Clicker Question Clicker Question

_________is(are) the generation of _________is(are) the generation of unregulated electrical discharges from unregulated electrical discharges from scar tissue in the gray matter of the brain, scar tissue in the gray matter of the brain, which causes the muscles in the body to which causes the muscles in the body to contract.contract.A) Polyneuritis (beriberi)A) Polyneuritis (beriberi)B) The voltaic pilesB) The voltaic pilesC) GalvanismC) GalvanismD) PellagraD) PellagraE) EpilepsyE) Epilepsy

Pale Blue Dot

Where are we?Where are we? Last time I discussed…Last time I discussed…

the evidence that led us to know that the nervous signal is the evidence that led us to know that the nervous signal is electrical.electrical.

biomechanical and bioelectrical devices produced by biomechanical and bioelectrical devices produced by bioengineers that interface with the nervous system. bioengineers that interface with the nervous system.

This time I will discuss…This time I will discuss… the structure of neurons.the structure of neurons. the blood-brain barrier.the blood-brain barrier. how neurons generate the electrical message known as an how neurons generate the electrical message known as an

action potential.action potential. multiple sclerosis (MS).multiple sclerosis (MS). synapses and excitatory and inhibitory postsynaptic synapses and excitatory and inhibitory postsynaptic

potentials. potentials. botulism and Botox.botulism and Botox.

Nerves Were Observed Under the Nerves Were Observed Under the Microscope By Antony van Leeuwenhoek Microscope By Antony van Leeuwenhoek

in 1675in 1675

Nerves are Fibrous, Not a Cavity Nerves are Fibrous, Not a Cavity through which the Animal Spirits Flow through which the Animal Spirits Flow ““I…observed, that after I…observed, that after those Nerves had been but those Nerves had been but a little while cut off from a little while cut off from the eye, the the eye, the filaments, of filaments, of which they are made upwhich they are made up, , did shrink up….And upon did shrink up….And upon this shrinking up, a little pit this shrinking up, a little pit comes to appear…and ‘tis comes to appear…and ‘tis this pit in all probability, this pit in all probability, that Galen took for a that Galen took for a cavity.”cavity.”

Stimulated Nerves Pass an Electrical Stimulated Nerves Pass an Electrical CurrentCurrent

Emil Du Bois-Emil Du Bois-Reymond (1848), a Reymond (1848), a student of Johannes student of Johannes Muller, provided Muller, provided evidence that the evidence that the nervous principle is nervous principle is electrical electrical by showing by showing that stimulated nerves that stimulated nerves pass an electrical pass an electrical current along their current along their length.length.

Nerves are Made of CellsNerves are Made of Cells

Theodor Schwann Theodor Schwann (1830s), a cofounder of (1830s), a cofounder of the cell theory, who was the cell theory, who was also working with also working with Johannes Muller, Johannes Muller, discovered that discovered that nucleus-containing nucleus-containing cells, now known as cells, now known as Schwann cellsSchwann cells, were a , were a component of nerves.component of nerves.

Schwann CellsSchwann Cells

Rudolf Virchow (1854), another of Johannes Muller’s students, discovered a fatty substance in the brain that he called myelin. Myelin is formed by the Schwann cells.

The Structure of NeuronsThe Structure of Neurons

Otto Deiters (1865) found that Otto Deiters (1865) found that nerves were also composed of nerves were also composed of another cell type, now known as another cell type, now known as neurons. neurons. The neurons have two The neurons have two different kinds of branching different kinds of branching processes attached to the cell processes attached to the cell body: one which was tree-like, body: one which was tree-like, which he called "which he called "protoplasmic protoplasmic extensionsextensions", and another which ", and another which was more like a long fiber, which was more like a long fiber, which he called "he called "axis cylinderaxis cylinder". ". Wilhelm His (1889) called the Wilhelm His (1889) called the tree-like extensions, tree-like extensions, dendritesdendrites; ; Rudolph von Kölliker (1896) Rudolph von Kölliker (1896) called the long projections called the long projections axonsaxons and the cell itself was named the and the cell itself was named the neuronneuron by Heinrich Wilhelm von by Heinrich Wilhelm von Waldeyer (1891).Waldeyer (1891).

The Dendrites, Axon and Cell Body The Dendrites, Axon and Cell Body of a Myelinated Neuronof a Myelinated Neuron

The Brain is Composed of a Giant The Brain is Composed of a Giant Network of NeuronsNetwork of Neurons

Joseph von Gerlach Joseph von Gerlach (1880) proposed that (1880) proposed that the recently the recently discovered nerve discovered nerve impulses studied by impulses studied by Emil du Bois-Emil du Bois-Reymond propagated Reymond propagated from cell to cell from cell to cell across the axons and across the axons and dendrites, and that dendrites, and that the brain was formed the brain was formed by giant nets made by giant nets made out of a large number out of a large number of interconnected of interconnected filaments. filaments.

The Brain is Composed of One Large The Brain is Composed of One Large CellCell

Camillo Golgi developed Camillo Golgi developed a silver stain that a silver stain that allowed the visualization allowed the visualization of the internal reticular of the internal reticular apparatus, now known apparatus, now known as the Golgi body.as the Golgi body.

After staining the brain, it After staining the brain, it seemed to Golgi, that all seemed to Golgi, that all the cells fused to form a the cells fused to form a single cell so that the single cell so that the brain consisted of a brain consisted of a continuous mass of continuous mass of tissue that shared a tissue that shared a single cytoplasm. single cytoplasm.

Disagreement on the Neural Disagreement on the Neural Structure of the Brain Structure of the Brain

Using Golgi’s silver stain, Santiago Using Golgi’s silver stain, Santiago Ramón y Cajal was able to see that Ramón y Cajal was able to see that the brain was not a single cell, but the brain was not a single cell, but composed of individual neuronscomposed of individual neurons..

Ramón y Cajal, with all due respect, Ramón y Cajal, with all due respect, disagreed with Golgi’s conclusion.disagreed with Golgi’s conclusion.

Both Ramón y Cajal and Golgi won the Both Ramón y Cajal and Golgi won the Nobel Prize in 1906 despite their Nobel Prize in 1906 despite their opposite views of the brain. opposite views of the brain.

Golgi got the prize for developing the Golgi got the prize for developing the techniques used to visualize the techniques used to visualize the nervous system and Ramón y Cajal nervous system and Ramón y Cajal got the prize for describing the correct got the prize for describing the correct structure of the nervous system.structure of the nervous system.

The Brain is Composed of Individual The Brain is Composed of Individual Cells (Neurons)Cells (Neurons)

Ramón y Cajal concluded Ramón y Cajal concluded that that neuronsneurons are discrete and are discrete and

autonomous autonomous cellscells that can that can interactinteract..

the the neuron neuron is the basic is the basic unit of the nervous system. unit of the nervous system.

there are gaps, now called there are gaps, now called synapsessynapses, that separate , that separate neurons.neurons.

Information is Information is transmitted in one transmitted in one directiondirection from dendrites to from dendrites to the axon.the axon.

Ramón y Cajal Traced the Networks of Neurons Ramón y Cajal Traced the Networks of Neurons Over Small and Large DistancesOver Small and Large Distances

Ramón y Cajal Traced the Networks of Neurons Ramón y Cajal Traced the Networks of Neurons Over Small and Large DistancesOver Small and Large Distances

Books by Santiago Ramón y CajalBooks by Santiago Ramón y Cajal

Blood Brain BarrierBlood Brain Barrier Paul EhrlichPaul Ehrlich (1870s) injected (1870s) injected

various aniline dyes, produced various aniline dyes, produced by the new German dye by the new German dye industry, into the blood stream of industry, into the blood stream of animals and found that the dye animals and found that the dye stained everything but the brain. stained everything but the brain.

His student, Edwin Goldmann His student, Edwin Goldmann (1913) injected the aniline dyes (1913) injected the aniline dyes into the brain fluid and found into the brain fluid and found that the brain stained, but not that the brain stained, but not the rest of the body.the rest of the body.

Lina Stern (1921) proposed that Lina Stern (1921) proposed that there was a there was a blood-brain barrierblood-brain barrier that separated the brain from the that separated the brain from the rest of the body.rest of the body.

Blood Brain BarrierBlood Brain Barrier Unlike the capillaries in the rest of the Unlike the capillaries in the rest of the

body that are “body that are “leakyleaky”, the capillaries in ”, the capillaries in the brain are tight because the the brain are tight because the membranes of the epithelial cells that membranes of the epithelial cells that make up the capillaries in the brain make up the capillaries in the brain are tightly appressed to each other.are tightly appressed to each other.

Because of this, any chemical that Because of this, any chemical that leaves the blood stream and enters leaves the blood stream and enters the brain must either be the brain must either be nonpolarnonpolar and and small small enough to pass through the enough to pass through the lipid bilayerlipid bilayer or must have a specific or must have a specific transport proteintransport protein to let it enter the to let it enter the intercellular milieu of the brain.intercellular milieu of the brain.

The blood brain barrier The blood brain barrier protects protects the the brain from viruses and toxins, but also brain from viruses and toxins, but also makes it a makes it a challenge to deliverchallenge to deliver some some drugs to the brain.drugs to the brain.

Cell Types in the BrainCell Types in the Brain The The blood-brain barrierblood-brain barrier is composed of is composed of glial cellsglial cells, ,

called called astrocytesastrocytes, which help prevent many , which help prevent many substances in the blood from entering the brain.substances in the blood from entering the brain.

OligodendrocytesOligodendrocytes in the central nervous system in the central nervous system (CNS), like the Schwann cells in the peripheral (CNS), like the Schwann cells in the peripheral nervous system (PNS) are nervous system (PNS) are glial cellsglial cells that surround that surround the axons and make up the myelin sheath.the axons and make up the myelin sheath.

The The glial cellsglial cells, which mean “glue cells” have multiple , which mean “glue cells” have multiple functions, including structurally supporting neurons functions, including structurally supporting neurons and regulating the biochemical balance of the brain. and regulating the biochemical balance of the brain. They were discovered in 1856 by Rudolf Virchow.They were discovered in 1856 by Rudolf Virchow.

The dendrites and cell bodies of the neurons make up The dendrites and cell bodies of the neurons make up the the gray mattergray matter of the brain and the axons make up of the brain and the axons make up the the white matterwhite matter..

The Cell Types in the BrainThe Cell Types in the Brain

Electrical Transmission Along NeuronsElectrical Transmission Along Neurons

The Plasma Membrane of NeuronsThe Plasma Membrane of Neurons

The Plasma Membrane Contains Receptor The Plasma Membrane Contains Receptor Proteins and Transport Proteins, Including Ion Proteins and Transport Proteins, Including Ion

Channels, and Ion Pumps Driven by the Energy Channels, and Ion Pumps Driven by the Energy of ATPof ATP

Ion channelsIon channels act as act as enzymesenzymes that reduce the that reduce the activation energyactivation energy or thermal energy that would or thermal energy that would be necessary to move a be necessary to move a charged ioncharged ion through a through a

hydrophobic lipid bilayerhydrophobic lipid bilayer..

It Would Take a Lot of Heat to Move a Charged It Would Take a Lot of Heat to Move a Charged Ion Through the Lipid Bilayer. Because of Ion Through the Lipid Bilayer. Because of

Channels, Ions Can Move Through Aqueous Channels, Ions Can Move Through Aqueous

Channels at Body TemperatureChannels at Body Temperature

The Influence of Ion Channels on the The Influence of Ion Channels on the Movement of Ions Across a MembraneMovement of Ions Across a Membrane

Hot Temperature→

Body Temperature→

Without the channel, the ions do not have enough energy at body temperature to pass through the plasma membrane.

An Unequal Distribution of Ions on the Two Sides An Unequal Distribution of Ions on the Two Sides of a Membrane Leads to a Voltage Across the of a Membrane Leads to a Voltage Across the Membrane Known as the Membrane PotentialMembrane Known as the Membrane Potential

Electrical Hyperpolarization of the Electrical Hyperpolarization of the MembraneMembrane

When the When the inside inside concentration of a positive ion is concentration of a positive ion is greatergreater than the outside concentration, the ion will tend than the outside concentration, the ion will tend to to diffusediffuse out ofout of the cell using its the cell using its thermal energythermal energy. .

The The electrical potential inside the cellelectrical potential inside the cell will become will become moremore negativenegative and the membrane will be and the membrane will be hyperpolarizedhyperpolarized..

At some point, the membrane potential will become so At some point, the membrane potential will become so negative that the outgoing positive ions will be attracted negative that the outgoing positive ions will be attracted back into the cell and the ions will be at back into the cell and the ions will be at equilibrium equilibrium at at thethe hyperpolarized hyperpolarized electrical potential. That is, the electrical potential. That is, the concentration difference driving the ions out of the cell concentration difference driving the ions out of the cell will be equivalent to the voltage driving the ions back will be equivalent to the voltage driving the ions back into the cell.into the cell.

Generation of an Electrical Generation of an Electrical Potential Across the MembranePotential Across the Membrane

Assume Assume inside inside of cell (1) and of cell (1) and outsideoutside of cell is (2) of cell is (2) and membrane is only permeable to the positive ion and membrane is only permeable to the positive ion (K(K++) as a result of the ion channels present. At ) as a result of the ion channels present. At equilibrium, membrane is electrically equilibrium, membrane is electrically hyperpolarizedhyperpolarized..

Initial Final (At Equilibrium)

Hyperpolarized and Depolarized Membranes

• The electrical potential outside the cell is considered to be 0 volts by definition.

• When the electrical potential inside the cell is more negative than 0 volts, the membrane is said to be hyperpolarized.

• When the electrical potential inside the cell is less negative than the hyperpolarized potential, the membrane is said to be depolarized.

Electrical Depolarization of the Electrical Depolarization of the MembraneMembrane

When the When the outsideoutside concentration of a positive ion is concentration of a positive ion is greatergreater than the inside concentration, the ion will tend than the inside concentration, the ion will tend to to diffusediffuse intointo the cell using its the cell using its thermal energythermal energy. .

If the membrane is already electrically hyperpolarized, If the membrane is already electrically hyperpolarized, the the electrical potential inside the cellelectrical potential inside the cell will become will become less negativeless negative and the membrane will be and the membrane will be depolarizeddepolarized..

At some point, the membrane potential will not be At some point, the membrane potential will not be negative enough to attract any more positive ions into negative enough to attract any more positive ions into the cell and the ions will be at the cell and the ions will be at equilibriumequilibrium at the at the depolarizeddepolarized electrical potential. That is, the electrical potential. That is, the concentration difference driving the ions into the cell is concentration difference driving the ions into the cell is equivalent to the depolarized voltage driving the ions equivalent to the depolarized voltage driving the ions out of the cell.out of the cell.

Generation of an Electrical Generation of an Electrical Potential Across the MembranePotential Across the Membrane

Assume Assume outsideoutside of cell (1) and of cell (1) and insideinside of cell is (2) of cell is (2) and membrane is only permeable to the positive ion and membrane is only permeable to the positive ion (Na(Na++) as a result of the ion channels present. At ) as a result of the ion channels present. At equilibrium, membrane is electrically equilibrium, membrane is electrically depolarizeddepolarized..

Initial Final (At Equilibrium)

High [NaCl] Low [NaCl]

Low [NaCl]High [NaCl]

Na+ Na+

Walther Nernst Derived an Equation Walther Nernst Derived an Equation that Predicts the Equilibrium Potentialthat Predicts the Equilibrium Potential

Nernst EquationNernst Equation

Equilibrium Potential = (kT/ze) ln ([ion]Equilibrium Potential = (kT/ze) ln ([ion]outout/[ion]/[ion]inin))

k = Boltzmann’s constant (1.38 x 10k = Boltzmann’s constant (1.38 x 10-23-23 J/K) J/K)T = Absolute Temperature (in K) = 310 K for humansT = Absolute Temperature (in K) = 310 K for humanse = elementary charge (1.6 x 10e = elementary charge (1.6 x 10-19-19 C/charge) C/charge)z = valence of ion (+1 for Kz = valence of ion (+1 for K+ + and Naand Na++))

(kT/ze) ln ([ion](kT/ze) ln ([ion]outout/[ion]/[ion]inin) is the voltage equivalent of the ) is the voltage equivalent of the concentration differenceconcentration difference

1 Volt = 1 J/C = 1 Joule/Coulomb ln 10 = 2.31 Volt = 1 J/C = 1 Joule/Coulomb ln 10 = 2.3

The Nernst EquationThe Nernst Equation

((kT/ze)kT/ze) is always positive and equal for both K is always positive and equal for both K+ +

and Naand Na++

ln ([ion]ln ([ion]outout/[ion]/[ion]inin)) is positive when the outside is positive when the outside concentration is greater than the inside concentration is greater than the inside concentration of an ion.concentration of an ion.

ln ([ion]ln ([ion]outout/[ion]/[ion]inin)) is negative when the outside is negative when the outside concentration is less than the inside concentration is less than the inside concentration of an ion.concentration of an ion.

ln ([ion]ln ([ion]outout/[ion]/[ion]inin)) is zero when the outside is zero when the outside concentration is equal to the inside concentration is equal to the inside concentration of an ion (= death).concentration of an ion (= death).

Natural Logs Are EasyNatural Logs Are Easy

Ln 1000 = 6.9Ln 1000 = 6.9 Ln 100 = 4.6Ln 100 = 4.6 Ln 10 = 2.3Ln 10 = 2.3 Ln 1 = 0Ln 1 = 0 Ln 0.1 = -2.3Ln 0.1 = -2.3 Ln 0.01 = -4.6Ln 0.01 = -4.6 Ln 0.001 = -6.9Ln 0.001 = -6.9

Resting Resting PotentialPotential

Because the KBecause the K++ concentration concentration is greater inside the cell than is greater inside the cell than outside the cell, Koutside the cell, K++ moving moving out of the cell tends to out of the cell tends to hyperpolarize the membrane.hyperpolarize the membrane.

The NaThe Na++ concentration is concentration is greater outside the cell than greater outside the cell than inside the cell, but since the inside the cell, but since the membrane at rest is relatively membrane at rest is relatively impermeable to Naimpermeable to Na++, Na, Na+ + has has little effect on the electrical little effect on the electrical potential of the membrane at potential of the membrane at rest.rest.

Consequently, the resting Consequently, the resting membrane potential is given membrane potential is given by the equilibrium potential by the equilibrium potential for Kfor K++..

Concentrations (in mol/mConcentrations (in mol/m33) and ) and Equilibrium Potentials (in V) of CationsEquilibrium Potentials (in V) of Cations

KK++ NaNa++

OutsideOutside 20 20 440440

InsideInside 400400 5050

Equilibrium Equilibrium -0.08 V-0.08 V +0.06V+0.06V

PotentialPotential

Measuring Membrane Potentials In Measuring Membrane Potentials In Neurons With MicroelectrodesNeurons With Microelectrodes

Edgar Adrian (1928) Edgar Adrian (1928) placed small glass placed small glass electrodes into many electrodes into many kinds of neurons and kinds of neurons and measured the measured the single single cellcell electrical variation electrical variation that contributed to the that contributed to the whole nervewhole nerve electrical electrical changes that had been changes that had been measured by Emil Du measured by Emil Du Bois-Reymond. Bois-Reymond.

The Action Potential: A Variation in The Action Potential: A Variation in Electrical PotentialElectrical Potential

The Nervous Signal is like the Morse Code

“If these records give a true measure of the activity in the sensory nerve fibres it is clear that they transmit their messages to the central nervous system in a very simple way. The message consists merely of a series of brief impulses….In any one fibre the waves are all of the same form….In fact, the sensory messages are scarcely more complex than a succession of dots in the Morse Code.”

__ __ . . . . . . .

ADRIAN'S LAWSADRIAN'S LAWS

Neurons Neurons communicate communicate with each other by with each other by sending a short episode of sending a short episode of electrical electrical pulsespulses, known as , known as action potentialsaction potentials, , along their fibers. along their fibers.

A stimulus either induces an action A stimulus either induces an action potential in a neuron or it does not. It is an potential in a neuron or it does not. It is an all-or-noneall-or-none response. response.

The pulses do not vary in amplitude but The pulses do not vary in amplitude but vary in the frequencyvary in the frequency of the pulses. of the pulses.

The frequency can be as high as 1000 The frequency can be as high as 1000 impulses per second. impulses per second.

Resting StateResting State

Initiation of an Action PotentialInitiation of an Action Potential

A stimulus A stimulus causes causes NaNa++ channels to channels to open open and the and the influx of influx of NaNa++ causes the causes the membrane membrane potential to potential to depolarize depolarize (become less (become less negative) negative) beyond a beyond a threshold.threshold.

Action Potential: Positive FeedbackAction Potential: Positive Feedback

The membrane The membrane depolarization depolarization activates additional activates additional NaNa++ channels channels, , whose whose conductanceconductance isis voltage-voltage-dependentdependent. This . This causes a lot more causes a lot more NaNa++ to enter the cell to enter the cell and the membrane and the membrane potential potential depolarizesdepolarizes further further (and even becomes (and even becomes positive). positive).

Action Potential: Negative FeedbackAction Potential: Negative Feedback

The NaThe Na++ channels do not remain open forever, but channels do not remain open forever, but become become inactivatedinactivated.. This causes the membrane to This causes the membrane to become become repolarizedrepolarized (hyperpolarized again). (hyperpolarized again).

Action Potential: KAction Potential: K++ ions ionsOnce the membrane potential Once the membrane potential is depolarized by the Nais depolarized by the Na++, the , the membrane potential is no membrane potential is no longer negative enough to longer negative enough to hold in the high concentration hold in the high concentration of Kof K++ ions and the K ions and the K++ ions ions begin to move out of the cell begin to move out of the cell through the through the KK++ channels channels. This . This enhanced enhanced KK++ efflux efflux, combined , combined with the inactivation of the Nawith the inactivation of the Na+ +

channels results in a return to channels results in a return to the the resting membraneresting membrane potential and the potential and the action action potentialpotential is over. is over.

Voltage Clamp ExperimentsVoltage Clamp Experiments The The activation activation and and inactivation inactivation of the of the

NaNa++ channel channel was studied by Alan was studied by Alan Hodgkin and Andrew Fielding Huxley Hodgkin and Andrew Fielding Huxley using a voltage clamp.using a voltage clamp.

The properties of the channel were The properties of the channel were determined by holding the axon determined by holding the axon membrane at a depolarized potential membrane at a depolarized potential (V).(V).

When the membrane is held at a When the membrane is held at a depolarizing potential, the Nadepolarizing potential, the Na++ channel channel is is activated activated and a and a currentcurrent (I) carried by (I) carried by NaNa++ passes. The current is proportional passes. The current is proportional to the membrane to the membrane conductanceconductance (G). (G). After a millisecond or so, the current After a millisecond or so, the current stops, indicating that the channel stops, indicating that the channel becomes becomes inactivatedinactivated. .

Voltage Clamp Experiments

Ohm’s LawV = IRR = V/IG = I/V

Equivalent Circuit of Axon MembraneEquivalent Circuit of Axon Membrane

Membrane and Membrane and channel conductance channel conductance can be determined can be determined using using Ohm’s LawOhm’s Law..

Equilibrium potentials Equilibrium potentials act as act as batteriesbatteries..

Channels act as Channels act as variable resistorsvariable resistors..

Lipid bilayer acts as Lipid bilayer acts as insulator in a insulator in a capacitorcapacitor..

Neurons are really Neurons are really miniature electrical miniature electrical devices!!!!!devices!!!!!

The Neuron Acts as if it is Composed of Electronic Parts

http://artisresistors.co.uk/gallery.html

Some Evidence for the Ionic Theory of Some Evidence for the Ionic Theory of Action PotentialsAction Potentials

An action potential can not be An action potential can not be generated unless there are generated unless there are NaNa+ + in the external mediumin the external medium..

Radioactive NaRadioactive Na++ are taken up are taken up by the neuron during an by the neuron during an action potential.action potential.

Pharmacological agents Pharmacological agents that that inhibit Nainhibit Na++ channels channels, , like like tetrodotoxintetrodotoxin, which is , which is isolated from the isolated from the puffer fishpuffer fish, , prevent the action potential.prevent the action potential.

Refractory Period and UnidirectionalityRefractory Period and Unidirectionality

The NaThe Na+ + channel remains inactivated for slightly channel remains inactivated for slightly longer than it takes to bring the membrane back longer than it takes to bring the membrane back to the resting potential. to the resting potential.

Thus, the section of membrane that just finished Thus, the section of membrane that just finished an action potential is not able to produce an action potential is not able to produce another one until the Naanother one until the Na+ + channel is no longer channel is no longer inactivated. inactivated.

The period of time necessary for the NaThe period of time necessary for the Na++ channel to become sensitive to a stimulus is channel to become sensitive to a stimulus is known as the known as the refractory periodrefractory period. .

The refractory period makes it possible for The refractory period makes it possible for an action potential to move down a neuron in an action potential to move down a neuron in only one directiononly one direction. .

Due to the Due to the refractory refractory period, the period, the

action potential action potential moves along moves along

the axon the axon unidirectionally.unidirectionally.

Nodes of RanvierNodes of Ranvier

The membranes of the glial cells that form the myelin sheath around The membranes of the glial cells that form the myelin sheath around the axon are almost purely lipid.the axon are almost purely lipid.

Since ions cannot pass through lipids, the myelin sheath acts as a Since ions cannot pass through lipids, the myelin sheath acts as a insulator around the conducting axon. insulator around the conducting axon.

Each Schwann cell is separated from the next by a Each Schwann cell is separated from the next by a node of Ranviernode of Ranvier, , where the sodium and potassium channels are. where the sodium and potassium channels are.

The combination of the glial cells and the nodes of Ranvier make an The combination of the glial cells and the nodes of Ranvier make an electrical electrical capacitorcapacitor that causes the voltage to “ that causes the voltage to “jumpjump” from ” from node to node to nodenode. .

Myelin Sheath Results in a High Conduction Myelin Sheath Results in a High Conduction Velocity Velocity

Action potentials move down the axon jumping from node to Action potentials move down the axon jumping from node to node at a rate of 150 m/s (= node at a rate of 150 m/s (= 330 mph330 mph). Without the myelin ). Without the myelin sheath, the action potential would travel about 5 m/s. sheath, the action potential would travel about 5 m/s.

Multiple SclerosisMultiple Sclerosis

Multiple sclerosisMultiple sclerosis is an is an autoimmune diseaseautoimmune disease in which in which the white blood cells of the the white blood cells of the body consider the body consider the oligodendrocytes that form the oligodendrocytes that form the myelin sheath around the myelin sheath around the neurons of the neurons of the central nervous central nervous systemsystem to be foreign invaders to be foreign invaders and destroy them.and destroy them.

The degeneration of the myelin The degeneration of the myelin sheath results in a slower sheath results in a slower conduction velocity of action conduction velocity of action potentials and a loss of control potentials and a loss of control of neural processes.of neural processes.

What Happens to the Electrical Impulse When it What Happens to the Electrical Impulse When it Gets to the End of the Cell? Gets to the End of the Cell?

How Can an Electrical Signal Stimulate Some How Can an Electrical Signal Stimulate Some Cells and Inhibit Others?Cells and Inhibit Others?

Stimulatory and Inhibitory Actions of Stimulatory and Inhibitory Actions of NeuronsNeurons

When one provokes a a reflex When one provokes a a reflex movement, a movement, a contraction contraction of one of one muscle is accompanied by a muscle is accompanied by a relaxationrelaxation of an opposing muscle. of an opposing muscle.

Since all muscles are stimulated by a Since all muscles are stimulated by a depolarizing voltage shock and all depolarizing voltage shock and all action potentials involve the action potentials involve the transmission of a membrane transmission of a membrane depolarization, Charles Sherrington depolarization, Charles Sherrington suggested that action potentials must suggested that action potentials must be capable of doing at least two be capable of doing at least two different things at synapses, one different things at synapses, one stimulatorystimulatory and one and one inhibitoryinhibitory..

Excitatory and Inhibitory SynapsesExcitatory and Inhibitory Synapses

While working on reflexes, While working on reflexes, Sherrington discovered Sherrington discovered that the there are two that the there are two types of types of synapses: synapses: excitatory and excitatory and inhibitoryinhibitory..

The same concepts of The same concepts of excitation and inhibition excitation and inhibition appeared again in the appeared again in the sympatheticsympathetic and the and the parasympatheticparasympathetic nervous nervous systems. systems.

Sympathetic and Parasympathetic Sympathetic and Parasympathetic Nervous SystemNervous System

Since the sympathetic and the parasympathetic Since the sympathetic and the parasympathetic nerve systems have opposite effects on cardiac nerve systems have opposite effects on cardiac muscle, there must be two different actions at muscle, there must be two different actions at their synapses: one their synapses: one excitatoryexcitatory, another one , another one inhibitoryinhibitory. .

No one could figure out how an electrical No one could figure out how an electrical message, in the form of an action potential going message, in the form of an action potential going to the same postsynaptic element would achieve to the same postsynaptic element would achieve totally opposite effects, so some turned to the totally opposite effects, so some turned to the idea that excitatory and inhibitory chemical idea that excitatory and inhibitory chemical messengers may be involved. messengers may be involved.

Chemical Synapses?Chemical Synapses?

Thomas Elliot (1904) could mimic the excitatory Thomas Elliot (1904) could mimic the excitatory effects of the effects of the sympatheticsympathetic nervous system on nervous system on cardiac muscle with an extract of the cardiac muscle with an extract of the adrenal adrenal medullamedulla known asknown as adrenaline.adrenaline.

Henry Dale (1920s) could mimic the inhibitory Henry Dale (1920s) could mimic the inhibitory effects of the effects of the parasympathetic parasympathetic nervous system nervous system on cardiac muscle with an extract fromon cardiac muscle with an extract from ergot of ergot of ryerye, , known asknown as acetylcholineacetylcholine..

Dale coined the terms "Dale coined the terms "adrenergicadrenergic" and " and ""cholinergiccholinergic" synapses to describe the " synapses to describe the chemicals that may couple the neural stimulus to chemicals that may couple the neural stimulus to the cardiac muscular response. the cardiac muscular response.

Henry DaleHenry Dale

By 1936, Henry Dale By 1936, Henry Dale concluded that, "concluded that, "According According to this relatively new to this relatively new evidence, a chemical evidence, a chemical mechanism of transmission mechanism of transmission is concerned, not only with is concerned, not only with the effects of autonomic the effects of autonomic nerves, but with the whole nerves, but with the whole of the efferent activities of of the efferent activities of the peripheral nervous the peripheral nervous system, whether voluntary system, whether voluntary or involuntary in function.or involuntary in function.""

Occam’s Razor Sliced a Little Too Occam’s Razor Sliced a Little Too CloseClose

Electrophysiologists did not want Electrophysiologists did not want to believe in chemical signals.to believe in chemical signals.

They invoked They invoked Occam’s RazorOccam’s Razor, , claiming that there is no need for claiming that there is no need for two kinds of signals.two kinds of signals.

In general, as scientists, we are In general, as scientists, we are reductionistsreductionists and try to simplify and try to simplify things as much as possible. But things as much as possible. But biological systems are never as biological systems are never as simple as reductionists postulate.simple as reductionists postulate.

Graded Potential ResponsesGraded Potential ResponsesJohn Eccles (1952) began to John Eccles (1952) began to insert microelectrodes into insert microelectrodes into the cell bodies of the cell bodies of post-post-synaptic neuronssynaptic neurons of the of the CNS. After stimulating either CNS. After stimulating either excitatory or inhibitory pre-excitatory or inhibitory pre-synaptic nerves, he synaptic nerves, he discovered that there were discovered that there were two kinds of two kinds of graded graded potential responsespotential responses in the in the post-synaptic cellpost-synaptic cell..

The Excitatory Graded PotentialThe Excitatory Graded Potential

The The excitatory response excitatory response depolarizeddepolarized the the post-synaptic post-synaptic nerve cellnerve cell, bringing the , bringing the membrane potential closer to membrane potential closer to the the thresholdthreshold. .

This would This would increase the increase the probabilityprobability of activating of activating voltage-dependent Navoltage-dependent Na++ channels and initiating an action channels and initiating an action potential in the potential in the post-synaptic post-synaptic cellcell..

The Inhibitory Graded PotentialThe Inhibitory Graded Potential

The The inhibitory response inhibitory response hyperpolarizedhyperpolarized the the post-post-synaptic nerve cellsynaptic nerve cell, bringing , bringing the membrane potential further the membrane potential further from the threshold. from the threshold.

This would This would decrease the decrease the probabilityprobability of activating of activating voltage-dependent Navoltage-dependent Na++ channels and initiating an action channels and initiating an action potential in the potential in the post-synaptic post-synaptic cellcell..

The Excitatory (EPSP) Graded The Excitatory (EPSP) Graded Potential Results from the Activation of Potential Results from the Activation of

Voltage-Independent NaVoltage-Independent Na+ + ChannelsChannels

The Inhibitory (IPSP) Graded Potential Results The Inhibitory (IPSP) Graded Potential Results from the Activation of Voltage-Independent Kfrom the Activation of Voltage-Independent K+ +

Channels or Voltage-Independent ClChannels or Voltage-Independent Cl- - Channels Channels

Integration by the Post-Synaptic Integration by the Post-Synaptic NeuronNeuron

The The sumsum of all the of all the excitatoryexcitatory (+) post (+) post synaptic potentials synaptic potentials (EPSP) and the (EPSP) and the inhibitoryinhibitory (-) post (-) post synaptic potentials synaptic potentials (IPSP) determine the (IPSP) determine the probability of probability of initiating an action initiating an action potentialpotential in the post- in the post-synaptic cell.synaptic cell.

Integration by the Post-Synaptic Integration by the Post-Synaptic Neuron: The Basis of Decision Making?Neuron: The Basis of Decision Making?

When a When a large number of excitatorylarge number of excitatory post- post-synaptic potentials (EPSP) and a small number synaptic potentials (EPSP) and a small number of inhibitory post-synaptic potentials (IPSP) are of inhibitory post-synaptic potentials (IPSP) are evoked, the post-synaptic membrane is evoked, the post-synaptic membrane is depolarized and the post synaptic neuron depolarized and the post synaptic neuron becomes becomes likelylikely to initiate an action potential. to initiate an action potential.

If a small number of excitatory post-synaptic If a small number of excitatory post-synaptic potentials (EPSP) and a potentials (EPSP) and a large number of large number of inhibitoryinhibitory post-synaptic potentials (IPSP) are post-synaptic potentials (IPSP) are evoked, the post-synaptic membrane becomes evoked, the post-synaptic membrane becomes hyperpolarized and the post synaptic neuron is hyperpolarized and the post synaptic neuron is unlikelyunlikely to initiate an action potential. to initiate an action potential.

The Post-Synaptic Cell is an Analog to The Post-Synaptic Cell is an Analog to Digital Converter Digital Converter

The Post-Synaptic Cell is also an The Post-Synaptic Cell is also an Integrator Integrator

In the Post-Synaptic Cell, In the Post-Synaptic Cell, the Majority Rulesthe Majority Rules

Integration Can Take Place Over Time (from a Integration Can Take Place Over Time (from a single Pre-synaptic Neuron) or Over Space (from single Pre-synaptic Neuron) or Over Space (from

Many Pre-synaptic Neurons)Many Pre-synaptic Neurons)

Excitatory and Inhibitory Excitatory and Inhibitory NeurotransmittersNeurotransmitters

Whether a pre-synaptic neuron is excitatory or Whether a pre-synaptic neuron is excitatory or inhibitory depends on the neurotransmitter that inhibitory depends on the neurotransmitter that is released.is released.

Excitatory neurotransmitters include:Excitatory neurotransmitters include: acetylcholine (neuromuscular junction of skeletal acetylcholine (neuromuscular junction of skeletal

muscle) muscle) noradrenalinenoradrenaline glutamate (an amino acid)glutamate (an amino acid)

Inhibitory neurotransmitters include:Inhibitory neurotransmitters include: acetylcholine (neuromuscular junction of cardiac acetylcholine (neuromuscular junction of cardiac

muscle)muscle) glycine (an amino acid) glycine (an amino acid) GABAGABA

How does an action potential trigger How does an action potential trigger neurotransmitter release in a neuromuscular neurotransmitter release in a neuromuscular

junction?junction?

The membrane depolarization at the The membrane depolarization at the pre-synaptic pre-synaptic membranemembrane due to the action potential opens due to the action potential opens calcium calcium channelschannels. The calcium entering the cell acts as a . The calcium entering the cell acts as a second second messengermessenger to trigger the to trigger the secretionsecretion of of acetylcholineacetylcholine by by exocytosis exocytosis into the into the neuromuscular synapseneuromuscular synapse. .

Stimulus-Response in NeuronsStimulus-Response in Neurons

StimulusStimulus: Action : Action potential (membrane potential (membrane depolarization)depolarization)

ReceptorReceptor: Voltage-: Voltage-dependent Cadependent Ca2+2+ channelschannels

Second MessengerSecond Messenger: : CaCa2+2+

ResponseResponse: Secretion : Secretion of neurotransmittersof neurotransmitters

Neuromuscular Junction of Skeletal MuscleNeuromuscular Junction of Skeletal Muscle

Acetylcholine Acetylcholine is the is the neurotransmitter released neurotransmitter released in the in the neuromuscular neuromuscular junctionjunction..

The acetylcholine The acetylcholine receptorreceptor is a Na is a Na++ channel. channel.

The activation of which The activation of which causes a depolarization causes a depolarization of the muscle cell of the muscle cell membrane, which causes membrane, which causes voltage-dependent Cavoltage-dependent Ca2+2+ channels to open, which channels to open, which causes the muscle to causes the muscle to contract. contract.

Food Poisoning: Botulism Food Poisoning: Botulism ((Clostridium botulinumClostridium botulinum))

Botulinum Toxin Causes Paralysis by Blocking Botulinum Toxin Causes Paralysis by Blocking Acetylcholine ReleaseAcetylcholine Release

Every Cloud Has a Silver LiningEvery Cloud Has a Silver Lining

Weight for weight, Weight for weight, botulinum toxinbotulinum toxin is the most toxic of is the most toxic of toxins.toxins.

However, it can be However, it can be used for cosmetic used for cosmetic reasons—where it reasons—where it is sold under the is sold under the name name botoxbotox..

Botox: Botulinum Toxin Injections Prevent Botox: Botulinum Toxin Injections Prevent Contraction of the Muscles that Result in Contraction of the Muscles that Result in

FrowningFrowning

Cosmetic Botox InjectionCosmetic Botox Injection

Cosmetic Botox InjectionsCosmetic Botox Injections

Botox Scam: Priscilla Presley Got Low Botox Scam: Priscilla Presley Got Low Grade Silicone Instead of a “Superior Grade Silicone Instead of a “Superior

Grade of Botox”Grade of Botox”

The Chemical Basis of the Individual’s The Chemical Basis of the Individual’s MindMind

As I will discuss in the next lecture, there are As I will discuss in the next lecture, there are many different neurotransmittersmany different neurotransmitters, especially , especially in the brain, that can induce either excitation or in the brain, that can induce either excitation or inhibition of the post-synaptic membrane. inhibition of the post-synaptic membrane.

Due to Due to differential transcriptiondifferential transcription and and alternative splicingalternative splicing, there is a , there is a variety of variety of receptorsreceptors for each neurotransmitter in different for each neurotransmitter in different post-synaptic neurons. Moreover, post-synaptic neurons. Moreover, allelic allelic differencesdifferences between individuals lead to between individuals lead to genetically-determined differences in receptors.genetically-determined differences in receptors.

The The near-limitless combinationsnear-limitless combinations allow for near allow for near infinite individual variations in the chemical basis infinite individual variations in the chemical basis of mind.of mind.

The Mind-Body Problem: Original The Mind-Body Problem: Original ThoughtsThoughts

Is the mind an Is the mind an emergent propertyemergent property of of hundreds of billions of material brain cells? hundreds of billions of material brain cells? If so, If so, One day it will be possible to electrically One day it will be possible to electrically

stimulate the brain with a number of stimulate the brain with a number of electrodes in such a way as to create an electrodes in such a way as to create an original thought.original thought.

One day it will be possible to introduce a One day it will be possible to introduce a combination of chemicals into the brain and combination of chemicals into the brain and create an original thought.create an original thought.

The Mind-Body Problem: Original The Mind-Body Problem: Original ThoughtsThoughts

Does the mind have its own energy that is Does the mind have its own energy that is capable of influencing the physico-capable of influencing the physico-chemical processes in the brain and chemical processes in the brain and induce action potentials? induce action potentials? According to Wilder Penfield (1975) According to Wilder Penfield (1975) “…there “…there

is no good evidence . . . that the brain alone is no good evidence . . . that the brain alone can carry out the work that the mind does. . . . can carry out the work that the mind does. . . . I believe that one should not pretend to draw I believe that one should not pretend to draw a final scientific conclusion, in man's study of a final scientific conclusion, in man's study of man, until the nature of the energy man, until the nature of the energy responsible for mind action is discovered, as responsible for mind action is discovered, as in my own opinion, it will be."in my own opinion, it will be."

Free WillFree Will

““Between stimulus Between stimulus and response there and response there is a space. In that is a space. In that space is our power space is our power to choose our to choose our response. In our response. In our response lies our response lies our growth and our growth and our freedom.”freedom.”

Viktor Frankl

Free WillFree Will

““The very serious and difficult The very serious and difficult question arises of whether…question arises of whether…free will is compatible with our free will is compatible with our scientific knowledge, which scientific knowledge, which plainly says that the concept of plainly says that the concept of a breach in causal continuity is a breach in causal continuity is not acceptable. From the point not acceptable. From the point of view of science, the reality of view of science, the reality of free will cannot be of free will cannot be conceded. On the other hand, conceded. On the other hand, as human beings, we depend as human beings, we depend on the belief that…our actions on the belief that…our actions are preceded by deliberation are preceded by deliberation and choice….”and choice….”

Hans Mohr

Free WillFree Will

““All I have to say is that All I have to say is that free will is a fact of free will is a fact of experience….Free will is experience….Free will is often denied on the often denied on the grounds that you can’t grounds that you can’t explain it, that it involved explain it, that it involved happenings inexplicable happenings inexplicable by present-day physics by present-day physics and physiology. To that I and physiology. To that I reply that our inability may reply that our inability may stem from the fact that stem from the fact that physics and physiology physics and physiology are still not adequately are still not adequately developed.…”developed.…” John Eccles

Science and Free WillScience and Free Will

I believe that we can exercise I believe that we can exercise and develop our neurons to and develop our neurons to transform food energy into transform food energy into “free will energy”, which acts “free will energy”, which acts locally (100 nm range) and at locally (100 nm range) and at levels of about 10levels of about 10-20-20 - 10 - 10-19-19 J. J.

Perhaps “free will energy” Perhaps “free will energy” could modify a calcium could modify a calcium channel in the presynaptic channel in the presynaptic neuron or modify a receptor neuron or modify a receptor in the postsynaptic neuron in the postsynaptic neuron and cause us to do or not do and cause us to do or not do something (e.g. something something (e.g. something that takes courage). that takes courage).

Zorba the GreekZorba the Greek

It may be that we can choose to convert our It may be that we can choose to convert our food into fat, work, or spirit.food into fat, work, or spirit.

Profiles in Courage AwardProfiles in Courage Award

In whatever arena of life In whatever arena of life one may meet the one may meet the challenge of challenge of couragecourage… … each…must decide for each…must decide for himself the course he himself the course he will follow….will follow….

——John F. Kennedy John F. Kennedy

Profiles in CourageProfiles in Courage

A Profile in Courage A Profile in Courage

Plant and animal cell biologist Werner Franke exposed illegal East German steroid research and the illegal doping of athletes.

Another Profile in Courage Another Profile in Courage

Dr. Ignacio Chapela Dr. Ignacio Chapela is courageous in is courageous in “disentangling reality “disentangling reality from corporate from corporate advertising” advertising” in his in his ecological studies at ecological studies at UC Berkeley.UC Berkeley.

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