main inputs (input zone) to the basal ganglia terminate inthe striatum with their neurons being the destinations ofmost of the pathway that reach the basal ganglia from otherparts of the brain.

The inputs from the cerebral cortex that reach the basalganglia found their destinations on the dendrites of the mediumspiny neurons in the corpus striatum.

Projections (Input) to the Basal GangliaThe connections between the

parts of the basal ganglia include:

The striatum projects to both GPeand GPi. a dopaminergic nigrostriatalprojection from the substantia nigrapars compacta to the striatum; and

a corresponding GABAergicprojection from the striatum tosubstantia nigra pars reticulata.

• GPe projects to the subthalamicnucleus, which in turn projects toboth GPe and GPi.

The principal output from thebasal ganglia is from GPi viathe thalamic fasciculus to the:

ventral lateral;

ventral anterior, and

centromedian nuclei of thethalamus.

From the thalamic nuclei, fibersproject to the prefrontal andpremotor cortex.

The substantia nigra also projectsto the thalamus.

Projections (output) from the Basal Ganglia

The main feature of theconnections of the basal ganglia isthat:

1. the cerebral cortex projects to thestriatum,

2. the striatum to GPi,

3. GPi to the thalamus, and

4. the thalamus back to the cortex,completing a loop.

The output from GPi to thethalamus is inhibitory, whereasthe output from the thalamus tothe cerebral cortex is excitatory.

Functions of the Basal Gangliai. Act by modifying ongoing activity in motor pathways.

ii. Inhibit muscle tone (proper tone – balance the excitatory andinhibitory inputs to motor neurons that innervate skeletal muscle).

iii. Select and maintain purposeful motor activity whilesuppressing unwanted patterns of movement

iv. Monitor and coordinate slow and sustained contractions,especially those related to posture and support.

v. Regulate attention and cognition

vi. Control timing and switching

vii. Motor planning and learning

Circuits within the Basal Ganglia System

A) Direct Pathway

The pathway to the cortex arises primarily in the internalglobus pallidus and reaches the motor cortex after a relay in theventral anterior (VA) and ventral lateral (VL) nuclei of thedorsal thalamus.

These two nuclei directly project to motor areas of the cortexthus completing a vast loop that originates in multiple corticalareas and terminates back in the motor areas of the frontal lobe.

In humans for e.g. the corpus striatum contains about 100million neurons, about 75% of which are medium spinyneurons.

Organization of the Basal Ganglia(direct pathway)

Substantia nigraPars reticulata

Chain of Nerve Cells Arranged in aChain of Nerve Cells Arranged in aDisinhibitoryDisinhibitory CircuitCircuit

In contrast, the main destination of their axons, the globuspallidus, comprises only about 700,000 cells.

Thus on the average about 140 medium spiny neuronsinnervate each pallidal cell.

The efferent neurons of the internal globus pallidus andsubtantia nigra reticulata together give rise to major pathwaysthat link the basal ganglia with upper motor neurons in the cortexand brain stem.

In contrast, the axons from the substantia nigra parsreticulata synapse on upper motor neurons in the superiorcolliculus that command eye movements without relay in thedorsal thalamus.

This difference between in globus pallidus and substantianigra pars reticulata is not absolute.

This is because many reticulata axons also project to thethalamus where they contact relay neurons that project to thefrontal eye fields of the premotor cortex.

Because the efferent cells of both the globus pallidus and thesustantia nigra pars reticulata are both GABAergic, the mainoutput of the basal ganglia is inhibitory.

These output zones (in contrast to the inactive medium spinyneurons) have high levels of spontaneous activity that tend toprevent unwanted movements by tonically inhibiting cells in thesuperior colliculus and thalamus.

The net effect of the excitatory inputs that reach the striatumfrom the cortex is to inhibit the tonically active inhibitory cellsof the globus pallidus and substantia nigra pars reticulata.

When the pallidal cells are inhibited, the thalamic neurons arethen disinhibited and relay signals from other sources to theupper motor neurons in the cortex.

This disinhibition is what normally allows the upper motorneurons to send commands to local circuit and lower motorneurons that initiate movements.

Conversely, an abnormal reduction in the tonic inhibition as aresult of basal ganglia dysfunction leads to excessiveexcitability of the upper motor neurons, and thus to theinvoluntary movement syndromes that are characteristic ofbasal ganglia disorders such as Huntington’s disease.

Chain of Nerve Cells Arranged in aChain of Nerve Cells Arranged in a DisinhibitoryDisinhibitory CircuitCircuit

DisinhibitionDisinhibition in the Direct Pathwayin the Direct Pathway

B) Indirect Pathway

This pathway serves to increase the level of tonic inhibitionand provides a second route that links the corpus striatum tothe internal globus pallidus and the subtantia nigra parsreticulata.

In this pathway, a population of medium spiny neuronsprojects to the external globus pallidus which in turn sendsprojections to the internal globus pallidus and to thesubthalamic nucleus of the ventral thalamus.

The subthalamic nucleus instead of projecting outside thebasal ganglia it projects excitatory neurons backwards into theinternal globus pallidus and the substantia nigra pars reticulata.

Organization of the Basal Ganglia (indirect pathway)

The indirect pathway influences the activity of the upper

motor neurons and serves to modulate the disinhibitory actions

of the direct pathway.

Normally, when the indirect pathway is activated by the

signals from the cerebral cortex the medium spiny neurons

discharge and inhibit the tonically active GABAergic neurons

of the external globus pallidus.

As, a result, the subthalamic cells become more active and by

virtue of their excitatory synapses with cells of the internal

globus pallidus and sustantia nigra reticulata, they increase the

inhibitory outflow of the basal ganglia.

Thus in contrast to the direct pathway, which whenactivated reduces tonic inhibition, the net effect of theindirect pathway is to increase inhibitory influences on theupper motor neurons.

Therefore, the indirect pathway can be regarded as a“brake” on the normal function of the direct pathway.

The consequences of imbalances in this fine controlmechanism are apparent in diseases that affect thesubthalamic nucleus.

These disorders remove a source of excitatory input tothe internal globus pallidus and substantia nigra parsreticulata, and thus abnormally reduce the inhibitoryoutflow of the basal ganglia.

A basal ganglia syndrome called the hemiballismus,which is characterized by violent, involuntary movementsof the limbs is the result of damage to subthalamicnucleus.

The involuntary movements are initiated by abnormaldischarges of the upper motor neurons that are receivingless tonic inhibition from basal ganglia.

Neurotransmitters of the Basal Ganglia

Corticostriatal projections are glutamatergic (excitatory)

Projections from caudate, putamen, GPi, Gpe, and SNprare all GABAergic (inhibitory)

Subthalamic nucleus projections to GPi are glutamatergic(excitatory)

Nigrostriatal projections are dopaminergic (eitherexcitatory or inhibitory, depending on striatal cell type)

Basal Ganglia Associated Neurodegenerative Disorders

Parkinson’s Disease

Age of onset >65 years old Uncommon before 40 years old Estimated 1.5% of population affected over 65 years old,

2.5% over 85 years old. Loss of dopamine producing neurons in the substantia

nigra (50-60%) 80% loss of striatal DA Etiology unknown Very recent discovery of several familial forms

On striatal MSNs of the direct pathway, dopamineexerts an excitatory influence because these cellsexpress D1 receptors, which are positively linked to cAMPformation and cell excitability.

On striatal MSNs of the indirect pathway, dopamineexerts an inhibitory influence because these cells expressD2 receptors, which are negatively coupled to cAMPformation and cell excitability.

Parkinson’s Disease Symptoms

Resting tremor Impairment of balance and coordination Muscle rigidity (cogwheel) Difficulty initiating movement Micrographia (shrinking handwriting) Decreased facial expression Late stages include depression, fatigue, sleep

disorders, hallucinations, psychosis and dementia Loss of DA to the striatum causes increased activity of

the indirect pathway and decreased activity in directpathway (D1, D2 receptors)

Cognitive Impairments in Parkinson’s Disease

Bradyphrenia: slowing of thought processes

Memory, specifically retrieving information innonstructured situations/spatial working memory

Emotional functioning: depression is common

Decrease in executive functioning

Some Parkinson’s Treatments

• L-DOPA: Dopamineprecursor allows moredopamine to be made byremaining cells.

• Subthalamic nucleusstimulation.

• Dopamine transplants-Stem cells.

Huntington disease (HD)

It is heritable

Progressive, untreatable, decreased function anddementia

Genetic defect in gene called huntington

Autosomal dominant– gene defect on chromosome 4– CAG repeats

• 70-100 - HD as juveniles• >40 – anticipation

Choreiform movements leading to severe impairment;death within 15 years

Loss of about 90% of striatal neurons, especially ofindirect pathway: overactivity of direct pathway:uncontrolled movements.

Five characteristic features of HD Heritability Chorea Behavioral/psychiatric disturbances Dementia Death within 15-20 years of onset

Mechanism of Huntington Disease

Striatal neurons givingrise to indirect pathwayare selectively lost

In advanced HD, lossof striatal neuronsprojecting to internalpallidum

Hemiballismus It is usually characterized by involuntary flingingmotions of the extremities.

The movements are often violent and have wideamplitudes of motion.

Some of the symptoms include:• Involuntary movements on one side of the body• Involuntary muscle spasms on one side of the body• Violent movements involving one side of the body• Usually arms are more affected than the legs

Learning Objectives

Describe the various types of long-term memory.

Define synaptic plasticity, long-term potentiation, long-termdepression, habituation, and sensitization, and their roles inlearning and memory.

List the parts of the brain that are involved in memory andtheir role in memory processing and storage.

Describe the abnormalities of brain structure and functionfound in Alzheimer disease.

PHYSIOLOGY OF LEARNING AND MEMORY

IntroductionA revolution in our understanding of brain function has been

brought about by the development and widespread availabilityof techniques of assessing the brain function.

Today, we have more than a dozen techniques that arerapidly evolving toward greater precision and a broader range ofapplication.

The most widely used methods are EEG, positron emissiontomography (PET), magnetic resonance imaging (MRI),functional MRI (fMRI), and magnetoencephalography (MEG).

Positron emission tomography is often used to measure localglucose metabolism, which is proportionate to neural activity,and fMRI is used to measure local amounts of oxygenatedblood.

These techniques make it possible to determine the activity invarious parts of the brain in healthy subjects and in those withvarious diseases.

They have been used to study not only simple responses, butalso complex aspects of learning, memory, and perception.

An example of the use of PET scans to study the functions ofthe cerebral cortex in processing words is shown in figure (nextslide).

Different portions of the cortex are activated when a person ishearing, seeing, speaking, or generating words.

Images of active areas of the brain in a male (left) and female (right) during a language task. Note thatmales use only one side of the brain whereas females use both sides of thebrain when language is being processed (Adapted from Medical Physiology: a Systems Approach byHershel and Michael. McGraw-Hill Company, 2011).

DefinitionsLearning is acquisition of

information that makes itpossible to alter behavior onthe basis of experience, andmemory is the retention andstorage of that information.

The two are obviouslyclosely related and should beconsidered together.

From a physiologic point ofview, memory is divided intoexplicit and implicit forms.

Areas concerned with encoding explicit memories. Theprefrontal cortex and the parahippocampal cortex of thebrain are active during the encoding of memories (Adaptedfrom Rugg (1998);. Memories are made of this. Science.281(5380):1151–1152.)

Areas concerned with encoding explicit memories. Theprefrontal cortex and the parahippocampal cortex of thebrain are active during the encoding of memories (Adaptedfrom Rugg (1998);. Memories are made of this. Science.281(5380):1151–1152.)

A) Explicit or DeclarativeMemory

It is associated withconsciousness (or at leastawareness).

It is dependent on thehippocampus and other partsof the medial temporal lobesof the brain for its retention.

Explicit memory issubdivided into:

Areas concerned with encoding explicit memories. Theprefrontal cortex and the parahippocampal cortex of thebrain are active during the encoding of memories (Adaptedfrom Rugg (1998);. Memories are made of this. Science.281(5380):1151–1152.)

episodic memory for events; and

semantic memory for facts (e.g., words, rules, andlanguage).

Explicit memories initially required for activities such as ridinga car can become implicit once the task is thoroughly learned.

B) Implicit or Non-declarative Memory

It does not involve awareness, and its retention does notusually involve processing in the hippocampus.

Implicit memory is subdivided into four types : (P2AN)

Procedural memory that includes skills and habits, which,once acquired, become unconscious and automatic.

Priming which means facilitation of recognition of words orobjects by prior exposure to them. An example is improvedrecall of a word when presented with the first few letters of it.

Non associative learning in which a person (one) learnsabout a single stimulus.

Associative learning, one learns about the relation of onestimulus to another.

Explicit memory and many forms of implicit memory aresubdivided into short term and long term memories

Types of Memory

1. Short term memory which lasts seconds to hours, duringwhich processing in the hippocampus and elsewhere leads tolong-term changes in synaptic strength.

During short term memory, the memory traces are subject todisruption by trauma and various drugs.

Working memory is a form of short-term memory thatkeeps information available, usually for very short periods, whilethe individual plans action based on it.

2. Long term memory, which stores memories for years andremarkably resistant to disruption.

Physiologic Mechanism of Learning and Memory(Synaptic Plasticity)

The key to memory is alteration in the strength of selectedsynaptic connections referred to as Synaptic Plasticity.

In all but the simplest of cases, the alteration involvesactivation of genes and protein synthesis.

This occurs during the change from short term workingmemory to long term memory.

If an intervention occurs too soon after a training session,acquisition of long term memory is impaired.

This is exemplified by the loss of memory for the eventsimmediately preceding brain concussion or electroshocktherapy (retrograde amnesia).

Short term and long term changes in synaptic function canoccur as a result of the history of discharge at a synapse.

This means that synaptic conduction can be strengthened orweakened on the basis of past experience.

These changes, which can be presynaptic or postsynaptic, areof great interest because they represent forms of learning andmemory.

One form of plastic change is post tetanic potentiation, theproduction of enhanced postsynaptic potentials in response tostimulation.

This enhancement lasts up to 60 seconds and occurs after abrief (tetanizing) train of stimuli in a presynaptic neuron.

The stimulation causes Ca2+ to accumulate in thepresynaptic neuron to such a degree that the intracellularbinding sites that keep cytoplasmic Ca2+ low are overwhelmed.

Habituation is a simple form of learning in which a stimulusis repeated many times.

The first time it is applied it is novel and evokes a reaction(the “what is it?” response); however, it evokes less and lesselectrical response as it is repeated.

Eventually, the subject becomes habituated to the stimulusand ignores it.

This is associated with decreased release of neurotransmitterfrom the presynaptic terminal because of decreasedintracellular Ca2+.

The decrease in intracellular Ca2+ is due to a gradualinactivation of Ca2+ channels.

It can be short term, or it can be prolonged if exposure to thebenign stimulus is repeated many times.

Habituation is a classic example of non associative learning.

Sensitization is the prolonged occurrence of augmentedpostsynaptic responses after a stimulus to which one hasbecome habituated is paired once or several times with aanother stimulus.

It is due to presynaptic facilitation and may occur as atransient response.

Concept of Long Term Potentiation (LTP)The LTP is a rapidly developing persistent enhancement of

the postsynaptic potential response to presynaptic stimulationafter a brief period of rapidly repeated stimulation of thepresynaptic neuron.

It resembles post tetanic potentiation but is much moreprolonged and can last for days.

Unlike post tetanic potentiation, LTP is initiated by anincrease in intracellular Ca2+ in the postsynaptic rather thanthe presynaptic neuron.

It occurs in many parts of the CNS but has been studied ingreatest detail in the hippocampus.

If it is reinforced by additional pairings of the stimulus andthe initial stimulus, it can exhibit features of short term or longterm memory.

The short-term prolongation of sensitization is due to a Ca2+-mediated change in adenylyl cyclase that increases productionof cAMP.

The LTP involves protein synthesis and growth of thepresynaptic and postsynaptic neurons and their connections.

There are two forms of LTP:

a) Mossy fiber LTP, which is presynaptic and independent ofN-methyl-d- aspartate (NMDA) receptors

b) Schaffer collateral LTP, which is postsynaptic and NMDAreceptor- dependent.

The hypothetical basis of the latter form is summarized in thefollowing figure (next slide).

Production of long-term potentiation (LTP) in Schaffer collaterals in the hippocampus (Courtesy of R.Nicoll)

Production of Long Term Potentiation (LTP) in SchafferCollaterals in the Hippocampus

Glutamate (Glu) released from the presynaptic neuron bindsto α-amino-3-hydroxyl-5- methyl-4-isoxazole-propionate(AMPA), N-methyl-d-aspartate (NMDA) and Kainate (recentlyfound) receptors in the membrane of the postsynaptic neuron.

The depolarization triggered by activation of the AMPAreceptors relieves the Mg2+ block in the NMDA receptorchannel, and Ca2+ enters the neuron with Na+.

The increase in cytoplasmic Ca2+ activates calmodulin(CaM), which in turn activates Ca2+/calmodulin kinase II(CaM kII).

The kinase phosphorylates the AMPA receptors (P),increasing their conductance, and moves more AMPA receptorsinto the synaptic cell membrane from cytoplasmic storage sites.

In addition, a chemical signal (PS) may pass to thepresynaptic neuron, producing a long-term increase in thequantal release of glutamate.

Working MemoryWorking memory areas are

connected to the hippocampusand the adjacent parahippocampalportions of the medial temporalcortex.

Bilateral destruction of theventral hippocampus, or Alzheimerdisease (described below) andsimilar disease processes thatdestroy its CA1 neurons, causesstriking defects in short-termmemory.

Individuals with such destructionhave intact working memory andremote memory.

Their implicit memoryprocesses are generallyintact.

Working memory areas areconnected to the hippocampusand the adjacent parahippocampalportions of the medial temporalcortex.

Bilateral destruction of theventral hippocampus, or Alzheimerdisease and similar diseaseprocesses that destroy its CA1neurons, causes striking defects inshort-term memory.

Individuals with such destructionhave intact working memory andremote memory. Their implicit memory

processes are generallyintact.

The hippocampus is closely associated with the overlyingparahippocampal cortex in the medial frontal lobe.

When subjects recall words, activity in their left frontal lobeand their left parahippocampal cortex increases, but when theyrecall pictures or scenes, activity takes place in their rightfrontal lobe and the parahippocampal cortex on both sides.

The connections of the hippocampus to the diencephalonare also involved in memory.

Some people with alcoholism related brain damage developimpairment of recent memory, and the memory loss correlateswell with the presence of pathologic changes in the mamillarybodies, which have extensive efferent connections to thehippocampus via the fornix.

The mamillary bodies project to the anterior thalamus viathe mamillothalamic tract.

From the thalamus, the fibers concerned with memory projectto the prefrontal cortex and from there to the basal forebrain.

From the basal forebrain, a diffuse cholinergic projectiongoes to all of the neocortex, the amygdala, and thehippocampus from the nucleus basalis of Meynert.

Severe loss of these fibers occurs in Alzheimer disease.

The amygdala is closely associated with the hippocampusand is concerned with encoding and recalling emotionallycharged memories.

During retrieval of fearful memories, the theta rhythms of theamygdala and the hippocampus become synchronized.

In healthy subjects, events associated with strong emotionsare remembered better than events without an emotionalcharge, but in patients with bilateral lesions of the amygdala,this difference is absent.

Long Term MemoryWhile the encoding process for short-term explicit memory

involves the hippocampus, long-term memories are stored invarious parts of the neocortex.

Various parts of the memories—visual, olfactory, auditory,etc. are located in the cortical regions concerned with thesefunctions.

These parts are tied together by long term changes in thestrength of transmission at relevant synaptic junctions so that allthe components are brought to consciousness when thememory is recalled.

Once long-term memories have been established, they canbe recalled or accessed by many different associations.

For example, the memory of a vivid scene can be evoked notonly by a similar scene, but also by a sound or smell associatedwith the scene.

Thus, each stored memory must have multiple routes, andmany memories have an emotional component.

Some Learning/Memory (Neurodegenerative) DisordersAlzheimer disease is the most common age-related

neurodegenerative disorder.

Memory decline initially manifests as a loss of episodic memory,which impedes recollection of recent events.

Loss of short-term memory is followed by general loss ofcognitive and other brain functions, the need for constant care,and, eventually, death.

The cytopathologic hallmarks of the disease are intracellularneurofibrillary tangles, made up in part of hyperphosphorylatedforms of the tau protein that normally binds to microtubules.

Comparison of a normal neuron (A) and one with abnormalities associated with Alzheimer disease(B) (Adapted from Kandel et al., (2000). Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

The Aβ peptides are products of a normal protein, amyloidprecursor protein (APP), a transmembrane protein thatprojects into the extracellular fluid (ECF) from all nerve cells.

This protein is hydrolyzed at three different sites by α-, β-,and γ-secretase, respectively. When APP is hydrolyzed by α-secretase, nontoxic peptide products are produced.

However, when it is hydrolyzed by β- and γ-secretase,polypeptides with 40–42 amino acids are produced; the actuallength varies because of variation in the site at which γ-secretase cuts the protein chain.

These polypeptides are toxic, the most toxic being Aβσ1–42.

The polypeptides form extracellular aggregates, which canstick to and Ca2+ ion channels, increasing Ca2+ influx.

Another pathology is the extracellular senile plaques, whichhave a core of β-amyloid peptides (Aβ) surrounded by alterednerve fibers and reactive glial cells.

They also initiate an inflammatory response, with productionof intracellular tangles and the damaged cells eventually die.

An interesting finding that may have broad physiologicimplications is that frequent effortful mental activities slow theonset of cognitive dementia due to Alzheimer disease andvascular disease.

The explanation for this “use it or lose it” phenomenon is asyet unknown, but it certainly suggests that the hippocampusand its connections have plasticity like other parts of the brain.

PHYSIOLOGY OF LANGUAGE AND SPEECHMemory and learning are functions of large parts of the brain.

On the other hand, centers controlling some of the other“higher functions of the nervous system,” particularly themechanisms related to language, are more or less localized tothe neocortex.

Human language functions depend more on one cerebralhemisphere than on the other. This is called the dominanthemisphere and is concerned with categorization andsymbolization.

The other hemisphere is not less developed “non-dominant”;instead, it is specialized in the area of spatiotemporal relations.

It is this hemisphere that is concerned, for example, with theidentification of objects by their form and plays a primary role inthe recognition of faces.

This contributes to the concept of complementaryspecialization of the hemispheres, one for sequential-analyticprocesses (the categorical hemisphere) and one forvisuospatial relations (the representational hemisphere).

The categorical hemisphere is concerned with languagefunctions. Lesions in the categorical hemisphere producelanguage disorders.

In contrast, lesions in the representational hemisphere leadto astereognosis, the inability to identify objects by feelingthem.

Hemispheric specialization is related to handedness.

In 96% of right-handed individuals, who constitute 91% ofthe human population, the left hemisphere is the dominant orcategorical hemisphere, and in the other 4%, the righthemisphere is dominant.

In 70% of left-handers, the left hemisphere is also thecategorical hemisphere; in 15%, the right hemisphere is thecategorical hemisphere; and in 15%, there is no clearlateralization.

Learning disabilities such as dyslexia (an impaired ability tolearn to read) are 12 times as common in left-handers as theyare in right-handers, possibly because some fundamentalabnormality in the left hemisphere led to a switch inhandedness early in development.

The spatial talents of lefthanders may be well above averageas a disproportionately large number of artists, musicians, andmathematicians are left-handed.

Some anatomic differences between the two hemispheresmay correlate with the functional differences.

The planum temporale, an area of the superior temporalgyrus that is involved in language-related auditory processing,is regularly larger on the left side than the right.

Imaging studies show that other portions of the upper surfaceof the left temporal lobe are larger in right-handed individuals,the right frontal lobe is normally thicker than the left, and the leftoccipital lobe is wider and protrudes across the midline.

In patients with schizophrenia, a disorder characterized by adistorted sense of reality, MRI studies show reduced volumes ofgray matter on the left side in the anterior hippocampus,amygdala, parahippocampal gyrus, and posterior superiortemporal gyrus.

The degree of reduction in the left superior temporal gyruscorrelates with the degree of disordered thinking in the disease.

There are also apparent abnormalities of dopaminergicsystems and cerebral blood flow in this disease.

SPINAL REFLEXESLearning ObjectivesAt the end of the following lesson, it is expected that the student

can: Describe the components of a reflex arc.

Describe the muscle spindles and their role in the stretch reflex.

Describe the functions of the Golgi tendon organs as part of afeedback system that maintains muscle force.

Define reciprocal innervation, inverse stretch reflex, and clonus.

Describe the short- and long-term effects of spinal cord injuryon spinal reflexes.

INTRODUCTION

The basic unit of integrated reflex activity is the reflex arc.

This arc consists of a sense organ, an afferent neuron,synapses within a central integrating station, an efferent neuron,and an effector organ.

The afferent neurons enter the central nervous system (CNS)via the spinal dorsal roots or cranial nerves and have their cellbodies in the dorsal root ganglia or in the homologous gangliafor the cranial nerves.

The efferent fibers leave the CNS via the spinal ventral rootsor corresponding motor cranial nerves.

Activity in the reflex arc starts in a sensory receptor with agenerator potential whose magnitude is proportional to thestrength of the stimulus.

This generates all-or-none action potentials in the afferentnerve, the number of action potentials being proportional to thesize of the generator potential.

In the CNS, the responses are again graded in terms ofexcitatory postsynaptic potentials (EPSPs) and inhibitorypostsynaptic potentials (IPSPs) at the synaptic junctions.

The postsynaptic potentials (PSPs) are either:

excitatory postsynaptic potentials (EPSPs), if their effect isto make the postsynaptic cell more likely to respond with anaction potential; or

inhibitory postsynaptic potentials (IPSPs), if they make thepostsynaptic cell less likely to fire an action potential.

All-or-none responses are generated in the efferent nerve.

Activity within the reflex arc is modified by the multiple inputsconverging on the efferent neurons or at any synaptic stationwithin the reflex loop.

The simplest reflex arc is one with a single synapse betweenthe afferent and efferent neurons.

Such arcs are monosynaptic, and reflexes occurring in themare called monosynaptic reflexes.

Reflex arcs in which one or more interneuron is interposedbetween the afferent and efferent neurons are calledpolysynaptic reflexes.

There can be anywhere from two to hundreds of synapses in apolysynaptic reflex arc.

It is evident that reflex activity is stereotyped and specific interms of both the stimulus and the response; a particularstimulus elicits a particular response.

The Stretch Reflex

This reflex is an example of monosynaptic reflex.

When a skeletal muscle with an intact nerve supply isstretched, it contracts.

The sense organ (receptor) is a small encapsulatedspindlelike or fusiform shaped structure called the musclespindle, located within the fleshy part of the muscle.

The impulses originating from the spindle are transmitted tothe CNS by fast sensory fibers (group Ia) that pass directly to themotor neurons that supply the same muscle.

The stretch reflex is the best-known and studied monosynapticreflex and is typified by the knee-jerk reflex.

The stimulus that initiates the reflex is stretch of the muscle,and the response is contraction of the same muscle.

The Withdrawal Reflex

The withdrawal reflex is a typical polysynaptic reflex thatoccurs in response to a painful stimulation of the skin orsubcutaneous tissues and muscle.

The response is flexor muscle contraction and inhibition ofextensor muscles, so that the body part stimulated is flexed andwithdrawn from the stimulus.

When a strong stimulus is applied to a limb, the responseincludes not only flexion and withdrawal of that limb, but alsoextension of the opposite limb.

This crossed extensor response is part of the withdrawalreflex.