Neuronal Physiology and Action Potentials Study Notes

Cellular Components of the Nervous System: Neurons and Glia

• Cellular Composition of the Nervous System:

  • Think of your nervous system as built from two main teams of cells: neurons (the high-tech communicators that process and pass along electrical and chemical signals) and glia or glial cells (the essential support crew that handle feeding, insulating, cleaning up, and protecting the brain).

  • Your brain houses roughly $86\,\text{billion}$ neurons! Every single thing you think, feel, or do comes from the intricate crosstalk among these billions of cells.

  • Cells and connections are packed together in insane densities; a tiny tissue snippet measuring just $1\,\text{mm}^3$ from a human cerebral cortex (taken during epilepsy surgery on a 45-year-old female) packs around $57{,}000$ cells and $150\,\text{million}$ synapses.

• Structural Diversity and Morphology of Neurons:

  • Neurons come in wild shapes and sizes—their soma (cell body) can span just a few micrometers, while their long axonal extensions can stretch for meters.

  • A single neuron can receive synaptic inputs from anywhere between one and tens of thousands of upstream sender neurons.

  • Major morphological types include:

    • Pyramidal cells: Found in cortical layers 3, 5, and 6, featuring pyramid-shaped somas and long apical dendrites reaching upward toward the brain's surface.

    • Purkinje cells: Spectacular cells located in the cerebellum with massive, flat, fan-like dendritic arbors that integrate thousands of inputs before firing signals to deep cerebellar nuclei.

    • Stellate cells: Star-shaped local circuit neurons that work locally in the cortex.

    • Chandelier cells: Specialized cortical interneurons named for their chandelier-like shape that form precise inhibitory synapses specifically on the axon initial segments of pyramidal cells.

  • Key functional drivers behind this morphological variety include:

    • Synthesis and release of distinct neurotransmitters.

    • Differential postsynaptic effects (whether they excite or inhibit neighboring cells).

    • Sampling of specific spatial and temporal input zones.

    • Execution of specialized computational operations.

    • Unique output targets and characteristic firing rhythms.

    • Metabolic and developmental constraints during growth.

• Structural Classifications of Neurons:

  • Multipolar Neurons: The standard neuronal layout in the central nervous system, sporting lots of branching dendrites and one single axon popping out of the cell body.

  • Bipolar Neurons: Neurons with two main branches shooting out from opposite sides of the soma: one single dendrite for input and one axon for output (like retinal bipolar cells in your eye).

  • Pseudo-unipolar Neurons: Feature one single process sticking out from the soma that quickly splits into two long axonal branches (a peripheral axon heading out to sensory receptors and a central axon entering the spinal cord), leaving the cell body hanging off to the side (like sensory neurons in the dorsal root ganglion).

• Functional Anatomy of the Neuron:

  • Dendrites: Tapered, branch-like extensions that act as the main input antennas, catching chemical neurotransmitter signals from presynaptic terminals.

  • Soma (Cell Body): The central hub containing the nucleus and major metabolic factories; it sums up all incoming electrical signals gathered by dendrites.

  • Axon: A uniform-diameter cable acting as the output pathway. Axons can stretch over short or long distances and branch into collateral terminals.

  • Axon Hillock: The cone-shaped base of the soma where the axon starts; it acts as the spike initiation zone because it is packed with a super-high density of voltage-gated ion channels.

  • Synapse: The specialized junction where an axon terminal meets a postsynaptic target cell (dendrite, soma, or axon) to pass messages via chemical neurotransmitters.

• Glial Cell Types and Functions:

  • Glia make up about $50\%$ of total brain volume. Glial somas are generally smaller than neuron somas, measuring between $5\,\mu\text{m}$ and $20\,\mu\text{m}$ in diameter (while neuron somas range from $5\,\mu\text{m}$ to $100\,\mu\text{m}$).

  • Astrocytes:

    • The most common glial cells in the central nervous system (CNS).

    • They wrap end-feet around blood vessels to construct and maintain the protective blood-brain barrier (BBB).

    • They regulate extracellular ion concentrations (especially mopping up excess $\text{K}^+$).

    • They clean up and recycle neurotransmitters (like glutamate) from the synaptic cleft.

    • They form scar tissue to isolate damaged brain areas and absorb metabolic toxins after injury.

  • Myelinating Glia:

    • Oligodendroglia (Oligodendrocytes): Found strictly in the CNS. A single oligodendrocyte extends multiple arms to wrap insulating fatty myelin sheaths around segments of up to roughly $50$ different axons.

    • Schwann Cells: Found strictly in the Peripheral Nervous System (PNS). Each Schwann cell wraps many layers of its own plasma membrane around a single $100\,\mu\text{m}$ segment of just one axon.

    • Nodes of Ranvier: Uninsulated gaps measuring $1\,\mu\text{m}$ between adjacent myelin segments where the axon membrane is exposed, allowing action potentials to jump rapidly down the line (saltatory conduction).

  • Microglia: Phagocytic cellular trash-collectors that serve as the main immune defense in the brain, gobbling up debris and dead cells.

  • Ependymal Cells: Ciliated cells lining the brain's ventricular system and spinal cord central canal, helping circulate cerebrospinal fluid (CSF).

  • Glial Pathology and CNS Tumors: Primary brain tumors (gliomas, astrocytomas, glioblastoma multiforme) almost always come from glial cells because glia retain the ability to divide. Cancers originating from adult neurons are extremely rare because mature neurons are post-mitotic and cannot undergo cell division.

Neuronal Cytoskeleton, Transport, and Neurodegenerative Pathology

• Subcellular Compartments and Organelles:

  • Cytosol: The salty fluid inside the cell containing water, dissolved inorganic ions, and soluble proteins.

  • Cytoplasm: Everything inside the cell membrane except the nucleus (combining the cytosol and organelles).

  • Mitochondria and Cellular Energy Production:

    • Mitochondria carry out cellular respiration using the formula:         $\text{Glucose} + \text{O}_2 \rightarrow \text{CO}_2 + \text{ATP}$

    • Adenosine Triphosphate (ATP) holds three phosphate groups; breaking off the end phosphate creates Adenosine Diphosphate (ADP) plus an inorganic phosphate ($\text{P}_i$), releasing usable energy to power cellular work.

    • The brain makes up only $2\%$ of body mass but gobbles up $20\%$ of all resting body energy ($\text{ATP}$). The $\text{Na}^+/\text{K}^+$ ATPase pump alone uses around $70\%$ of the brain's total ATP budget!

• Central Dogma and Gene Expression in Neurons:

  • The cell nucleus transcribes DNA instructions into messenger RNA (mRNA). mRNA then travels out into the cytoplasm, where ribosomes translate it into chains of amino acids (proteins).

  • Free Ribosomes vs. Rough Endoplasmic Reticulum (ER):

    • Proteins made on free ribosomes (floating freely in cytosol) stay inside as internal structural or cytosolic proteins.

    • Proteins made on ribosomes attached to the rough ER get built directly into membranes (like ion channels, receptors, transporters) or packed for secretion.

  • Even though almost every cell in your body shares identical DNA, what makes neurons special is gene expression. The human brain expresses between $55\%$ and $85\%$ of the approximately $19{,}000$ protein-coding genes in our genome, driving our incredible neuronal diversity.

• Dendritic Spines and Synaptic Plasticity:

  • Dendritic spines are tiny knob-like bumps poking off dendritic shafts that receive the vast majority of excitatory synaptic connections.

  • Dendrites are classified as either spiny or smooth.

  • Spine density and shape (head size, neck length) constantly reconfigure during development, learning, and experience.

  • Environmental Enrichment Experiments: Laboratory rats raised in fun, enriched environments (with toys, companions, and physical challenges) grow significantly higher dendritic spine densities and more complex dendritic branches compared to isolated rats in boring, empty cages.

• Spine Pathology in Intellectual Impairments:

  • Misformed dendritic spines directly correlate with cognitive challenges:

    • General Unspecified Intellectual Impairment: Neurons display long, thin, spindly dendritic spines rather than healthy mushroom shapes.

    • Fragile X Syndrome: The leading inherited genetic cause of autism spectrum disorder. Neurons show an unusually dense array of long, immature, thin spines because the brain fails to perform normal synaptic pruning during development.

• The Neuronal Cytoskeleton:

  • The internal structural scaffolding of a neuron relies on three distinct protein filament systems:

    • Microfilaments: Measuring $5\,\text{nm}$ in diameter, built from double-stranded actin polymers; densely packed right beneath the cell membrane and inside dendritic spines.

    • Neurofilaments: Measuring $10\,\text{nm}$ in diameter; intermediate filaments that provide strong mechanical structural support along axons.

    • Microtubules: Measuring $20\,\text{nm}$ in diameter; hollow tubes made of polymerized tubulin dimers that run down axons and dendrites like railroad tracks for molecular transport.

• Microtubule-Associated Proteins (MAPs) and Alzheimer's Pathology:

  • Microtubule-Associated Proteins (MAPs) act like structural ties holding microtubules together. A vital MAP called tau protein bridges parallel microtubules to keep axonal tracks stable.

  • Alzheimer's Disease Pathology:

    • Macroscopic Level: Brain tissue shrinks dramatically (cortical atrophy), gyri (ridges) narrow, sulci (furrows) widen, and fluid-filled ventricles expand as massive numbers of neurons die.

    • Microscopic Level: Extracellular $\beta$--amyloid plaques (clumps of misfolded $\beta$--amyloid proteins) build up outside cells, while intracellular neurofibrillary tangles (tangles of hyperphosphorylated tau proteins) choke cells inside.

    • The count of neurofibrillary tangles inside cells tracks cognitive decline far more closely than the total plaque burden outside.

  • $\beta$--Amyloid Hypothesis and Prion-like Tau Propagation:

    1. Neurons abnormally dump excess $\beta$--amyloid ($\beta\text{A}$), which aggregates into extracellular plaques.

    2. Plaque exposure triggers hyperphosphorylation of tau proteins (attaching way too many phosphate molecules).

    3. Hyperphosphorylated tau detaches from tubulin, causing the microtubule tracks to break down and wreck cellular transport.

    4. Detached tau clumps into toxic neurofibrillary tangles that kill the neuron.

    5. Misfolded tau spreads outward to neighboring connected neurons like a prion, causing healthy tau in nearby cells to misfold as well.

• Axoplasmic Transport Mechanisms:

  • Axons lack mature rough ER and free ribosomes, meaning they can hardly make any proteins locally. All essential proteins, enzymes, and vesicles made in the soma must be shipped actively down the axon.

  • Anterograde Transport: Freight movement heading forward from soma down to axon terminals. Powered by the motor protein kinesin, which literally steps along microtubules toward their $(+)$ ends in $10\,\text{nm}$ to $20\,\text{nm}$ steps using ATP energy.

  • Retrograde Transport: Freight movement heading backward from axon terminals to the soma. Powered by the motor protein dynein moving toward the $(-)$ ends of microtubules, bringing back recycled materials, trophic signals, or cellular feedback.

• Pathogens Exploiting Axoplasmic Transport:

  • Herpes Simplex Virus Type 1 (HSV-1): Sneaks into sensory nerve endings through skin breaks $\rightarrow$ hitches a ride via retrograde transport up to the soma in sensory ganglia where it hides dormant $\rightarrow$ reactivates during stress or illness $\rightarrow$ travels via anterograde transport back down to nerve endings, causing cold sores.

  • Rabies Virus: Enters through an infected animal bite $\rightarrow$ invades nerve terminals $\rightarrow$ travels via retrograde transport to the spinal cord and brain $\rightarrow$ multiplies in central neurons, causing encephalopathy and hydrophobia $\rightarrow$ travels via anterograde transport down autonomic nerves to salivary glands to spread to the next host.

The Neuronal Membrane at Rest and Electrochemical Equilibrium

• Electrophysiological Measurement Techniques:

  • Non-Invasive Macro-Recordings: Electroencephalography (EEG) tracks scalp electrical potentials from thousands of firing cortical neurons; Magnetoencephalography (MEG) measures tiny magnetic fields generated by neuronal currents; functional Magnetic Resonance Imaging (fMRI) maps blood oxygen changes (BOLD signal) to pinpoint active brain regions.

  • Microelectrode Single-Cell Recordings:

    • Intracellular Recording: A microscopic glass pipette pierces the cell membrane to measure internal electrical voltage ($V_m$) relative to an outside ground. It captures complete action potentials ($+40\,\text{mV}$ peak) and baseline resting potential ($-65\,\text{mV}$).

    • Extracellular Recording: The electrode sits just outside the neuron, detecting current flow as action potentials zip past, producing small, upside-down microvolt-scale ($\mu\text{V}$) voltage spikes.

• Definition of Resting Membrane Potential ($V_m$):

  • $V_m$ represents the steady voltage difference across the cell membrane when the neuron is quiet at rest (not firing action potentials or responding to active synaptic inputs).

  • In a resting neuron, the inside cytosol is electrically negative compared to the outside fluid, maintaining a resting potential around $V_m \approx -65\,\text{mV}$.

• Ion Concentration Distributions Across the Resting Membrane:

  • Neurons maintain dramatically different ion concentrations inside versus outside, often summarized as a "salty banana" (high potassium $\text{K}^+$ inside like a banana, surrounded by salty sodium $\text{Na}^+$ and chloride $\text{Cl}^-$ outside like seawater):

    • Potassium ($\text{K}^+$): Concentrated heavily inside ($100\,\text{mM}$ internal vs. $5\,\text{mM}$ extracellular fluid / $3\,\text{mM}$ CSF).

    • Sodium ($\text{Na}^+$): Concentrated heavily outside ($150\,\text{mM}$ extracellular vs. $15\,\text{mM}$ internal).

    • Chloride ($\text{Cl}^-$): Concentrated heavily outside ($150\,\text{mM}$ extracellular vs. $13\,\text{mM}$ internal).

    • Calcium ($\text{Ca}^{2+}$): Kept extremely low inside ($0.0002\,\text{mM}$ internal vs. $2\,\text{mM}$ extracellular).

  • These vital concentration gradients are built and maintained non-stop by energy-hungry transport pumps like the $\text{Na}^+/\text{K}^+$ ATPase pump, which continuously pumps $3\,\text{Na}^+$ out for every $2\,\text{K}^+$ brought in.