Neurophysiology: Action Potentials and Signal Transmission and Regulation and Clinical Applications

Structural and Functional Organization of the Nervous System

• The nervous system's organization is categorized into sensory and motor functions.

• General Senses:     - Includes information from internal organs.     - Includes taste and olfaction (smell).

• Special Senses:     - Vision.     - Hearing.     - Balance.

• Components of Nerve Signal Transmission (Reflex Arc example):     1. Stimulus: The external or internal change that triggers a response.     2. Receptor: Detects the stimulus.     3. Sensory Neuron: Conducts the signal from the receptor toward the central nervous system (CNS).     4. Interneuron: Located within the spinal cord or brain; processes information and connects sensory to motor neurons.     5. Motor Neuron: Carries the signal from the CNS to the effector.     6. Effector: The muscle or gland that performs the response.

Objectives of Neurophysiology

1. Understating how electrical signals propagate along the axon.

2. Understanding how signals transmit through synapses.

3. Understanding how signals transmit to effector cells.

4. Understanding how the same pattern of connections gives rise to computation.

5. Explaining how the pattern of connections is modified by experience.

Fundamental Concepts of Electricity in Biology

• Electric Current: Defined as the movement of charged particles.

• An increase in the number of moving particles results in a greater current.

• Ion: The word that refers to a "charged particle."

Characteristics of the Plasma Membrane

• The plasma membrane separates two distinct environments:     - Cytosol: The intracellular environment.     - Interstitial Fluid: The extracellular environment.

• Semi-permeability:     - Some molecules can diffuse across the lipid bilayer while others cannot.     - Small hydrophobic molecules and gases, such as Oxygen ($O_2$) and Carbon Dioxide ($CO_2$), cross membranes rapidly.     - The membrane restricts the diffusion of charged molecules, including ions, carbohydrates, and amino acids.     - The passage of restricted molecules relies on specific transport proteins embedded in the membrane.

Chemical Concentration Gradients

• There is an unequal distribution of ions across the cell membrane.

• Key ions and their distributions:     - Potassium ($K^+$)     - Sodium ($Na^+$)     - Chloride ($Cl^-$)     - Calcium ($Ca^{2+}$)

• Cytosol Characteristics: Contains a greater concentration of $K^+$, inorganic phosphate ($P_i$), and proteins.

• Interstitial Fluid (IF) Characteristics: Contains a greater concentration of $Na^+$ and $Cl^-$.

Membrane Transport Proteins

• Pumps:     - Move substances against their concentration gradient (from areas of low concentration to high concentration).     - Require energy from the breakdown of ATP ($ATP \rightarrow ADP + P_i$).     - Examples: Sodium-potassium ($Na^+/K^+$) pump and calcium ($Ca^{2+}$) pump in the plasma membrane.

• Leak Channels:     - These are always open.     - Allow substances to move down their concentration gradient (passive diffusion).

• Gated Channels:     - Open and close in response to specific stimuli.     - Allow specific types of ions to diffuse only when the gate is open.

Classes of Gated Channels

1. Mechanically Gated Channels:     - Respond to physical membrane distortion.     - Found in sensory receptors for touch, pressure, and vibration.

2. Chemically Gated Channels:     - Open in the presence of specific chemicals at a binding site.     - Example: Acetylcholine ($ACh$) binding to a receptor gate.

3. Voltage-Gated Channels:     - Respond to changes in transmembrane potential (voltage).     - Possess activation gates (to open) and inactivation gates (to close).     - These are characteristic of excitable membranes.     - They exist in three states: Closed (resting state), Open (activation state), and Closed (inactivation state).

Resting Membrane Potential (RMP)

• Definition: The relative difference in electrical charge across the plasma membrane when a cell is at rest.

• Property: The cell is said to be polarized.

• Measurement:     - Voltage: A measure of the amount of difference in electrical charge, measured in volts ($V$) or millivolts ($mV$).     - RMP is an indicator of relative potential energy.

• Typical RMP: $-70\,mV$.

• Establishing RMP:     - Maintained by the $Na^+/K^+$ pump and $K^+$ leak channels.     - The pump requires ATP to move $Na^+$ out and $K^+$ into the cytosol.

Action Potential Terminology

• Depolarization: A change in membrane potential to a more positive value.

• Repolarization: A change in membrane potential that returns it to a negative value.

• Hyperpolarization: A change in membrane potential that makes it more negative than the RMP (lower than $-70\,mV$).

• Threshold: A minimum intensity of the signal that will produce a specific response (around $-55\,mV$ to $-50\,mV$).

• Action Potential: A localized change in electrical potential, from about $-70\,mV$ to $+30\,mV$ and back again, occurring across a nerve fiber during the transmission of a nerve impulse.

Step-by-Step Events of an Action Potential

1. Resting State: The unstimulated axon has a resting membrane potential of $-70\,mV$.

2. Threshold Reached: The axon hillock is depolarized to threshold.

3. Depolarization: Voltage-gated $Na^+$ channels open and $Na^+$ enters the cell rapidly. This reverses the polarity from negative to positive ($-50\,mV \rightarrow +30\,mV$).

4. Repolarization: Voltage-gated $Na^+$ channels close (entering the inactivation state) and voltage-gated $K^+$ channels open. $K^+$ moves out of the cell into the interstitial fluid. Polarity is reversed from positive to negative ($+30\,mV \rightarrow -70\,mV$).

5. Hyperpolarization: Voltage-gated $K^+$ channels stay open longer than the time needed to reach RMP. The membrane potential becomes less than $-70\,mV$.

6. Return to Resting Conditions: Voltage-gated $K^+$ channels close. The plasma membrane returns to RMP via the activity of $Na^+/K^+$ pumps.

Propagation of the Nerve Signal

• Continuous Conduction:     - Occurs in unmyelinated axons.     - Involves the sequential opening of voltage-gated $Na^+$ and $K^+$ channels along the entire length of the axon.

• Saltatory Conduction (Saltatory Propagation):     - Occurs in myelinated axons.     - Myelinated regions are well insulated, which prevents ion movement.     - Nodes of Ranvier: Unmyelinated regions containing a large number of voltage-gated $Na^+$ and $K^+$ channels.     - Action potentials are propagated only at the nodes of Ranvier, appearing to "jump" from node to node.

• Advantages of Saltatory Conduction:     - Increases the speed of transmission by approximately 100-fold.     - Conserves energy because the $Na^+/K^+$ pump only needs to operate at the nodes, and fewer total ions must be transported.

Events at the Neuromuscular Junction

• The neuromuscular junction is the synapse between a motor neuron and a muscle fiber.

• Process:     1. The Action Potential (AP) reaches the synaptic knob.     2. Voltage-gated Calcium ($Ca^{2+}$) channels open.     3. The influx of Calcium into the bulb activates enzymes.     4. Vesicles containing neurotransmitters dock and release their contents into the synaptic cleft.     5. For skeletal muscles, the neurotransmitter is always Acetylcholine ($ACh$).     6. ACh binds to receptors on the motor end plate (sarcolemma), which are chemically gated $Na^+$ channels.     7. $Na^+$ enters the muscle fiber, triggering muscle contraction.     8. Acetylcholinesterase: An enzyme in the synaptic cleft that breaks down $ACh$ molecules to terminate the signal.

• Note: A similar process occurs at synapses between two neurons.

Clinical Applications and Pathologies

• Myasthenia Gravis: An autoimmune disease where the body produces antibodies against Acetylcholine ($ACh$) receptors, leading to muscle weakness.

• Curare: A substance that binds to $ACh$ receptors without activating them, effectively blocking muscle stimulation and leading to paralysis.

• Botulinum Toxin: Prevents the release of the neurotransmitter from the synaptic vesicles into the synapse.

• Nerve Gas: Inhibits the enzyme acetylcholinesterase in the synapse, leading to prolonged muscle contraction as $ACh$ is not broken down.

• Pufferfish Toxin (Tetrodotoxin): Irreversibly binds to voltage-gated $Na^+$ channels, preventing the generation of action potentials.

• Multiple Sclerosis: A condition characterized by the degeneration of myelin, which slows or disrupts nerve signal propagation.