Unit 5: Neurophysiology in Mammals

1. Resting Potential, Graded Potential, and Action Potential

Resting Membrane Potential (RMP)

The resting membrane potential represents the electrical potential difference (voltage across the plasma membrane of a non-conducting, resting neuron or muscle cell.

Resting Membrane Potential (RMP): The standard electrical potential difference across the neuronal plasma membrane at rest, typically measuring approximately -70 mV, where the inside of the cell is negative relative to the outside.

Origin and Ionic Basis of RMP:

• Sodium-Potassium Pump (Na+/K+ ATPase): Actively transports 3 Na+ ions out of the cell for every 2 K+ ions moved inward using ATP. This electrogenic action directly maintains concentration gradients and contributes to negative intracellular charge.
• Differential Membrane Permeability: Resting neuronal membranes contain numerous open K+ leak channels and very few Na+ leak channels. K+ diffuses outward down its concentration gradient faster than Na+ enters, leaving net negative charge behind.
• Intracellular Non-diffusible Anions: High concentrations of negatively charged proteins, organic phosphates, and sulfates are trapped inside the cytoplasm, reinforcing internal negativity.

Graded Potentials

Graded potentials are localized changes in membrane potential that vary in magnitude depending on the strength of the stimulus. They occur primarily in the dendrites and soma of neurons.

Graded Potential: A local, proportional electrical change in the membrane potential that decays over distance and time and does not follow the all-or-none principle.

Key Properties of Graded Potentials:

• Proportional Amplitude: Stimulus intensity directly dictates potential magnitude. A stronger stimulus opens more ion channels.
• Decremental Conduction: The electrical change decays as it spreads passively away from the site of origin due to charge leakage through the membrane.
• No Refractory Period: Successive graded potentials can combine at the membrane.
• Summation: Can be additive. Spatial summation occurs when multiple local potentials arrive simultaneously at different loci; temporal summation occurs when high-frequency potentials arrive at a single locus in rapid succession.

Action Potentials

An action potential is a rapid, temporary, and self-propagating reversal of membrane potential that travels along the axon of an excitable cell.

Action Potential: A rapid sequence of membrane potential changes characterized by depolarization, overshoot, repolarization, and hyperpolarization, operating strictly on an all-or-none basis.

Phases of an Action Potential:

1. Resting State: Voltage-gated Na+ and K+ channels remain closed. Membrane potential stays at -70 mV.
2. Depolarization Phase: A threshold stimulus (reaching approximately -55 mV) triggers the opening of activation gates on voltage-gated Na+ channels. Rapid Na+ influx shifts membrane potential toward positive values (+30 mV to +40 mV), causing an overshoot.
3. Repolarization Phase: Inactivation gates on voltage-gated Na+ channels close, stopping Na+ influx. Simultaneously, voltage-gated K+ channels fully open, allowing rapid K+ efflux, returning potential toward resting levels.
4. Hyperpolarization (Undershoot) Phase: K+ channels close slowly, causing temporary excess K+ efflux that drives potential below the resting level (around -80 mV). The Na+/K+ pump and leak channels restore standard RMP.

Important Properties and Laws:

• All-or-None Law: If a stimulus reaches threshold intensity (-55 mV), a full action potential is generated. Increasing stimulus strength beyond threshold does not increase action potential amplitude.
• Absolute Refractory Period: Period during depolarization and early repolarization when voltage-gated Na+ channels are either open or inactivated. No second action potential can be fired, regardless of stimulus strength.
• Relative Refractory Period: Period following absolute refractory period where voltage-gated Na+ channels have reset, but K+ channels remain open. A second action potential can be triggered, but requires a stronger-than-normal stimulus.

Conduction Across Myelinated and Non-Myelinated Fibres

Action potentials must propagate down the axon without losing signal strength.

Conduction in Non-Myelinated Fibres (Continuous Conduction):

• Action potential depolarizes adjacent membrane segments sequentially through local current flows.
• Voltage-gated channels exist along the entire uninsulated axon length.
• Conduction speed is relatively slow (0.5 to 2 m/s) and requires substantial energy for ion pumping across the entire axolemma.

Conduction in Myelinated Fibres (Saltatory Conduction):

• Myelin sheaths formed by Schwann cells (peripheral nervous system) or oligodendrocytes (central nervous system) act as electrical insulators.
• Voltage-gated Na+ channels are densely concentrated only at the gaps between myelin sheaths, termed the Nodes of Ranvier.
• Current flows passively inside the axon from node to node, causing the action potential to "jump" between nodes.
• Saltatory conduction increases speed dramatically (up to 120 m/s) and conserves cellular energy.

Comparison Table: Graded Potential vs. Action Potential

Comparison Table: Continuous vs. Saltatory Conduction

2. Mechanism of Synaptic Transmission, EPSPs, and IPSPs

Structure of a Synapse

A synapse is a specialized junction through which neurons signal to each other or to non-neuronal cells such as muscles or glands. It consists of three primary elements:

• Presynaptic Axon Terminal: Contains synaptic vesicles filled with chemical neurotransmitters and abundant mitochondria.
• Synaptic Cleft: A fluid-filled extracellular space (20-40 nm wide) separating presynaptic and postsynaptic membranes.
• Postsynaptic Membrane: Contains specific ligand-gated ion channels or metabotropic receptors.

Step-by-Step Mechanism of Chemical Synaptic Transmission

1. Action Potential Arrival: The action potential reaches the presynaptic axon terminal, causing local depolarization.
2. Calcium Channel Activation: Depolarization opens presynaptic voltage-gated Ca2+ channels, causing Ca2+ ions to flow into the terminal down their electrochemical gradient.
3. Vesicle Exocytosis: Elevated intracellular Ca2+ binds to synaptotagmin, triggering synaptic vesicle fusion with the presynaptic membrane and releasing neurotransmitter into the cleft via exocytosis.
4. Receptor Binding: Neurotransmitters diffuse across the cleft and bind to specific receptors on the postsynaptic membrane.
5. Postsynaptic Response: Receptor activation opens or closes ion channels, producing local postsynaptic potentials.
6. Neurotransmitter Inactivation: Signal transmission is terminated by enzymatic degradation, glial or neuronal reuptake, or passive diffusion away from the cleft.

Postsynaptic Potentials: EPSPs and IPSPs

Binding of neurotransmitters causes local, graded changes in postsynaptic membrane potential.

Excitatory Postsynaptic Potential (EPSP): A temporary local depolarization of the postsynaptic membrane caused by net inward movement of positive ions (such as Na+ or Ca2+), bringing the membrane potential closer to threshold.

Inhibitory Postsynaptic Potential (IPSP): A temporary local hyperpolarization of the postsynaptic membrane caused by inward movement of Cl- or outward movement of K+, moving membrane potential further from threshold.

Integration of Signals: Neurons compute thousands of incoming EPSPs and IPSPs at the axon hillock. If the net summation exceeds the threshold value, an action potential is initiated.

Comparison Table: EPSP vs. IPSP

3. Neurotransmitters: Types and Functions

Neurotransmitters are endogenous chemical messengers released by neurons to transmit signals across chemical synapses.

Classification by Chemical Structure

1. Acetylcholine (ACh):

• Synthesized from choline and acetyl-CoA by choline acetyltransferase.
• Functions at neuromuscular junctions, autonomic ganglia, parasympathetic neuroeffector junctions, and CNS cognitive pathways.
• Degraded by acetylcholinesterase (AChE) in the synaptic cleft.

2. Biogenic Amines (Monoamines):

• Catecholamines: Synthesized from tyrosine. Includes Dopamine (motor control, reward/motivation), Norepinephrine (alertness, sympathetic arousal), and Epinephrine (stress response).
• Indolamines: Includes Serotonin (5-HT), synthesized from tryptophan, regulating mood, sleep, appetite, and circadian rhythms.
• Imidazolamines: Includes Histamine, regulating wakefulness and inflammatory responses.

3. Amino Acids:

• Glutamate: Principal excitatory neurotransmitter in the mammalian CNS; crucial for synaptic plasticity, learning, and long-term potentiation (LTP).
• GABA (Gamma-Aminobutyric Acid): Primary inhibitory neurotransmitter in the brain; synthesized from glutamate by glutamate decarboxylase.
• Glycine: Primary inhibitory neurotransmitter in the spinal cord and brainstem.

4. Neuropeptides:

• Larger molecules synthesized in the soma; include Substance P (pain perception) and Endorphins/Enkephalins (endogenous opioids modulating pain and mood).

5. Unconventional / Gaseous Neurotransmitters:

• Nitric Oxide (NO): Synthesized on demand, diffuses across membranes without vesicular storage; acts as a retrograde messenger to regulate vascular tone and synaptic plasticity.

Summary Table: Key Neurotransmitters

4. Neurodegenerative Disorders and Electroencephalography (EEG)

Neurodegenerative Disorders

Neurodegenerative disorders are progressive conditions characterized by structural and functional loss of neurons in the central nervous system.

1. Alzheimer's Disease (AD)

Alzheimer's disease is the leading cause of dementia in older mammals, resulting in cognitive decline, memory impairment, and behavioral changes.

• Pathological Hallmarks:
  • Extracellular Amyloid Beta Plaques: Aggregates of insoluble amyloid-beta (A-beta) peptides formed by abnormal cleavage of Amyloid Precursor Protein (APP).
  • Intracellular Neurofibrillary Tangles (NFTs): Hyperphosphorylated tau protein aggregates that disrupt the neuronal microtubule transport system.
• Neurochemical Deficit: Progressive loss of cholinergic neurons, particularly in the basal forebrain (Nucleus Basalis of Meynert), leading to severe drops in acetylcholine levels.
• Clinical Symptoms: Short-term memory loss, disorientation, language impairment, executive dysfunction, and eventual inability to perform activities of daily living.

2. Parkinson's Disease (PD)

Parkinson's disease is a progressive movement disorder caused by selective neurodegeneration within motor pathways.

• Pathological Hallmarks:
  • Dopaminergic Loss: Degeneration of dopamine-producing neurons in the substantia nigra pars compacta, which project to the striatum (nigrostriatal pathway).
  • Lewy Bodies: Intracellular protein inclusions containing aggregated alpha-synuclein.
• Clinical Symptoms (Classic Motor Triad plus Instability):
  • Resting Tremor: "Pill-rolling" tremor at rest.
  • Bradykinesia: Slowness of voluntary movement execution.
  • Muscle Rigidity: Increased resistance to passive stretch ("lead-pipe" or "cogwheel" rigidity).
  • Postural Instability: Impaired balance and gait disturbances.

Electroencephalography (EEG)

Electroencephalography is a non-invasive diagnostic technique used to record electrical activity generated by the brain.

Electroencephalogram (EEG): A recording of summed voltage fluctuations produced by ionic current flows within neurons of the cerebral cortex, measured via electrodes placed on the scalp.

Physiological Origin: The EEG wave patterns reflect the summation of post-synaptic potentials (EPSPs and IPSPs) from large populations of synchronously activated cortical pyramidal neurons aligned perpendicular to the cortical surface.

EEG Brain Wave Rhythms

EEG waves are classified according to their frequency (Hertz, Hz) and amplitude (microvolts, uV).

• Alpha Waves (8-13 Hz): Rhythm seen in awake, relaxed individuals with eyes closed. Highest amplitude in occipital regions. Disappears upon opening eyes or engaging in mental task (alpha block).
• Beta Waves (14-30 Hz): High-frequency, low-amplitude waves recorded in awake, alert, mentally active individuals with eyes open. Dominant in frontal and parietal lobes.
• Theta Waves (4-7 Hz): Medium-frequency waves normal in children, and in adults during light sleep or emotional distress. Pathological in awake adults.
• Delta Waves (0.5-3.5 Hz): Low-frequency, high-amplitude waves dominant during deep, slow-wave sleep in normal adults, and in infants. Presence in awake adults indicates severe structural brain lesions or damage.

Comparison Table: EEG Wave Characteristics

Clinical Applications of EEG

• Diagnosis of Epilepsy: Identifies abnormal spike-and-wave discharges, helping classify seizure types and pinpoint epileptic foci.
• Sleep Disorder Analysis: Forms an essential part of polysomnography to stage NREM and REM sleep phases and identify sleep apnea or narcolepsy.
• Assessment of Encephalopathy and Coma: Evaluates depth of unconsciousness and severity of metabolic or toxic brain dysfunction.
• Confirmation of Brain Death: Isoelectric (flatline) EEG confirms complete absence of cortical electrical activity.