Nervous System Physiology

Nervous System Physiology

• Nervous system is responsible for picking up signals from internal and external environments.
• It conducts these signals to the CNS.
• It integrates the signals to form responses like thoughts, senses, movements, and balance.
• Functions of the nervous system include sensory system, motor system, limbic system(behavior and motivation), sleep-wakefulness, thinking and thoughts, planning, learning, memory, intelligence, and consciousness.
• Neurons are 100 billion in the brain, and 100 trillion cells in the body.
• The defining characteristic of neurons is electrical excitability – the ability to produce action potentials (impulses) in response to stimuli.

Neurons- Cell Body

• The soma is the metabolic center of the neuron.
• It integrates signals.
• The nucleus contains genetic material and prominent nucleolus (high synthetic activity)
• Nissl bodies are rough endoplasmic reticulum and free ribosomes for protein synthesis. They are involved in the replacement of neuronal cellular components during growth and repair.
• Neurofilaments (neurofibrils) are bundles of intermediate filaments, giving the cell shape and support.
• Microtubules are involved in moving materials within the cell.

Neurons- Dendrites

• Dendrites receive messages from other neurons.
• They are short, tapering, and highly branched structures.
• Dendrites are the input portion of the neuron.

Neurons- Axon

• Axons carry information away from the cell body, and are the longest part of the neuron.
• Impulses arise at the junction of the axon hillock and initial segment.
• Swollen tips (synaptic end bulbs) contain vesicles filled with neurotransmitters.
• Axon endings have fine processes called axon terminals.
• Cytoplasm is called axoplasm.
• Plasma membrane is called axolemma.
• Axon collaterals emerge from the axon.

Axonal Transport

• Cell bodies are the location for most protein synthesis (e.g., neurotransmitters & repair proteins).
• Axons or axon terminals require proteins
• (1) Slow axonal flow: Axoplasm moves only anterograde direction (away from cell body) at 1-5 mm/day. This replenishes axoplasm in regenerating or maturing neurons.
• (2) Fast axonal flow: Moves organelles and materials along the surface of microtubules at 200-400 mm per day. It transports material in both directions. Degenerating mitochondria is transported in the retrograde direction for recycling, and new mitochondria move down the axon.
• Polypeptides packaged into vesicles are attached to the molecular motors (kinesin for anterograde movement and dynein for retrograde movement), which move them along microtubules.

Glial Cells

• Microglia act as phagocytes clearing away dead cells and protecting the CNS from disease by phagocytosis of microbes. At injured sites, they clear away debris.
• Macroglia (astrocytes): Star-shaped with many processes, forming the blood-brain barrier, regulating nutrient concentrations, maintaining pH & [K+], taking up excess neurotransmitters, assisting in neuronal migration during brain development, and performing repairs (scar formation).
• Oligodendroglia myelinate axons of the central nervous system (CNS).
• Schwann cells myelinate axons of the peripheral nervous system (PNS).
• Ependymal cells form epithelial membrane lining cerebral cavities that contain Cerebrospinal Fluid(CSF). They produce and circulate CSF.
• Satellite cells are flat cells surrounding peripheral axons, supporting neurons in the peripheral nervous system (PNS).

Nerve Action Potential

• Nerve signals are transmitted by action potentials.
• Action potentials are rapid changes in resting membrane potential that rapidly spread along the nerve fiber membrane.
• At rest, before action potential begins, conductance for K+ is ~75 times more than that for Na+.
• The membrane is polarized.
• At the onset of action potential, Na channels become activated, Na conductance increases by 5000-fold, leading to Na influx, and membrane potential shifts rapidly in a positive direction(depolarization).
• After depolarization, rapid diffusion of K+ efflux establishes the normal negative resting membrane potential (repolarization).

Receptor Potential/Graded Potentials

• When ion channels open with stimuli in receptors, receptor potentials are generated which are not all-or-none like action potentials.
• If receptor potential rises above threshold, action potential occurs in nerve fiber.
• As intensity of stimuli increases, the amplitude of receptor potential and consequently the frequency of action potential increase.
• Examples of graded potentials include synaptic potentials (EPSP&IPSPs) and receptor potentials.

Properties of Graded Potentials vs Action Potentials

• Graded potentials can be depolarization or hyperpolarization while action potentials are only depolarization.
• Graded potentials are initiated by stimuli, neurotransmitters, or spontaneously, but action potentials are initiated by graded potentials.
• In graded potentials, amplitude varies with the size of the initiating event while in action potentials, it is independent.
• Graded potentials can be summed over time and space, unlike action potentials which cannot be summed.
• Graded potentials have no threshold while action potentials do.
• Graded potentials have no refractory periods while action potentials do.
• In graded potentials, amplitude decreases with distance, while in action potentials, it is conducted without decrement and amplified to a constant value at every point along the membrane.
• Graded potentials are not all-or-none, while action potentials are all-or-none.

Synapses

• Synapses are junctions between neurons.
• Types of synapses include electrical and chemical.
• In electrical synapses, gap junctions conduct ions freely, synchronizing the electrical activity of large populations of neurons.
• In chemical synapses, neurotransmitters transmit signals. The region belonging to the initiating neuron is called the presynaptic membrane, and the region belonging to the receiving neuron is called the postsynaptic membrane. The space in between is called the synaptic cleft.
• There are three types of synapses: axo-dendritic, axo-somatic, and axo-axonic.

Presynaptic Terminals

• The synaptic gap is between the end of the axon and the postsynaptic membrane.
• The synaptic cleft is 200-300 A°.
• The presynaptic terminal has two internal structures: Transmitter vesicles that contain neurotransmitters, and mitochondria that provide ATP which is used for synthesizing neurotransmitters.

Receptors for Neurotransmitter

• Receptors for neurotransmitters are located on the postsynaptic membrane.
• Some presynaptic neurons also have receptors for the transmitters they release,called autoreceptors.
• Autoreceptors are often important in regulating the amount of transmitter released subsequently.

Transmitter Release from Presynaptic Terminals

• If an action potential depolarizes the presynaptic membrane, voltage-gated Ca++ channels open, causing Ca++ to flow into the axon terminal and [Ca++]i to increase.
• Ca++ binding to calmodulin activates Ca-calmodulin dependent protein kinase (CaMK). CaMK phosphorylates synapsin I, uncaging vesicles, which become free .
• Ca++ also binds to synaptotagin, promoting fusion of the vesicle with the presynaptic membrane.
• SNARE proteins (synaptobrevin, Syntaxin 1, and SNAP 25 ) pull vesicles closer for transmitter release to be released to the synaptic cleft.

The Sequence of events that lead to Postsynaptic Changes

• Action potential arrives at the axon terminal
• Depolarization opens voltage-gated Ca++ channels
• Ca++ enters the presynaptic cell
• Ca++ causes vesicles filled with neurotransmitter to migrate towards the presynaptic and merges with the presynaptic membrane
• Neurotransmitter is released into the synaptic cleft by exocytosis.
• Transmitter diffuses through synaptic cleft, binding to receptors in the postsynaptic membrane.
• Synaptic potentials (EPSP or IPSPs) develop.

Transmitter Substance

• Receptor molecules on postsynaptic membrane have: Binding component that protrudes outward from the membrane; Ionophore component that passes through the membrane..
• Receptor ionophore can be (1) An ion channel (ionotropic receptor) or (2) a second messenger activator (metabotropic receptor) causing prolonged postsynaptic excitation/inhibition.

Excitatory or Inhibitory Receptors

• Some receptors cause excitation of postsynaptic neuron (EPSP), opening of Na+ channels resulting in Na+ influx, depolarization (excitation).
• Others cause inhibition of postsynaptic neuron (IPSP), opening of Cl− channels resulting in Cl− influx, repolarization (inhibition).

Excitatory Postsynaptic Potential (EPSP)

• Discharge of axon terminals causes release of excitatory neurotransmitter.
• Nat moves into postsynaptic cell through receptor channels, depolarizing it to −45 mV (If reaching threshold it elicits action potentials (in the initial segment of the axon – axon hillock)).

Inhibitory Postsynaptic Potential (IPSP)

• Discharge of axon terminals causes release of inhibitor neurotransmitter.
• Chloride ion moves into the interior through receptor channels.
• This leads to hyperpolarizing potential (-70 mV) compared to resting (-65 mV).
• Nernst potential for Cl–~−70 mV
• K+ efflux also makes membrane potential more negative (Nernst potential for K+ ~−70−95 mV;).

Summation in Neurons

• EPSP due to fast neurotransmitters dies away in ~15 ms.
• Neuropeptides can excite/inhibit postsynaptic neurons for msec to hours.
• The strength is increased by the frequency of nerve impulses.
• Simultaneous postsynaptic potentials from multiple terminals summate.
• Repeated discharges from single terminals, if rapidly enough, summative.

Neuromuscular Junction

• The synapse between a motor neuron and a skeletal muscle fiber is called neuromuscular junction.
• Skeletal muscle fibers are innervated by large, myelinated nerve fibers. Each fiber branches, stimulating 3–500 muscle fibers.
• Each nerve ending makes a neuromuscular junction with the muscle fiber.
• The postsynaptic region is called the motor end plate.

Secretion of Acetylcholine by the Nerve Terminals

• As an action potential spreads, voltage-gated Ca++ channels open, and Ca++ flows into the nerve terminal.
• Vesicles fuse with the neural membrane and empty acetylcholine into the synaptic space by exocytosis.

Acethylcholine on postsynaptic muscle fiber membrane

• Acetylcholine binds to nicotinic acetylcholine receptors on the postsynaptic membrane.
• Nicotinic receptors are permeable to Na+, K+, and possibly Ca++ inducing Na+ influx and creating a local positive potential change (end-plate potential).
• If the end-plate potential exceeds threshold, a self-regenerative action potential develops and spreads along the muscle membrane, triggering muscle contraction.

Destruction of Released Acetylcholine

• Acetylcholine persists in the synaptic space to activate acetylcholine receptors.
• It's rapidly removed by two means:
  • Most of the acetylcholine is destroyed by acetylcholinesterase.
  • A small amount diffuses out of the synaptic space.
• Botulinum toxin decreases the quantity of acetylcholine release.

Neurotransmitters (transmitters)& Receptors

• Study of neurotransmitters and their receptors.
• Examples of neurotransmitters include:
• Acetylcholine, Norepinephrine, Serotonin, Dopamine, Histamine, GABA, Glycine.

Catecholamines

• Catecholamines include adrenaline, noradrenaline, and dopamine.
• Norepinephrine synthesis begins in the axoplasm of the nerve ending and is completed inside the secretory vesicles.
• Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of adrenaline, noradrenaline, and dopamine.

Norepinephrine

• Norepinephrine is secreted by nerve terminals (of adrenergic nerve fibers) in the axoplasm, but is completed inside the secretory vesicles. Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of noradrenaline, adrenaline, and dopamine.
• Removal after secretion occurs by: re-uptake into nerve endings by an active transport (~65% of the secreted NE), diffusion away into the surrounding body fluids into blood (most remaining NE), and destruction by tissue enzymes(monoamine oxidase (MAO) found in nerve endings; catechol-O- methyl transferase ( COMPT), found in diffusely in all tissues).
• Norepinephrine is found in the Locus ceruleus in pons (controls brain activity, wakefulness), and in postganglionic neurons of the sympathetic nervous system.
• a-adrenergic receptors (α1, α2), β-adrenergic receptors (β1, β2), all affect by activating channels through second messenger systems, a1 affecting phospholipase C (PLC),resulting in [Ca++]i increase, a2 inactivating adenylate cyclase decreasing cAMP, and β1/β2 activating adenylate cyclase, and increasing cAMP activating protein kinase, and phosphorylating proteins, opening ion channels.

Serotonin (5-HT)

• Serotonin is secreted by nuclei originating in the median raphe of the brainstem, projecting to many brain and spinal cord areas (especially to the dorsal horns of spinal cord and hypothalamus).
• Functions: mood control, anxiety, aggression, pain pathways inhibition, sexual behavior, feeding, sleep, memory, response to stress, cognition, locomotion, reward, and decision-making.
• 7 families of 5HT receptors, including 5-HT1, 2, 3, 4, 5, 6, and 7, including ionotropic 5-HT3 and metabotropic 5-HT1-7 receptors.
• Serotonin released into the synaptic space is cleared by two mechanisms: metabolism by MAO-A and reuptake by serotonin transporter (SERT).
• Selective serotonin reuptake inhibitors (SSRIs) are used to treat mental disorders.

Dopamine

• Secreted by neurons originating in the substantia nigra; often with inhibitory effects.
• Lack of dopamine in neurons can cause Parkinson's disease.
• Dopamine pathways include: mesolimbic, nigrostriatal, mesocortical, and tuberoinfundibular tracts.
• Dopamine receptors (D1, D5) are coupled to Gs alpha stimulating adenylate cyclase activity, resulting in cAMP formation (excitation or inhibition depending on the target ion channels).
• Dopamine receptors (D2, D3, D4) are coupled to Gi alpha inhibiting cAMP formation (mostly inhibition of the target neuron).

Histamine

• Histamine axons originate from the posterior hypothalamus (tuberomammillary nucleus—TMN) and innervate most CNS regions.
• Active solely during waking, histamine maintains wakefulness and attention.

Glycine

• Secreted mainly at synapses in the spinal cord, acting as an inhibitory transmitter.
• Glycine is the smallest amino acid(20).
• Glycine is blocked by strychnine.
• A co-agonist with glutamate for NMDA receptors in the brain.
• Tetanus toxin blocks GABA and glycine release.

Gamma-Aminobutyric Acid (GABA)

• Secreted by nerve terminals in the spinal cord, cerebellum, basal ganglia, and cortex.
• Always causes inhibition.
• Synthesized from glutamate using L-glutamic acid decarboxylase (GAD), with pyridoxal phosphate (active form of vitamin B6) as a cofactor.

GABA receptors

• Two types of GABA receptors: GABAa and GABAb.

• GABAa receptors are ionotropic, conducting Cl− ions selectively.

• GABAb receptors are metabotropic, linked via G-proteins to K channels.

Review USMLE Questions

• Includes questions on NMDA receptor activation by glutamate, dopamine receptor deficiency in Parkinson's disease, types of neurotransmitters, and autonomic actions.

Organization of the Nervous System

• Embryonic and adult brain regions, corresponding structures, and major levels of CNS function (spinal cord, lower brain, higher brain).

Peripheral Nervous System

• Contains somatic and visceral sensory and motor divisions.

Explore the complex functions of the nervous system, including its components, such as neurons, and their roles in sensory processing, motor commands, and cognitive functions. This quiz covers the basic principles of how signals are transmitted and integrated within the central nervous system. Test your knowledge about the anatomy and physiology of the nervous system.