Action Potentials (L6-

primary ions carry electrical signals in neruons

Na+ , K+ , Cl- , and Ca2+

Mechanism of Na+ and K+ channel opeing during action potential

channels detect changes in membrane potential and reversibly change shape, allowing transient current slow within a narrow time window

direction of current and ion movement in voltage-gated Na+ channels

inward current; Na+ ions enter the cell

response speed and gating characteristics of voltage-gated Na+ channels

fast response time; controlled by voltage-regulated and time-dependent gates

direction of current and ion movement in voltage-gated K+ channels

putward current; K+ ions exit the cell

response speed and regulation of voltage-gated K_ chanels

slow response time; both opening and closing depend on membrane potential

number of conformation states: voltage-gated Na+ channels vs voltage-gated K+ channel

Na+ channels have 3 states (Closed/resting, open, inactivated); K+ channels have 2 states (closed open)

ball and chain model of Na+ channel inactivation

when the channel is closed, the “ball” tethered by a peptide chain floats freely. When the pore opens, the ball is attached to the open pore and physically blocks it

experimental evidence 1 for the ball and chain model

enzymatic removal or deletion via site-directed mutagenesis of the ‘ball’ structure eliminates channel inactivation

experimental evidence 2 for the ball and chain model

adding a synthetic peptide matching the ‘ball’ amino acid sequence restoes inactivation in channels where the ball was previously removed

effect of increasing axonal membrane depolarization on channel conductance

greater membrane depolarization increases the open probability, recruitment, and conductance of both voltage-gated Na+ and K+ channels

comparison of Na+ vs K+ conductance changes over time during depolarization

Na+ conductance increases rapidly immediately after depolarization and inactivates in under 1 ms. K+ conductance increases after a delay and does not rapidly inactivate

conductance changes during the Threshold phase

Initial depolarizing stimulus opens enough voltage-gated Na+ channels so that inward Na+ current exceeds outward background currents, triggering a positive feedback loop

conductance changes during the depolarization phase

Na+ conductance increases rapidly due to fast-opening voltage-gated Na+ channels, causing massive inward Na+ influx K+ channels begin slowly transitioning toward open

Conductance changes at the peak of the action potential

Na+ conductance reaches its max and begins rapidly declining due to ball-and-chain inactivation; delayed voltage-gated K+ channels fully open, raising K+ conductance

Conductance changes during the repolarization

Na+ conductance is minimal due to channel inactivation; high K+ conductance causes outward K+ exit, driving membrane potential back toward equilibrium

conductance changes during After-hyperpolarization (undershoot)

slowing-closing voltage-gated K+ channels remain open, keeping K+ conductance temporarily higher than at resting potential and driving VM toward EK

Stages of the action potential:

1. Resting membrane potential is near E(K), P(K) > P(Na) due to leaky K+ channels. K+ and Na+ voltage-gates are closed although Na+ time-dependent gate is open

2. Membrane is brought to threshold voltage by depolarizing stimulus causing the Na+ voltage-dependent gate to open

3. Na+ flows through open time-dependent and voltage dependent gates. Flow of Na+ into the cell rapidly depolarizes the membrane, causing more Na+ channels to open

4. Closure of time-dependent Na+ gate and delayed opening of voltage-gated K+ channels halts membrane depolarization

5. Open voltage-gated K+ channels repolarize the membrane back to a negative membrane potential

6. Slowly closing voltage-gated K+ channels hyperpolarize membrane towards E(K); Na+ channels return to closed resting value

   1. Negative feedback because of hyperpolarizing causes gate closure for K+

1st stage of the action potential

Resting membrane potential is near E(K) , P(K) >P(Na) due to leaky K+ channels. K+ and Na+ voltage-gates are closed although Na+ time-dependent gate is open

2nd stage of action potential

Membrane is brought to threshold voltage by depolarizing stimulus causing the Na+ voltage-dependent gate to open

3rd stage of action potential

Na+ flows through open time-dependent and voltage dependent gates. Flow of Na+ into the cell rapidly depolarizes the membrane, causing more Na+ channels to open

4th stage if action potential

Closure of time-dependent Na+ gate and delayed opening of voltage-gated K+ channels halts membrane depolarization

5th stage of action potentiak

Open voltage-gated K+ channels repolarize the membrane back to a negative membrane potential

6th stage of action potential

1. Slowly closing voltage-gated K+ channels hyperpolarize membrane towards E(K); Na+ channels return to closed resting value

   1. Negative feedback because of hyperpolarizing causes gate closure for K+

What will lowering external Na+ concentrations do to the driving force on sodium ions?

Lower driving force

If Na+ in fact the ion responsible for the rising phase of the action potential, how will this affect the action potential?

The peak of action potential becomes smaller 

Lower peaks b/c lower concentrations

Activation of Na+ and K+ voltage gated channels and the action potential:

positive feedback: Na+ entry causes depolarization, which opens more voltage gated Na+ channels, which causes more depolarization

negative feedback: voltage gated K+ channels bring the action potential to an end and induce their own closing

Stimulus intensity signaled by:

rate and population coding

rate coding

1. Strong stimulus allows threshold to be reached earlier in the refractory period 

2. Stronger stimulus elicits larger receptor potential and higher firing rate

population coding

1.  Individual receptors differ in their sensory thresholds

2. Stronger stimulus excites more receptors‹

encoding mechanism for stimulus strength given the All-or-None Principle

because individual action potentials have fixed amplitude and duration, stimulus intensity, and duration are encoded by the frequency (rate_ and temporal pattern of action potentials, not by potential size

Labelled Line Coding

a neural coding strategy where individual neurons are highly specific/tuned to a single distinct stimulus or feature (eg, a neuron that fires exclusively in response to a bee)

determing stimulus identity in a Labelled line system

Identity is determined by identifying which specific dedicated neuron (or group of identical line-specific neurons) displays the highest firing rate.

Distributed/ Population coding

A coding mechanism where information is represented across the joint pattern of firing rates in an ensemble (population) of broadly tuned neurons, rather than by single highly specific cells.

Advantage of population coding over specificity/labelled-line coding

It allows a small population of broadly-tuned feature neurons to represent a vast number of unique stimuli combinatorially, without requiring a unique dedicated neuron for every object.

combinatorial decoding example using feature-tuned neurons

A stimulus like a 'fly' can be represented when a danger-tuned neuron fires low, a 'big'-tuned neuron fires high, and a 'small'- tuned neuron fires low, identifying the object without a fly- specific cell.

Refractory Period

1. During an action potential a second stimulus will not produce an action potential

2. Limits the rate potentials are generated and key in determining the direction of propagation ensure only one direction

3. Have to wait to have an amplitude like first one --> can’t make action potential

4. Action potentials can vary across cell types → neurons generate action potentials but differ in way action potentials are generated

Absolute Refractory Period:

It begins with the activation of voltage-gated Na+ channels. Na+ channels either open or inactivate from first action potential

Ends when their inactivation is removed

Neuron incapable of generating another action potential no matter how strong the stimulus

Ensures each action potential is separate and distinct

Relative Refractory Period:

A brief period after the absolute refractory period when repolarization is occurring

It begins when Na+ channel inactivation is removed and ends when the voltage-gated K+ channels deactivate

Threshold for action potential significantly elevated, a strong stimulus can reopen the Na+ gates and allow another action potential

absolute and relative refractory period

Refractory Period during falling phase

1. Inactivation of the Na+ channels is maximal- few if any channels are available to increase Na+ conductance

2. K+ conductance is very large

1. During relative refractory periods, a very large increase in the Na+ conductance is required to override the K+ conductance and initiate a regenerative depolarization

Action potentials can vary across cell types:

1. Duration of action potentials can range from as little as 200 microseconds to many milliseconds

2. Rate can vary from a few action potentials/seconds to frequencies near 1000/second

3. Differences are related to variations in the channel types underlying depolarization and repolarization

How would rapid repolarization influence the action potential frequency

1. by shortening the overall duration of each individual spike.

2. When a cell repolarizes quickly, it accelerates the cycle and allows for a higher rate of firing due to the following mechanisms:

3. Shortened Refractory Period

4. Faster Membrane Resetting

Shortened refractory period

Fast repolarization enables voltage-gated sodium channels to recover from inactivation much sooner, directly reducing the cell's absolute and relative refractory periods.

Faster Membrane Resetting

The membrane potential returns to its negative resting state rapidly, allowing the cell to be re-stimulated and fire a subsequent action potential almost immediately.

action potentials

code stimulus intensity through change in frequency

graded potential

code stimulus intensity through changes in amplitude

Graded Potential Leading to an Action Potential

If a graded potential is strong, it will cause the cell to fire an action potential(s)

Graded vs action potential

	Graded Potential	Action Potential
Type of Signal	Input signals	Regenerating conduction signal
Takes Place	Dendrites, cell body	Axon trigger zone
Ion Channels Involved	mechanical , chemical, voltage-gated	Voltage-gated channels
Ions Involved	Na+ , Cl- , Ca2+	Na+ and K+
Type of Signal	Depolarizing or hyperpolarizing	depolarizing
Strength of Signal	Stimulus dependent, can be summed	All or none, cannot be summed
Initiator of Signal	Entry of ions through channel	Above threshold stimulus
Unique Characteristics	Summation, Stimulus Strength	Threshold, Refractory Period
magnitude	Graded (different amplitudes)	Fixed amplitude
Other names	PSP (postsynaptic potentials), APP (end-plate potentials, receptor potentials)	Spike or impulse

Action Potential Propagation

1. The action potential flows along the nerve axon

2. Some current is passively lost through the membrane. Two strategies to improve conduction properties:

   1. Increasing diameter of the axon-decreasing the internal resistance

   2. Myelination-increases electrical insulation around the axon

3. Concentric wrappings of the membrane of glial cells

4. Act as high resistance, low capacitance electrical insulators

5. Allows rapid nerve impulse conduction- faster propagation of than non-myelinated fibers of the same axon diameter (10-120 m/sec compared to 1 m/sec)

2 strategies to improve conduction properties

1. Increasing diameter of the axon-decreasing the internal resistance

2. Myelination-increases electrical insulation around the axon

Glial Cells

1. Non-neuronal cells in the brain: neuroglia (or nerve glue)

2. outnumber neurons

3. Support cells that provide nutrients to neurons (astrocytes) and the removal of damaged neurons and infection agents (microglia)

4. Myelin sheaths are made from glia: oligodendrocytes in the CNS and Schwann cells in the PNS

5. Also participate in the uptake and metabolism of the neurotransmitters and intracellular signaling

Myelination

• the process of wrapping nerve fibers in a protective, fatty layer called a myelin sheath, which helps electrical signals travel much faster and more efficiently through the brain and body

The Wire (Axon): Think of a nerve cell's long fiber (the axon) as a copper wire carrying an electrical message.

The Insulation (Myelin): Myelination is like wrapping that wire in rubber electrical tape.

The Result: Just as tape keeps electricity from leaking out of a wire, myelin keeps neural signals strong and lets them "jump" down the fiber, making messages move up to 100 times faster.

Oligodendrocytes:

myelin forming glial cells in the central nervous system. A single oligodendrocyte uses multiple branch like extensions to myelinate multiple separate axons (up to 60) simultaneously

Schwan cells

myelin-forming glial cells in the peripheral nervous system. A single Schwann cell forms myelin around just one axon segment

how does myelination act as an insulator

A multilayered sheath of plasma membrane that wraps around axons and acts as an insulator. Thus, even though the axial path is high resistance due to the small axon diameter, current flows down the length of axon, not through the membrane

Explain how refractory periods limit firing frequency and help produce unidirectional action-potential propagation

Refractory periods set a strict upper limit on how fast a neuron can fire and ensure that action potentials travel in only one direction down the axon.

Here is how they accomplish both:

1. Limiting Firing Frequency

During an action potential, voltage-gated sodium Na+ channels open and then rapidly enter a closed, inactive state.

• Absolute Refractory Period: While these Na channels are inactivated, they cannot be reopened by another stimulus, no matter how strong. This creates a hard physical limit on the maximum number of action potentials a neuron can send per second (firing frequency).

• Relative Refractory Period: Immediately following, voltage-gated potassium K+ channels remain open, causing hyperpolarization. A new action potential can only be triggered by a much stronger stimulus than usual.

2. Ensuring Unidirectional Propagation

An action potential moves down an axon because the depolarization of one membrane segment generates local currents that depolarize the adjacent patch of membrane.

• As the action potential moves forward to Segment B, the previous Segment A enters its absolute refractory period.

• When current passively spreads backward from Segment B to Segment A, Segment A's Na+ channels are inactivated and cannot depolarize again.

• Therefore, the action potential can only successfully excite the resting, excitable membrane ahead of it (Segment C), forcing the electrical impulse to travel exclusively in a single, forward direction toward the axon terminal.

Limiting Firing Frequency

During an action potential, voltage-gated sodium Na+ channels open and then rapidly enter a closed, inactive state.

• Absolute Refractory Period: While these Na channels are inactivated, they cannot be reopened by another stimulus, no matter how strong. This creates a hard physical limit on the maximum number of action potentials a neuron can send per second (firing frequency).

• Relative Refractory Period: Immediately following, voltage-gated potassium K+ channels remain open, causing hyperpolarization. A new action potential can only be triggered by a much stronger stimulus than usual.

Ensuring Unidirectional Propagation

An action potential moves down an axon because the depolarization of one membrane segment generates local currents that depolarize the adjacent patch of membrane.

• As the action potential moves forward to Segment B, the previous Segment A enters its absolute refractory period.

• When current passively spreads backward from Segment B to Segment A, Segment A's Na+ channels are inactivated and cannot depolarize again.

• Therefore, the action potential can only successfully excite the resting, excitable membrane ahead of it (Segment C), forcing the electrical impulse to travel exclusively in a single, forward direction toward the axon terminal.

2 types of signal propagation

1. Continuous (Direct) conduction for unmyelinated axons

2. Saltatory conduction for myelinated axons

Continuous Conduction

• Unmyelinated Axons

• Voltage-gated channels must open sequentially all the way down the entire axon membrane.

• The action potential travels like a slow wave because every single patch of membrane must regenerate the signal.

• speed of propagations are slow, typically ranging from 0.5 to 10 m/s.

Salvatory Conduction

• Myelinated Axons

• Voltage gated K+ and Na+ channels are located at the nodes

• The myelin sheath acts as an electrical insulator preventing ion leakage through the membrane.

  • Myelin prevents current flow through the membrane

• Current moves rapidly and passively beneath the insulated sections.

• The signal is regenerated only at exposed gaps, creating a rapid "jumping" effect from node to node.

• Speeds reach up to 150 m/s. [1, 2, 3, 4]

Nodes of Ranvier

The myelin sheath is interrupted at regular intervals, forming short uncovered regions

How Myelin and Nodes of Ranvier Increase Speed and Efficiency

• Myelin Insulation: Myelin wraps around the axon to increase membrane resistance and decrease capacitance, allowing passive electrical signals to travel fast and far without fading.

• Nodes of Ranvier: These short, uncovered gaps interrupt the myelin sheath at regular intervals and contain dense clusters of voltage-gated Na+ and K+ channels.

• Regenerative Leaps: When the passive current reaches a node, it triggers these channels to fire, regenerating a full-strength action potential that swiftly moves to the next gap.

• Refractory Period: Backward propagation is prevented because the Na+ channels in the recently fired section behind the signal are inactivated in a refractory state.

In what case would it not be helpful to have myelinated neurons?

When the distance the signal has to travel and the available space is very small (eg, gray matter of the brain and spinal cord)

What prevents the action potential from spreading backwards in an unmyelinated axon?

Depolarization of action potential spreads in both directions, but doesn’t cause a backward propagation because previous section just completed an action potential - Na+ channels are inactivated (refractory)