Fundamentals of the Nervous System and Nervous Tissue 11 P A R T B Fundamentals of the Nervous System and Nervous Tissue

Neurophysiology 1: Channels, Gates, & Gradients

Action potentials, or nerve impulses, are: Neurophysiology Neurons are highly irritable / excitable / able to rapidly change their voltage Action potentials, or nerve impulses, are: Electrical impulses carried along the length of axons Always the same regardless of stimulus (“all or none phenomena” – no such thing as big or small a.p.s) The first functional feature of the nervous system (the second is synaptic transmission) See http://web.lemoyne.edu/~hevern/psy340_09S/lectures/psy340.02.2.neural.impulse.htmle

Electricity Definitions Voltage (V) – measure of potential energy generated by separated charge Potential difference – voltage measured between two points Current (I) – the flow of electrical charge between two points Resistance (R) – hindrance to charge flow Insulator – substance with high electrical resistance Conductor – substance with low electrical resistance

Electrical Current and the Body Reflects the flow of ions rather than electrons There is a potential on either side of membranes when: The number of ions is different across the membrane The membrane provides a resistance to ion flow

Types of plasma membrane ion channels: Role of Ion Channels Types of plasma membrane ion channels: Passive, or leakage, channels – always open Active channels or gates – usually closed, open when signaled Chemically gated channels – open with binding of a specific neurotransmitter Voltage-gated channels – open and close in response to changes in the membrane potential Mechanically gated channels – open and close in response to physical deformation of receptors

Operation of a Chemically-Gated Channel Example: Na+-K+ gated channel Closed when a neurotransmitter is not bound to the extracellular receptor Na+ cannot enter the cell and K+ cannot exit the cell Open when a neurotransmitter is attached to the receptor Na+ enters the cell and K+ exits the cell

Operation of a Gated Channel Figure 11.6a

Operation of a Voltage-Gated Channel Example: Na+ channel Closed when the intracellular environment is negative Na+ cannot enter the cell Open when the intracellular environment is positive Na+ can enter the cell

Operation of a Voltage-Gated Channel Figure 11.6b

When gated channels are open: Ions move quickly across the membrane Movement is along their electrochemical gradients An electrical current is created Voltage changes across the membrane

Electrochemical Gradient Ions flow along their chemical gradient when they move from an area of high concentration to an area of low concentration Ions flow along their electrical gradient when they move toward an area of opposite charge Electrochemical gradient – the electrical and chemical gradients taken together

Electrochemical Gradients in Neurons K+ Na+ Proteins -

Electrochemical Gradients in Neurons Sodium Potassium Intracellular Concentration Extracellular Concentration Chemical Gradient Electrical Gradient Combined Electrochemical Gradient Movement During Action Potential

Electrochemical Gradients in Neurons Sodium Potassium Intracellular Concentration Low High Extracellular Concentration Chemical Gradient Attracted Inward (Diffusion) Attracted Outward Electrical Gradient (Since cell is -70 mV and Na is positive) (Since cell is -70 mV and K is positive) Combined Electrochemical Gradient Strongly Attracted Inward Movement During Action Potential Flows Rapidly Into Cell Flows Slowly Out of Cell

Neurophysiology 2: Electrical Events in Neurons

Resting Membrane Potential (Vr) The potential difference (–70 mV) across the membrane of a resting neuron It is generated by different concentrations of Na+, K+, Cl, and protein anions (A) Ionic differences are the consequence of: Differential permeability of the neurilemma to Na+ and K+ Operation of the sodium-potassium pump using energy from splitting ATP to move Na+ and K+ against their concentration gradients (3 Na+ pumped out and 2 K+ pumped in for each ATP molecule)

Measuring Mebrane Potential Figure 11.7

Resting Membrane Potential (Vr) ATP Figure 11.8

Three Voltage Potentials Resting Potentials: Neurons are waiting to receive a signal Graded Potentials: Neurons have received one or more signals, and are combining their voltages (the signals can be either excitatory or inhibitory, and they vary in their size = “graded”) Action Potentials: Neurons are sending a signal after receiving enough excitatory input

Resting Potential Neurons at rest have a voltage potential of approx. -70 mV (inside the cell) RP results from combination of electrical forces and chemical forces acting on Na+, K+, Cl-, and various anions Passive channels allow a few ions to cross the membrane randomly Active gates are closed

Membrane Potentials: Signals Used to integrate, send, and receive information Membrane potential changes are produced by: Changes in membrane permeability to ions Alterations of ion concentrations across the membrane Types of signals – graded potentials and action potentials

Changes in Membrane Potential Changes are caused by three events Depolarization – the inside of the membrane becomes less negative Repolarization – the membrane returns to its resting membrane potential Hyperpolarization – the inside of the membrane becomes more negative than the resting potential

Changes in Membrane Potential Figure 11.9

Graded Potentials Short-lived, local changes in membrane potential Decrease in intensity with distance Magnitude varies directly with the strength of the stimulus Sufficiently strong graded potentials can initiate action potentials

Graded Potentials Figure 11.10

Graded Potentials Voltage changes are decremental Current is quickly dissipated due to the leaky plasma membrane Only travel over short distances

Graded Potentials Figure 11.11

Graded Potentials Voltage changes that vary in size are called graded potentials They are temporary, occur at synapses (on the post-synaptic membrane), vary in size according to the strength of the stimulus, and spread in all directions along the membrane for short distances (they get weaker farther from the synapse, and the distance they spread depends on the stimulus strength) There are two kinds: EPSPs and IPSPs

Postsynaptic Potentials Neurotransmitter receptors mediate changes in membrane potential according to: The amount of neurotransmitter released The amount of time the neurotransmitter is bound to receptors The two types of postsynaptic potentials are: EPSP – excitatory postsynaptic potentials IPSP – inhibitory postsynaptic potentials PLAY InterActive Physiology ®: Nervous System II: Synaptic Transmission, pages 7–12

Excitatory Post-Synaptic Potentials (EPSPs) EPSPs occur when a synapse sends a signal for the next neuron to fire an AP EPSPs depolarize the membrane slightly by opening chemical gates for sodium If the membrane is depolarized enough, the post-synaptic neuron will fire an AP The amount of depolarization required for an AP is called the threshold – usually around -50 to -55mV

Excitatory Postsynaptic Potentials EPSPs are graded potentials that can initiate an action potential in an axon Use only chemically gated channels Na+ and K+ flow in opposite directions at the same time Postsynaptic membranes do not generate action potentials

Excitatory Postsynaptic Potential (EPSP) Figure 11.19a

Inhibitory Post-Synaptic Potentials (IPSPs) IPSPs occur when a synapse sends a signal for the next neuron NOT to fire an AP IPSPs hyperpolarize the membrane slightly by opening chemical gates for chlorine (Cl- enters cell)

Inhibitory Synapses and IPSPs Neurotransmitter binding to a receptor at inhibitory synapses: Causes the membrane to become more permeable to potassium and chloride ions Leaves the charge on the inner surface negative Reduces the postsynaptic neuron’s ability to produce an action potential

Inhibitory Postsynaptic (IPSP) Figure 11.19b

Changes in Membrane Potential EPSP!!! IPSP!!! EPSP or IPSP?? Figure 11.9

Integration of Graded Potentials EPSPs add together, while IPSPs subtract – so the voltage around synapses is always rising and falling slightly (it is depolarizing and hyperpolarizing) If the overall voltage reaches threshold at the axon hillock, the neuron fires an AP This combination, or integration, of EPSPs & IPSPs is how neurons make decisions

Summation A single EPSP cannot induce an action potential EPSPs must summate temporally or spatially to induce an action potential Temporal summation – presynaptic neurons transmit impulses in rapid-fire order

IPSPs can also summate with EPSPs, canceling each other out Summation Spatial summation – postsynaptic neuron is stimulated by a large number of terminals at the same time IPSPs can also summate with EPSPs, canceling each other out PLAY InterActive Physiology ®: Nervous System II: Synaptic Potentials

Summation Figure 11.20

Neurophys 3: Action Potentials

The Role of Action Potentials APs are the electrical component of neuronal communication (synaptic transmission is the chemical component) APs send an electrical signal from the cell body of one neuron, down its axon, and to its axon terminals, where the electrical signal is converted into a chemical signal by the process of synaptic transmission

AP Characteristics All-or-None Phenomena (once they start, they keep going – and they are always the same size) Propogate in one direction only – from axon hillock to axon terminal Consist of a quick depolarization followed by a repolarization – then a hyperpolarization before the neuron recovers to the RP Since stimulus intensity is not coded by AP size, it must be coded by AP frequency (more APs indicate a larger stimulus)

Structure of Na+ Gates Na+ gates have two mechanisms that close them, so we say that the gate is closed, open, or inactivated These are voltage-activated gates, opening when the membrane is depolarized to threshold Closed Open Inactivated

Action of Na+ Gates During the AP Closed during RP Open when membrane reaches threshold, allowing Na+ to enter cell, resulting in rising phase of AP Inactivated when the AP reaches its peak Reset to closed state during hyperpolarization

Action of K+ Gates During the AP Simpler gate than Na+, since it is either open or closed – also voltage activated Closed during RP Open more slowly than Na+ gate, about the time when the AP reaches its peak Allow K+ ions to exit the cell, repolarizing the membrane and resulting in the falling phase of the AP Stay open longer than Na+ gate, resulting in hyperpolarization when the voltage overshoots the RP

1: Resting Potential

2: Rising Phase

3: Falling Phase

4: Overshoot

Summary of Gate Actions during APs Sodium Gate Potassium Gate Resting Potential Rising Phase Falling Phase Overshoot

Summary of Gate Actions during APs Sodium Gate Potassium Gate Resting Potential Closed Rising Phase Open Falling Phase Inactivated Overshoot

Refractory Periods After a neuron has fired an AP, it is unable to fire again until the refractory period has passed Two types: absolute refractory period and relative refractory period

Absolute Refractory Period The neuron is completely unable to send another AP during this time, no matter how intense the stimulus Occurs during rising phase and part of falling phase Since Na+ gates are already open, neuron can’t send another signal The absolute refractory period serves to: Ensure that each action potential is separate Enforce one-way transmission of nerve impulses

Relative Refractory Period The neuron is usually unable to send another AP during this time, but if the stimulus is strong enough, it will fire again Occurs during end of falling phase and overshoot Na+ gates are closed, but K+ are open – so the stimulus must be very strong to reach threshold again

Absolute and Relative Refractory Periods Figure 11.15

Action Potentials (APs) A brief reversal of membrane potential with a total amplitude of 100 mV Action potentials are only generated by muscle cells and neurons They do not decrease in strength over distance They are the principal means of neural communication An action potential in the axon of a neuron is a nerve impulse PLAY InterActive Physiology ®: Nervous System I: The Action Potential

Action Potential: Resting State Na+ and K+ channels are closed Leakage accounts for small movements of Na+ and K+ Each Na+ channel has two voltage-regulated gates Activation gates – closed in the resting state Inactivation gates – open in the resting state Figure 11.12.1

Action Potential: Depolarization Phase Na+ permeability increases; membrane potential reverses Na+ gates are opened; K+ gates are closed Threshold – a critical level of depolarization (-55 to -50 mV) At threshold, depolarization becomes self-generating Figure 11.12.2

Action Potential: Repolarization Phase Sodium inactivation gates close Membrane permeability to Na+ declines to resting levels As sodium gates close, voltage-sensitive K+ gates open K+ exits the cell and internal negativity of the resting neuron is restored Figure 11.12.3

Action Potential: Hyperpolarization Potassium gates remain open, causing an excessive efflux of K+ This efflux causes hyperpolarization of the membrane (undershoot) The neuron is insensitive to stimulus and depolarization during this time Figure 11.12.4

Action Potential: Role of the Sodium-Potassium Pump Repolarization Restores the resting electrical conditions of the neuron Does not restore the resting ionic conditions Ionic redistribution back to resting conditions is restored by the sodium-potassium pump

Phases of the Action Potential 1 – resting state 2 – depolarization phase 3 – repolarization phase 4 – hyperpolarization Figure 11.12

Propagation of an Action Potential (Time = 0ms) Na+ influx causes a patch of the axonal membrane to depolarize Positive ions in the axoplasm move toward the polarized (negative) portion of the membrane Sodium gates are shown as closing, open, or closed

Propagation of an Action Potential (Time = 0ms) Figure 11.13a

Propagation of an Action Potential (Time = 2ms) Ions of the extracellular fluid move toward the area of greatest negative charge A current is created that depolarizes the adjacent membrane in a forward direction The impulse propagates away from its point of origin

Propagation of an Action Potential (Time = 2ms) Figure 11.13b

Propagation of an Action Potential (Time = 4ms) The action potential moves away from the stimulus Where sodium gates are closing, potassium gates are open and create a current flow

Propagation of an Action Potential (Time = 4ms) Figure 11.13c

Threshold and Action Potentials Threshold – membrane is depolarized by 15 to 20 mV Established by the total amount of current flowing through the membrane Weak (subthreshold) stimuli are not relayed into action potentials Strong (threshold) stimuli are relayed into action potentials All-or-none phenomenon – action potentials either happen completely, or not at all

Coding for Stimulus Intensity All action potentials are alike and are independent of stimulus intensity Strong stimuli can generate an action potential more often than weaker stimuli The CNS determines stimulus intensity by the frequency of impulse transmission

Stimulus Strength and AP Frequency Figure 11.14

The refractory period is broken into two sections Refractory Periods A refractory period is a time at the end of an action potential when another a.p. can NOToccur The refractory period is broken into two sections Absolute Refractory Period – impossible to have another a.p. Relative Refractory Period – possible to have another a.p., but difficult

Absolute Refractory Period Time from the opening of the Na+ activation gates until the closing of inactivation gates The absolute refractory period: Prevents the neuron from generating an action potential Ensures that each action potential is separate Enforces one-way transmission of nerve impulses “Absolutely no way to fire another AP”

Relative Refractory Period The interval following the absolute refractory period when: Sodium gates are closed Potassium gates are open Repolarization is occurring The threshold level is elevated, allowing strong stimuli to increase the frequency of action potential events “Relatively difficult to have a second AP”

Absolute and Relative Refractory Periods Figure 11.15

Conduction Velocities of Axons Conduction velocities vary widely among neurons Rate of impulse propagation is determined by: Axon diameter – the larger the diameter, the faster the impulse Presence of a myelin sheath – myelination dramatically increases impulse speed PLAY InterActive Physiology ®: Nervous System I: Action Potential, page 17

Saltatory Conduction Current passes through a myelinated axon only at the nodes of Ranvier Voltage-gated Na+ channels are concentrated at these nodes Action potentials are triggered only at the nodes and jump from one node to the next Much faster than conduction along unmyelinated axons

Saltatory Conduction Figure 11.16

Multiple Sclerosis (MS) An autoimmune disease that mainly affects young adults Symptoms: visual disturbances, weakness, loss of muscular control, and urinary incontinence Nerve fibers are severed and myelin sheaths in the CNS become nonfunctional scleroses Shunting and short-circuiting of nerve impulses occurs

Multiple Sclerosis: Treatment The advent of disease-modifying drugs including interferon beta-1a and -1b, Avonex, Betaseran, and Copazone: Hold symptoms at bay Reduce complications Reduce disability