Exam 1

Fundamentals of Neurophysiology

• Definition of Neurophysiology:

  • Neurophysiology is literally defined as the study of life processes within neurons that utilize electrical and chemical signals for communication.

  • Neurons communicate differently from other cells by employing both electricity and chemical messengers.

• Source of Electricity in Neurons:

  • Neuronal electricity arises from ions, which are charged molecules dissolved in fluids.

  • Because ions carry positive or negative charges, they generate specific voltages across membranes, resulting in positive or negative electrical potentials.

• Source of Chemical Signals in Neurons:

  • The chemical messengers utilized by the nervous system are neurotransmitters.

  • Neurotransmitters are released by neurons in the brain and nervous system to trigger specific downstream events and cellular responses.

• Key Governing Principles of Neural Information Processing:

  • Gathering Sensory Information: For the nervous system to process information, sensory organs (such as the eyes, nose, and auditory system in the ears) must first gather stimuli from the environment.

  • Sensory Relay Pathways: Sensory information is brought toward the brain and central nervous system via structures such as the dorsal root ganglia.

  • Neural Circuit Formation: Information is relayed sequentially from neuron to neuron within organized functional groups called circuits. A neural circuit consists of continuous chains where one neuron connects to the next.

  • Information Processing Sequence:

  1. Sensory input enters through structures such as the dorsal root ganglion.

  2. Transmitted signals are routed to the brain.

  3. Specialized interneurons integrate the incoming signals.

  4. An output signal is generated (e.g., motor output).

  • Pacing and Processing in Neural Chains: Each neuron within a circuit receives incoming signals, processes and integrates those signals locally, and then transmits the refined signal forward to the next neuron in the chain.

• Modes of Communication:

  • Intercellular Communication: Communication occurring between two distinct neurons (cell-partner formation across synaptic connections).

  • Intracellular Communication: Signal processing, integration, and transmission occurring within a single neuron.

• Circuit Organization and Multi-Input Integration:

  • Circuit Structure Example: A sensory neuron brings in environmental information, a facilitating interneuron integrates this incoming data, and a motor neuron delivers the output signal.

  • Complex Dendritic Reception: A single neuron does not receive input from just one source; the dendrites of a single neuron can receive simultaneous inputs from thousands to millions of other neurons.

  • Decision-Making via Integration: The receiving neuron processes all simultaneous incoming signals at once, determining which inputs to prioritize and integrate into a cohesive output.

• Presynaptic and Postsynaptic Dynamics:

  • Neurotransmitters act as chemical messengers between neurons.

  • The axon terminal of a presynaptic neuron releases neurotransmitters into the synaptic space.

  • These neurotransmitters cross the gap and bind to specific receptors situated on the postsynaptic neuron.

  • Receptors binding neurotransmitters trigger cascading intracellular signaling events in the postsynaptic cell.

• Functional Anatomy of Intracellular Signaling:

  • Dendrites: Act as the primary receiving structure of the neuron, collecting incoming chemical and electrical inputs.

  • Axon Hillock: Located at the junction between the cell body (soma) and the axon; highlighted as the critical site where incoming information is integrated and where the decision to fire an action potential (activate the neuron) is made.

  • Axon: Serves as the conducting region of the neuron, transferring electrical signals across distances.

  • Axon Terminals: Act as the output site where neurotransmitters are released to pass the signal to adjacent cells.

• Action Potential Definition and Propagation:

  • Action Potential Definition: A rapid electrical signal characterized by a sudden shift in the electrical voltage across the neuronal membrane.

  • Role of Nodes of Ranvier:

  • Oligodendrocytes insulate sections of axons with myelin sheaths, leaving small uninsulated gaps called the Nodes of Ranvier.

  • As ionic charges flow internally down the continuous cytoplasm of the axon, they naturally diffuse and lose signal strength.

  • The Nodes of Ranvier contain clusters of specialized channels and receptors that recharge the electrical signal continuously along the axon.

  • Recharging ensures that the action potential maintains full electrical strength as it travels from the soma to the axon terminal, successfully driving neurotransmitter release.

Neuronal Membrane Structure & Experimental Discovery

• Phospholipid Bilayer Architecture:

  • Neuronal Cell Membrane: Composed of a phospholipid bilayer containing two distinct layers of lipid molecules.

  • Phospholipid Structure:

  • Phosphate Heads: Polar, circular hydrophilic regions that face outward toward water-rich environments (extracellular fluid and intracellular fluid/cytoplasm).

  • Fatty Acid Tails: Nonpolar chains of fat, two attached to each phosphate head, facing inward toward each other to form a hydrophobic core that repels water.

• Membrane Proteins:

  • Specialized functional units such as receptors, transporters, and channels are proteins embedded directly within the phospholipid bilayer.

  • Amphipathic Protein Structure: Embedded membrane proteins feature hydrophilic regions that interact with the phosphate heads and surrounding fluid, as well as hydrophobic regions that nestle within the interior fatty acid tails.

• Experimental Demonstration of Resting Membrane Potential:

  • Experimental Setup:

  • An isolated neuron is placed in a petri dish containing physiological liquid media.

  • Two electrodes are used: a reference electrode placed in the bath media and a recording electrode.

  • Reference Electrode Importance: Establishes a baseline/background electrical measure to isolate the specific electrical activity of the neuron from artifactual background noise.

  • Both electrodes are connected to an amplifier (to scale up signals measured in millivolts) and routed to an acquisition system or oscilloscope.

  • Measurements and Baseline Determination:

  • When both the recording electrode and reference electrode are placed in the dish media, the system measures a baseline differential of $0\,\text{mV}$.

  • When the recording electrode is inserted inside the neuronal cell membrane (intracellular space), the system measures a negative potential of $-65\,\text{mV}$.

  • Conclusions:

  • Repeated testing demonstrates that the intracellular environment of neurons is consistently negative relative to the surrounding extracellular media.

  • Electrically Excitable Cells in the Body: This negative electrical property and voltage usage is shared by other excitable tissues, such as cardiac cells (whose voltage shifts produce the characteristic blips on echocardiograms/ECGs).

Ionic Concentrations & Electrochemical Forces

• Nature and Formation of Ions:

  • Ions are charge-carrying molecules or elements formed when atoms gain or lose electrons to achieve chemical stability.

  • Cations: Positively charged ions (having fewer outer-shell electrons).

  • Anions: Negatively charged ions (having additional electrons; more electrons yield greater negative charge).

• Key Physiological Ions in Neurophysiology:

  • Sodium ($\text{Na}^+$): Monovalent cation carrying a single positive charge.

  • Potassium ($\text{K}^+$): Monovalent cation carrying a single positive charge.

  • Chloride ($\text{Cl}^-$): Monovalent anion carrying a single negative charge.

  • Calcium ($\text{Ca}^{2+}$): Divalent cation carrying a double positive charge.

  • Magnesium ($\text{Mg}^{2+}$): Divalent cation involved in secondary neural functions.

  • Cerebrospinal Fluid (CSF) Composition: The protective fluid surrounding the brain consists primarily of dissolved $\text{Na}^+$, $\text{K}^+$, $\text{Cl}^-$, $\text{Ca}^{2+}$, and $\text{Mg}^{2+}$.

• Distribution of Ions Across the Neuronal Membrane:

  • Extracellular Fluid (Outside the Cell):

  • High concentration of Sodium ($\text{Na}^+$).

  • High concentration of Calcium ($\text{Ca}^{2+}$).

  • High concentration of Chloride ($\text{Cl}^-$).

  • Net charge is positive relative to the inside.

  • Intracellular Fluid (Inside the Cell):

  • High concentration of Potassium ($\text{K}^+$).

  • High concentration of large, negatively charged intracellular proteins.

  • Net charge is negative relative to the outside.

  • Primary Origin of Negative Intracellular Potential: The overwhelming abundance of negatively charged proteins fixed inside the cytoplasm gives the interior of the neuron its net negative charge.

• Mechanisms of Ionic Movement Across Membranes:

  • Impermeability of Phospholipid Bilayer: Charged ions cannot pass directly through the hydrophobic lipid tail region of the membrane due to their charge and hydration shells.

  • Transmembrane Ion Channels: Protein structures spanning the membrane that form specialized pores allowing specific ions to cross.

  • Selectivity: Channels permit either cations or anions, but not both. Selectivity is driven by charge interactions and physical pore size.

  • Size Discrimination Example: Sodium ions ($\text{Na}^+$) are physically larger than potassium ions ($\text{K}^+$). Consequently, a potassium channel pore is too small to allow $\text{Na}^+$ ions to pass.

  • Gating States: Channels can transition between open states (permitting ion flow) and closed states (blocking ion flow).

  • Leaky Channels: Specific ion channels (such as leaky potassium channels) remain permanently open, allowing continuous passive diffusion of $\text{K}^+$ ions across the membrane.

• Forces Driving Ionic Motion:

  • Concentration Force (Chemical Gradient / Diffusion):

  • Particles passively migrate down their concentration gradient from an area of high concentration to an area of low concentration to reach equilibrium.

  • Analogy: Individuals crammed in a densely packed room naturally seek to move outside into empty space to escape high concentration.

  • Liquid Diffusion Analogy: Pouring red dye into one corner of a rectangular water tub results in the dye spreading out until uniform red color (equilibrium) is established throughout the entire volume.

  • Electrical Force (Electrostatic Gradient):

  • Opposite charges attract ($+\text{ attracts }-$; $-\text{ attracts }+$).

  • Like charges repel ($+\text{ repels }+$; $-\text{ repels }-$).

  • Example: Positively charged $\text{K}^+$ ions inside the cell are attracted to and held near the inner membrane by the abundant negatively charged intracellular proteins.

Resting Membrane Potential & Active Transport

• Resting Membrane Potential ($V_m$):

  • Definition: The electrical charge/voltage measured across the neuronal cell membrane when the neuron is at rest (neither sending nor receiving active signals).

  • Voltage Measurement: Typically $-65\,\text{mV}$ in baseline reference neurons.

  • Physiological Range: Across various populations of neurons, resting membrane potential ranges between $-60\,\text{mV}$ and $-70\,\text{mV}$.

  • Range Determinant: Differences in baseline resting potentials across different neurons are driven by variations in the internal concentration and density of fixed negatively charged proteins.

• Active Gradient Maintenance: The Sodium-Potassium Pump:

  • Necessity: After an action potential fires, $\text{Na}^+$ accumulates inside the cell and $\text{K}^+$ accumulates outside, reversing the optimal resting state. The cell requires an active energy-driven process to reset ionic balances.

  • Sodium-Potassium ATPase Pump Characteristics:

  • A specialized transmembrane protein pump embedded in the phospholipid bilayer.

  • Operates via active transport, consuming metabolic energy in the form of Adenosine Triphosphate (ATP).

  • Stoichiometric Exchange Ratio:

  • For every individual ATP molecule consumed, the pump actively extrudes $3\,\text{Na}^+$ ions out of the intracellular compartment and imports $2\,\text{K}^+$ ions into the intracellular compartment.

  • Stoichiometry: $3\,\text{Na}^+\text{ (out)} : 2\,\text{K}^+\text{ (in)}$.

  • Timing: Actively operates following action potentials to restore ionic concentration gradients back to resting parameters.

Postsynaptic Potentials & Integration Mechanisms

• Ligand-Gated Ion Channels (Ionotropic Receptors):

  • Definition: Receptors and ion channels whose gate opening is directly controlled by the binding of a specific chemical messenger (ligand/neurotransmitter).

  • Localization: Distributed densely across the dendritic trees and soma of neurons.

  • Operational Mechanism Example (Acetylcholine Receptor):

  • Acetylcholine (ACh) acts as a ligand and binds to extracellular binding sites on an ACh receptor.

  • Binding induces a conformational change, opening a selective $\text{Na}^+$ channel pore.

  • $\text{Na}^+$ ions enter the cell down both their concentration gradient (high outside to low inside) and electrical gradient (positive ion pulled toward negative interior).

• Postsynaptic Voltage Shifts:

  • Excitatory Postsynaptic Potential (EPSP):

  • Caused by the opening of cation channels (e.g., $\text{Na}^+$ channels) letting positive charge enter the cell.

  • Results in Depolarization: The intracellular potential becomes less negative, moving closer to $0\,\text{mV}$.

  • Voltage Shift Example: If resting potential is $-65\,\text{mV}$ and an influx of $+40\,\text{mV}$ worth of positive ions occurs, the local membrane potential shifts to $-25\,\text{mV}$ (more depolarized/positive).

  • Inhibitory Postsynaptic Potential (IPSP):

  • Caused by the opening of anion channels (e.g., $\text{Cl}^-$ channels) letting negative charge enter the cell.

  • Results in Hyperpolarization: The intracellular potential becomes more negative, moving further away from $0\,\text{mV}$ (e.g., shifting from $-65\,\text{mV}$ to $-75\,\text{mV}$).

  • Hyperpolarization decreases the likelihood of action potential generation.

• Signal Attenuation and Summation:

  • Cytoplasmic Diffusion: Ions entering via dendritic or somatic synapses flow through the internal fluid toward the axon hillock. As they travel, ions diffuse through the cytoplasm, causing the local electrical charge to diminish (attenuate) over distance.

  • Necessity for Multiple Inputs: A single isolated EPSP is generally too weak to trigger an action potential; multiple inputs must combine.

  • Spatial Summation:

  • Integration of postsynaptic potentials originating from different physical locations across the neuron (e.g., apical dendrites, basal dendrites, soma) that arrive at the axon hillock at the same time.

  • Temporal Summation:

  • Integration of postsynaptic potentials originating from a single synaptic location that fire in rapid succession over time.

  • Signals arriving in close temporal proximity sum together; signals separated by large time gaps (e.g., 5 minutes apart) decay and fail to summate.

• Threshold Potential for Action Potential Activation:

  • Threshold Voltage Definition: The critical intracellular voltage level that must be attained at the axon hillock to trigger an action potential.

  • Non-Negotiable Threshold Value: $-40\,\text{mV}$ (with a physiological range across neuronal types spanning $-55\,\text{mV}$ to $-40\,\text{mV}$).

  • Decision Rule at Axon Hillock:

  • If the sum of incoming EPSPs and IPSPs depolarizes the axon hillock membrane potential to $-40\,\text{mV}$ (or within $-55\,\text{mV}$ to $-40\,\text{mV}$), an action potential is triggered 100% of the time.

  • If the net voltage fails to reach the threshold, no action potential is generated.

Action Potential Dynamics & Propagation

• Phases of the Action Potential:

  1. Resting State: The neuron is stable at its resting membrane potential ($-60\,\text{mV}$ to $-70\,\text{mV}$, e.g., $-70\,\text{mV}$).

  2. Subthreshold EPSPs: Initial weak depolarizing inputs produce minor EPSP bumps that fail to reach threshold.

  3. Threshold Reached: Sufficient spatial/temporal summation of EPSPs depolarizes the axon hillock to the threshold potential ($-55\,\text{mV}$ to $-40\,\text{mV}$).

  4. Depolarization (Ascending Limb / Rising Phase):

  • Triggered upon reaching threshold.

  • Massive influx of positive cations causes rapid depolarization, driving the intracellular potential from negative up toward zero and into positive figures.

  • Action Potential Peak: Peaks strictly at $+40\,\text{mV}$. Action potentials do not scale in amplitude; peak voltage never exceeds $+40\,\text{mV}$.

  1. Repolarization (Descending Limb / Falling Phase):

  • Following the $+40\,\text{mV}$ peak, positive charge exits/negative charge resets the cell, driving the potential rapidly back down toward negative values.

  1. Hyperpolarization (Undershoot / Refractory Period):

  • The membrane potential overshoots resting potential, becoming more negative than rest (e.g., dipping below $-70\,\text{mV}$).

  • Refractory Period State: During this hyperpolarized phase, the neuron is dormant and incapable of firing another action potential because the electrical gap to reach threshold is too large.

  1. Return to Rest: Active transport mechanisms (such as the $\text{Na}^+/\text{K}^+$ pump) restore ionic distribution, returning the membrane potential to $-70\,\text{mV}$.

• Propagation Down the Axon:

  • Initiated strictly at the axon hillock.

  • Propagates sequentially down the axon, regenerating at full peak amplitude ($+40\,\text{mV}$) at each consecutive Node of Ranvier until reaching the terminal to drive neurotransmitter release.