Physiology of Excitable Tissues

Physiology of Excitable Tissues

• Excitable tissues are capable of generating and transmitting electrochemical impulses along the membrane, known as action potential.
• Examples of excitable tissues include muscle tissue, nervous tissue, and glandular tissue.

Classification of Stimuli

• By type of energy: mechanical, thermal, electrical, and chemical
• By origin: natural or artificial
• By nature of stimuli: rhythmic, arrhythmic, and individual
• By correspondence of receptor and stimulus: adequate and inadequate
• By strength: subthreshold, threshold, submaximal, maximal, and supramaximal

Strength of Stimuli

• Subthreshold stimuli: do not evoke any response
• Threshold stimulus: just sufficient to elicit response and produce minimal contraction
• Submaximal stimuli: produce a graded response
• Maximal stimulus: produces the maximal response
• Supramaximal stimulus: exceeds the maximal value, but does not increase the response beyond the maximal response

Automaticity

• The potential ability of excitable tissue to generate excitation and cause responses without external stimulus
• Some cells can switch from resting state to functional activity state spontaneously, without an external stimulus

Natural States of Excitable Tissue

• Physiological resting state (PRS): a passive stage with minimal metabolic intensity
• Functional activity state (FAS): a stage of activity when the cell performs its specific function, with a significant increase in metabolism
• Restoration stage: a transitional stage during which the cell returns to PRS

Membrane Potential

• The potential difference between the inside and outside of the cell under resting conditions
• Resting membrane potential (RMP) values for different cells:
  • Nerve cells (neurons): ~ -70 mV
  • Skeletal muscle cells: ~ -90 mV
  • Smooth muscle cells: ~ -60 mV
• RMP is generated by the unequal distribution of ions between the inside and outside of the cell

Action Potential

• A reversible change in polarization that occurs in the cell membrane
• Three stages:
  1. Depolarization: rapid change in membrane potential, opening of Na+ channels
  2. Repolarization: permeability of the cell membrane to K ions increases, K ions flow out of the cell
  3. Hyperpolarization: change in potential that makes the membrane more polarized, caused by efflux of potassium ions and closing of potassium channels

Refractory Period

• A period of time during which an organ or cell is incapable of repeating a particular action
• Absolute refractory period: corresponds to depolarization and repolarization
• Relative refractory period: corresponds to hyperpolarization

Muscles

• Muscle cells are called muscle fibers, which are narrow and long, and comprise ~36% of the body mass.
• There are three types of muscle fibers: smooth, skeletal, and cardiac.

Smooth Muscle

• Smooth muscle fibers are smaller than striated muscle fibers, with each cell containing one nucleus.
• More cells can be produced during a lifetime.
• There are two types of smooth muscle:
  • Visceral or single-unit smooth muscle: responds to stimulation as a single unit, with gap junctions allowing electrical signals to spread rapidly.
  • Multi-unit smooth muscle: muscle fibers are less well organized, require multiple nerve fibers to stimulate, and do not react to humoral irritants.

Smooth Muscle vs. Skeletal Muscle

• Smooth muscles are innervated by the autonomic nervous system, have automaticity, and contractions are slower and last longer.
• Smooth muscles can remain in a state of contraction for a long time, and consume little energy compared to skeletal muscles.
• Smooth muscles have plasticity, allowing them to stretch significantly.

Cardiac Muscle (Myocardium)

• Cardiac muscle works continuously, has automaticity, and muscle fibers are short, branched, and bound in a meshwork.
• All myocardial cells have the same excitability, contracting simultaneously and equally strongly.
• Cardiac muscle is not under voluntary control.

Skeletal Muscle

• Skeletal muscle is attached to the skeleton, skin, and fascia, and can be controlled by the animal's will.
• Skeletal muscle fibers are arranged parallel, and groups of muscle fibers form bundles, muscles.
• Skeletal muscle as an organ includes nerves and blood vessels.
• Skeletal muscle functions include ensuring movements, controlling body posture, supporting, heat production, and defense.

Skeletal Muscle Physiological Properties

• Skeletal muscle has excitability, contractility, conductivity, stretchability, elasticity, and plasticity.

Skeletal Muscle Structure

• Skeletal muscle cells are long, cylindrical, and striated, with multiple nuclei.
• Muscle fibers are dominated by myofibrils, which consist of myofilaments.
• Myofibrils are organized in a repetitive pattern, with the smallest unit being the sarcomere.

Microscopic Anatomy of a Skeletal Muscle Fiber

• A skeletal muscle fiber consists of:
  • Sarcolemma (muscle fiber cell membrane)
  • Sarcoplasm (muscle fiber cytoplasm)
  • Sarcoplasmic reticulum (smooth endoplasmic reticulum)
  • Transverse tubules (formed by invaginations of the sarcolemma)
  • Myofibril (bundle of thread-like contractile elements)
  • Myofilaments (extremely fine thread-like proteins)

Myofilaments

• There are four types of myofilaments:
  • Thick filaments (myosin)
  • Thin filaments (actin)
  • Elastic filaments (titin)
  • Non-elastic filaments (nebulin)

Functional Division of Structural Elements

• Motor (contractile): actin, myosin
• Regulators: tropomyosin, troponin
• Structural: nebulin, titin, α-actinin, myomesin, transverse tubules

Sarcomere

• The sarcomere is the smallest contractile unit of a muscle fiber, a compartment of myofibrils.
• A sarcomere consists of:
  • Z line
  • M line
  • H zone
  • I band
  • A band

Sliding Filament Theory of Muscular Contraction

• The actin and myosin filaments within the sarcomeres bind to create cross-bridges and slide past one another, creating a contraction.
• The theory explains how cross-bridges are formed and the subsequent contraction of muscle.

Skeletal Muscle Contraction

• The process of skeletal muscle contraction involves:
  1. Release of neurotransmitter acetylcholine at the efferent somatic neuron-muscle synapse.
  2. Action potential occurring and spreading through the sarcolemma and T tubules.
  3. Release of Ca ions and spread into the sarcoplasm.
  4. Combination of calcium ions with troponin, exposing actin binding sites.
  5. Attachment of the activated myosin head to the actin binding site.
  6. Movement of the myosin head, producing a power stroke, resulting in the sliding of the filaments.
  7. Detachment of the myosin head from the actin site, and return to its original position.
  8. Repeated cycle of contraction as long as calcium and ATP are present.

Muscle Contraction Mechanism

• Voluntary muscle contraction is regulated by the motor center of the cerebral cortex
• Involuntary contraction is regulated by the lower centers, e.g., in the spinal cord
• Information with impulses from the CNS is carried by motor neurons, which are brought to the muscle fiber through synapses
• An action potential occurs, and the muscle contracts, but only with enough Ca ions
• Ca ions are needed for:
  • The release of neurotransmitter from the axon terminal
  • Binding to troponin, causing a position change in tropomyosin, exposing the actin sites that myosin will attach to for muscle contraction

Requirements for Skeletal Muscle Contraction

• Neural stimulus
• Calcium in the muscle cells
• ATP must be available for energy

Mechanism of Skeletal Muscle Relaxation

• No impulses are sent from the CNS to the motor center
• The release of the neurotransmitter ACH stops in the neuro-muscular synapse
• ACH-esterase neutralizes already released ACH at the synapse, stopping the generation of action potentials
• Ca2+ releasing channels close, and efflux of ions to the extracellular environment occurs
• The blocking effect of Ca ions to troponin and tropomyosin stops
• Transverse bridges of acto-myosin complex collapse, and the previous structural order is restored

RIGOR MORTIS

• The condition where muscles tense up after death

Stopping a Contraction

• Energy system fatigue: No more ATP left in the muscle cell
• Nervous system fatigue: The nervous system cannot create impulses sufficiently or quickly enough to maintain the stimulus and cause calcium release
• Voluntary nervous system control: The nerve that tells the muscle to contract stops sending signals
• Sensory nervous system information: Feedback from sensory neurons indicating muscle injury or other factors

Muscle Metabolism (Energy)

• Muscles perform hard work and need a lot of energy
• Energy is required for both muscle contraction and relaxation
• Chemical energy is released and converted into mechanical and thermal energy
• ATP is the only energy source used directly for contractile activity
• ATP is derived from creatine phosphate (CP), muscle glycogen, and lipids
• ATP is resynthesized from these sources through various pathways:
  • Transfer of high-energy phosphate from CP to ADP
  • Anaerobic Glycolysis
  • Oxidative phosphorylation

Energy Coverage of Muscle Contraction

• The ATP-CP system: Energy is derived from ATP molecules present in muscles, and creatine phosphate is used to quickly regenerate ATP
• Anaerobic Glycolysis: Energy is produced from glycogen, and 2 ATP and 2 pyruvic acid molecules are generated
• Oxidative phosphorylation: Energy is produced from glucose, pyruvic acid, and free fatty acids, and 36 ATP molecules are generated

Nervous Tissue

Division of the Nervous System (NS)

• The nervous system is divided into two subdivisions: the central nervous system (CNS) and the peripheral nervous system (PNS)
• The CNS includes the brain and spinal cord
• The PNS includes nerves that go to the CNS (afferent) and from the CNS to muscles and internal organs (efferent)

Neuron

• Neurons are the main functional structural units that form the grey matter of the brain and ganglia
• Upon receiving stimuli, nerve cells switch from a physiological resting state to a functional activity state
• Neurons are responsible for computation and communication in the nervous system
• They are electrically active and release chemical signals to communicate between each other and with target cells

Neuroglia Cells

• Neuroglia cells provide nourishment and support to neurons
• Types of neuroglia cells:
  • Astrocytes: maintain the blood-brain barrier and preserve the chemical environment
  • Oligodendrocytes: myelinate axons in the CNS
  • Ependymal cells: line ventricles and central canal and are involved in cerebrospinal fluid production
  • Microglia: remove cell debris, wastes, and pathogens
  • Schwann cells: myelinate axons in the PNS
  • Satellite cells: regulate nutrient and neurotransmitter levels around neurons in ganglia

Neuron Classification by Shape

• Unipolar neurons: have one process that includes both an axon and a dendrite
• Bipolar neurons: have two processes, an axon and a dendrite, that extend from each end of the cell body
• Multipolar neurons: have more than two processes, an axon, and two or more dendrites

Axonal Transport

• Axonal transport is a cellular process responsible for the movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body
• Movements along axons occur in two ways:
  • Anterograde transport: from the cell body to the synapse
  • Retrograde transport: from the axon termini to the cell body

Classification of Nerve Fibers

• By function:
  • Somatic: innervate skeletal muscles
  • Autonomic: innervate internal organs and blood vessels
  • Secretory: innervate glands and stimulate secretion
  • Sensory (afferent): transmit impulses to the CNS
  • Motor (efferent): carry impulses toward the body surface
  • Interneurons (association neurons): any neurons between a sensory and a motor neuron
• By structure: myelinated and unmyelinated nerve fibers
• By type of synapse and neurotransmitter: adrenergic, cholinergic, peptidergic, etc.
• By diameter and conduction velocity

Direct and Indirect Binding to Postsynaptic Receptors

• There are two types of receptor channels:
  • Direct (ionotropic receptors): allow ions to pass through the membrane, neurotransmitter acts as a key to open the ion channel, and it's the fastest type of channel (0.5 ms)
  • Indirect (metabotropic or G protein coupled receptors): binding of neurotransmitter to receptor causes release of a secondary messenger, which indirectly activates nearby ion channels, and it's a slower process (30 ms to 1 second)

Postsynaptic Potentials

• Postsynaptic potentials can be either excitatory (depolarizing) or inhibitory (hyperpolarizing)
• Excitatory Postsynaptic Potentials (EPSPs):
  • Excitatory ion channels are permeable to Na+ and K+
  • Binding of excitatory neurotransmitter to receptor on postsynaptic membrane causes partial depolarization of postsynaptic cell membrane, increasing the likelihood of an action potential (AP)
• Inhibitory Postsynaptic Potentials (IPSPs):
  • Inhibitory ion channels are permeable to Cl- and K+
  • Binding of inhibitory neurotransmitter to receptor on postsynaptic membrane causes hyperpolarization of postsynaptic membrane, making it more difficult for the cell membrane potential to reach threshold, thereby reducing the likelihood of an action potential (AP)

Excitatory and Inhibitory Synapses

• Excitatory synapses: presynaptic neuron releases an excitatory transmitter (e.g., glutamate), which depolarizes the postsynaptic cell membrane, increasing the likelihood of an action potential (AP)
• Inhibitory synapses: presynaptic neuron releases an inhibitory neurotransmitter (e.g., GABA), which hyperpolarizes the postsynaptic cell membrane, reducing the likelihood of an action potential (AP)

Inhibition

• Inhibition is a reversible change in the excitability of a nerve cell, decreasing its functional activity
• Inhibition is important in regulating various opposing processes, such as coordinating the action of flexors and extensors
• Disruptions in inhibitory processes can lead to disturbances in the nervous system, such as neurosis, depression, etc.

Types of Inhibition

• By localization: presynaptic (indirect) and postsynaptic (direct)
• By the nature of the process: mainly hyperpolarization (and occasionally strong depolarization)

Patterns of Neurotransmission

• A, B, C, D, E, and F are neurons in a tract that projects from left to right
• Neurons B, D, and E release excitatory neurotransmitters, while neurons A and F release inhibitory neurotransmitters
• The net effect of neuronal interactions on neurotransmission from B to C is shown in a table

Inactivation of Neurotransmitters

• Enzymatic deactivation: acetylcholine is broken down into acetate and choline in the synaptic gap
• Reuptake: some neurotransmitters are removed by specific transporter proteins on the presynaptic membrane
• Simple diffusion: neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated from the body

Classification of Reflexes

• Inborn reflexes or unconditioned reflexes
• Learned (acquired) reflexes or conditioned reflexes

Reflex Arc

• The reflex arc contains five basic components:
  1. Sensory receptor
  2. Sensory (afferent) neuron
  3. Interneuron in the central nervous system
  4. Motor (efferent) neuron
  5. Effector (target organ)

Autonomic Nervous System

• Is not subject to the will of the animal
• Innervates mainly internal organs and blood vessels
• Autonomic nerve centers are scattered in different parts of the CNS
• Autonomic reflexes have a relatively long reflex time
• Autonomic reactions are diffuse, involving many organs

Neurotransmitters/Receptors

• Acetylcholine is the neurotransmitter of the parasympathetic nervous system
• Norepinephrine is the neurotransmitter of the sympathetic nervous system
• There are several types of receptors in the postsynaptic membrane:
  • M-cholinoreceptors (Muscarinic acetylcholine receptors)
  • N-cholinoreceptors (Nicotinic acetylcholine receptors)
  • Adrenoreceptors (α and β)

Receptors

• A cellular receptor is a molecule that responds to external and/or internal environment changes

• Receptors detect stimulus from different modalities (energy forms) and convert them into electrical signals

• Classification of receptors based on what type of irritation they perceive:

  • Photoreceptors
  • Mechanoreceptors
  • Thermoreceptors
  • Osmoreceptors
  • Chemoreceptors
  • Nociceptors### Ion Channel-Linked Receptors

• Ion channel-linked receptors bind a ligand and open a channel through the membrane, allowing specific ions to pass through in milliseconds.

• Signaling molecules act as keys to open ion channels.

• These receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and GABA.

GABA Receptors

• GABA receptors respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the CNS.
• There are three classes of GABA receptors:
  • Ionotropic (ligand-gated) GABAA receptors
  • Metabotropic (G protein-coupled) GABAB receptors
  • Ionotropic (ligand-gated) GABAC receptors (structurally different from GABAA)

Neurotransmitter Transmission

• Neurotransmitter release from presynaptic cells is triggered by Ca ions entering the cell through action potentials.
• Neurotransmitters pass through the synaptic gap and connect with their receptors on the postsynaptic plasmalemma.
• Ion channels open by direct or indirect binding, resulting in a postsynaptic potential.
• Approximately 30,000-50,000 neurotransmitter molecules are released in neuromuscular synapses, and 200,000-500,000 in nerve-nerve synapses.
• Enzymes that deactivate neurotransmitters, such as cholinesterase, are present in the synaptic gap.

Excitatory Neurotransmitters

• Excitatory neurotransmitters cause a depolarization called the excitatory postsynaptic potential (EPSP).
• EPSP opens Na and Ca ion channels, but inhibits the activity of K and Cl ions.
• Each neurotransmitter has its own specific receptor.

Synaptic Transmission

• Excitation in synapses is transferred only in one way, from the presynaptic membrane to the postsynaptic membrane.
• Receptors that respond to neurotransmitters are located only on the postsynaptic membrane.
• The time it takes for the impulse to propagate across the synapses is called the synaptic delay.

Peripheral Nervous System (PNS)

• The PNS is the communication link between the Central Nervous System (CNS) and muscles and glands. • The PNS has two divisions: the Autonomic Nervous System (ANS) and the Somatic Nervous System. • The ANS is the involuntary branch of the PNS, innervating cardiac muscle, smooth muscle, most exocrine glands, some endocrine glands, and adipose tissue. • The Somatic Nervous System is subject to voluntary control, innervating skeletal muscle.

Autonomic Nervous System (ANS)

• The ANS has two subdivisions: the Sympathetic Nervous System and the Parasympathetic Nervous System. • The Sympathetic Nervous System originates from the thoracic and lumbar regions of the spinal cord. • The Parasympathetic Nervous System originates from the cranial and sacral areas of the CNS. • Sympathetic preganglionic fibers are shorter, while parasympathetic preganglionic fibers are longer. • Sympathetic postganglionic fibers release norepinephrine, which binds to α1, α2, β1, β2 adrenoreceptors. • Parasympathetic postganglionic fibers release acetylcholine, which binds to M-cholinoreceptors.

Brain Anatomy

Cerebrum

• The cerebrum consists of two cerebral hemispheres, the right and the left. • The cerebrum is the largest part of the brain, containing the cerebral cortex, hippocampus, and basal ganglia. • The cerebrum controls emotions, hearing, vision, and voluntary actions with the assistance of the cerebellum.

Cerebral Hemispheres

• Each hemisphere is divided into four lobes: frontal, parietal, occipital, and temporal. • The right hemisphere controls and processes signals from the left side of the body, while the left hemisphere controls and processes signals from the right side of the body.

Cerebral Cortex

• The cerebral cortex is a thin layer of gray matter covering the surface of the cerebral hemispheres. • It is the highest part of the CNS, the most complex in structure and function, and associated with behavior, analysis of the external environment, instincts, and cognitive abilities. • Each hemisphere has a motor zone and a sensory zone, functionally divided into regions such as visual area, auditory area, and speech area.

Basal Ganglia

• The basal ganglia are a group of structures found deep within the cerebral hemispheres, including the caudate, putamen, and globus pallidus. • The basal ganglia are involved in movement, cognitive, emotional, and movement-related functions, and facilitation of desired movements and inhibition of unwanted movements.

Hypothalamus

• The hypothalamus is involved in the synthesis of neurohormones and their secretion to the hypophysis (pituitary gland). • The hypothalamus produces vasopressin and oxytocin, which are transported via the hypothalamo-hypophyseal tract to the neurohypophysis. • The hypothalamus also produces hypothalamic hypophysiotropic hormones, which are transported via the blood capillaries to the adenohypophysis.

Epithalamus

• The epithalamus produces melatonin, signaling nighttime sleep. • It connects the limbic system to other parts of the brain.

Cerebellum

• The cerebellum is divided into two distinct parts: the oldest part involved in balance adjustment, and the newest part involved in coordination of muscle activity. • The cerebellum maintains posture and balance, and is involved in orientation and alertness reflex, and in the development of conditioned reflexes.

Amygdala

• The amygdala is an almond-shaped structure located next to the hippocampus. • It is involved in emotional responses, including feelings of happiness, fear, anger, and anxiety, and formation of new memories. • The amygdala is linked with the fight-or-flight response and can influence the body's automatic fear response.

Damage to the Limbic System

• Amygdala damage can result in more aggression, irritability, loss of control of emotions, and deficits in recognizing emotions. • Hippocampus damage can lead to deficits in learning and memory. • Hypothalamus damage can affect the production of certain hormones, leading to mood and emotion disorders. • Uncontrolled emotions can result in more aggression, anxiety, and agitation, as well as olfactory impairments, memory impairments, and abnormal biological rhythms.

Reticular Formation (RAS)

• The reticular formation is a set of interconnected nuclei located throughout the brainstem. • It is a network of neurons that play a crucial role in regulating sleep, arousal, and attention.