Nervous and Muscular System

Central Nervous System: Brain

During development, the CNS forms from a long tube. As the anterior part of the tube, which becomes the brain, folds during its continuing formation, initially three different regions become apparent, identified as the forebrain, midbrain, and hindbrain. These regions continue to develop, forming subdivisions. The forebrain develops into two major subdivisions, the cerebrum and the diencephalon. The midbrain remains as a single major division. The hindbrain develops into three parts: the pons, medulla oblongata, and the cerebellum. The pons, medulla oblongata, and the midbrain are heavily interconnected and share many similar functions; for that reason and their anatomical location, they are considered together as the brainstem. The brain also contains four interconnected cavities, the cerebral ventricles, which are filled with fluid and which provide support for the brain.

Forebrain: The Cerebrum

The larger component of the forebrain, the cerebrum, consists of the right and left cerebral hemispheres as well as some associated structures on the underside of the brain. The cerebral hemispheres consist of the cerebral cortex—an outer shell of gray matter composed primarily of cell bodies that give the area a gray appearance–and an inner layer of white matter, composed primarily of myelinated fiber tracts. The cerebral cortex in turn overlies cell clusters, which are also gray matter and are collectively termed the subcortical nuclei. The fiber tracts consist of the many nerve fibers that bring information into the cerebrum, carry information out, and connect different areas within a hemisphere. The cortex layers of the left and right cerebral hemispheres, although largely separated by a deep longitudinal division, are connected by a massive bundle of nerve fibers known as the corpus callosum.

Cerebral Cortex The cerebral cortex of each cerebral hemisphere is divided into four lobes, named after the overlying skull bones covering the brain: the frontal, parietal, occipital, and temporal lobes. Although it averages only 3 mm in thickness, the cerebral cortex is highly folded. This results in an area containing cortical neurons that is four times larger than it would be without folding, yet does not appreciably increase the volume of the brain. This folding also results in the characteristic external appearance of the human cerebrum, with its sinuous ridges called gyri (singular, gyrus) separated by grooves called sulci (singular, sulcus). The cells of the human cerebral cortex are organized in six distinct layers, composed of varying sizes and numbers of two basic types: pyramidal cells (named for the shape of their cell bodies) and nonpyramidal cells. The pyramidal cells form the major output cells of the cerebral cortex, sending their axons to other parts of the cortex and to other parts of the CNS. Nonpyramidal cells are mostly involved in receiving inputs into the cerebral cortex and in local processing of information. This elaboration of the human cerebral cortex into multiple cell layers, like its highly folded structure, allows for an increase in the number and integration of neurons for signal processing. Such specialization of structural surface area to enhance function in organs throughout the body affirms the general principle of physiology that structure and function are related. This is supported by the fact that an increase in the number of cell layers in the cerebral cortex has paralleled the increase in behavioral and cognitive complexity in vertebrate evolution. For example, reptiles have just three layers in the cortex, and dolphins have five. Some regions of the human brain with ancient evolutionary origins, such as the olfactory cortex, persist in having only three cell layers.

The cerebral cortex is one of the most complex integrating areas of the nervous system. It is here that basic afferent information is collected and processed into meaningful perceptual images, and control over the systems that govern the movement of the skeletal muscles is refined. Nerve fibers enter the cerebral cortex predominantly from the diencephalon and areas of the brainstem; there is also extensive signaling between areas within the cerebral cortex. Some of the input fibers convey information about specific events in the environment, whereas others control levels of cortical excitability, determine states of arousal, and direct attention to specific stimuli.

Basal Nuclei The subcortical nuclei are heterogeneous groups of gray matters that lie deep within the cerebral hemispheres. Predominant among them are the basal nuclei (often, but less correctly referred to as basal ganglia), which have an important function in controlling movement and posture and in more complex aspects of behavior.

Limbic System Thus far, we have described discrete anatomical areas of the forebrain. Some of these forebrain areas, consisting of both gray and white matter, are also classified together in a functional system called the limbic system. This interconnected group of brain structures includes portions of frontal-lobe cortex, temporal lobe, thalamus, and hypothalamus, as well as the fiber pathways that connect them. Besides being connected with each other, the parts of the limbic system connect with many other parts of the CNS. Structures within the limbic system are associated with learning, emotional experience and behavior, and a wide variety of visceral and endocrine functions.

Forebrain: The Diencephalon

The diencephalon, which is divided in two by the narrow third cerebral ventricle, is the second component of the forebrain. It contains the thalamus, hypothalamus, and epithalamus. The thalamus is a collection of several large nuclei that serve as synaptic relay stations and important integrating centers for most inputs to the cortex, and it has a key function in general arousal. The thalamus also is involved in focusing attention. For example, it is responsible for filtering out extraneous sensory information such as might occur when you try to concentrate on a private conversation at a loud, crowded party. The hypothalamus lies below the thalamus and is on the undersurface of the brain; like the thalamus, it contains numerous different nuclei. These nuclei and their pathways form the master command center for neural and endocrine coordination. Indeed, the hypothalamus is the single most important control area for homeostatic regulation of the internal environment. Behaviors having to do with preservation of the individual (for example, eating and drinking) and preservation of the species (reproduction) are among the many functions of the hypothalamus. The hypothalamus

lies directly above and is connected by a stalk to the pituitary gland, an important endocrine structure that the hypothalamus regulates. As mentioned earlier, some parts of the hypothalamus and thalamus are also considered part of the limbic system.  The epithalamus is a small mass of tissue that includes the pineal gland, which participates in the control of circadian rhythms through release of the hormone melatonin.

Hindbrain: The Cerebellum

The cerebellum consists of an outer layer of cells, the cerebellar cortex (do not confuse this with the cerebral cortex), and several deeper cell clusters. Although the cerebellum does not initiate voluntary movements, it is an important center for coordinating movements and for controlling posture and balance. To carry out these functions, the cerebellum receives information from the muscles and joints, skin, eyes, vestibular apparatus, viscera, and the parts of the brain involved in control of movement. Although the cerebellum’s function is almost exclusively motor, recent research strongly suggests that it also may be involved in some forms of learning. The other components of the hindbrain—the pons and medulla oblongata—are considered together with the midbrain.

Brainstem: The Midbrain, Pons, and Medulla Oblongata

All the nerve fibers that relay signals between the forebrain, cerebellum, and spinal cord pass through the brainstem. Running through the core of the brainstem and consisting of loosely arranged nuclei intermingled with bundles of axons is the reticular formation, the one part of the brain absolutely essential for life. It receives and integrates input from all regions of the CNS and processes a great deal of neural information. The reticular formation is involved in motor functions, cardiovascular and respiratory control, and the mechanisms that regulate sleep and wakefulness and that focus attention. Most of the biogenic amine neurotransmitters are released from the axons of cells in the reticular formation. Because of the far-reaching projections of these cells, these neurotransmitters affect all levels of the nervous system.

The pathways that convey information from the reticular formation to the upper portions of the brain stimulate arousal and wakefulness. They also direct attention to specific events by selectively stimulating neurons in some areas of the brain while inhibiting others. The fibers that descend from the reticular formation to the spinal cord influence activity in both efferent and afferent neurons. Considerable interaction takes place between the reticular pathways that go up to the forebrain, down to the spinal cord, and to the cerebellum. For example, all three components function in controlling muscle activity. The reticular formation encompasses a large portion of the brainstem, and many areas within the reticular formation serve distinct functions. For example, some reticular formation neurons are clustered together, forming brainstem nuclei and integrating centers. These include the cardiovascular, respiratory, swallowing, and vomiting centers. The reticular formation also has nuclei important in eye-movement control and the reflexive orientation of the body in space. In addition, the brainstem contains nuclei involved in processing information for 10 of the 12 pairs of cranial nerves. These are the peripheral nerves that connect directly with the brain and innervate the muscles, glands, and sensory receptors of the head, as well as many organs in the thoracic and abdominal cavities.

Central Nervous System: Spinal Cord

The spinal cord lies within the bony vertebral column. It is a slender cylinder of soft tissue about as big around as your little finger. The central butterfly-shaped area (in cross section) of gray matter is composed of interneurons, the cell bodies and dendrites of efferent neurons, the entering axons of afferent neurons, and glial cells. The regions of gray matter projecting toward the back of the body are called the dorsal horns, whereas those oriented toward the front are the ventral horns. The gray matter is surrounded by white matter, which consists of groups of myelinated axons. These groups of fiber tracts run longitudinally through the cord, some descending to relay information from the brain to the spinal cord, others ascending to transmit information to the brain. Pathways also transmit information between different levels of the spinal cord. Groups of afferent fibers that enter the spinal cord from the peripheral nerves enter on the dorsal side of the cord via the dorsal roots. Small bumps on the dorsal roots, the dorsal root ganglia, contain the cell bodies of these afferent neurons. The axons of

efferent neurons leave the spinal cord on the ventral side via the ventral roots. A short distance from the cord, the dorsal and ventral roots from the same level combine to form a spinal nerve, one on each side of the spinal cord, carrying two-way information from afferents and efferents.

Peripheral Nervous System

Neurons in the PNS transmit signals between the CNS and receptors and effectors in all other parts of the body. As noted earlier, the axons are grouped into bundles called nerves. The PNS has 43 pairs of nerves: 12 pairs of cranial nerves and 31 pairs of spinal nerves that connect with the spinal cord. The 31 pairs of spinal nerves are designated by the vertebral levels from which they exit: cervical, thoracic, lumbar, sacral, and coccygeal. Neurons in the spinal nerves at each level generally communicate with nearby structures, controlling muscles and glands as well as receiving sensory input. The eight pairs of cervical nerves innervate the

neck, shoulders, arms, and hands. The 12 pairs of thoracic nerves are associated with the chest and upper abdomen. The five pairs of lumbar nerves are associated with the lower abdomen, hips, and legs; the five pairs of sacral nerves are associated with the genitals and lower digestive tract. A single pair of coccygeal nerves associated with the skin over the region of the tailbone brings the total to 31 pairs. These peripheral nerves can contain nerve fibers that are the axons of efferent neurons, afferent neurons, or both.  Therefore, fibers in a nerve may be classified as belonging to the efferent or the afferent division of the PNS. All the spinal nerves contain both afferent and efferent fibers, whereas some of the cranial nerves contain only afferent fibers (the optic nerves from the eyes, for example) or only efferent fibers (the hypoglossal nerve to muscles of the tongue, for example). As noted earlier, afferent neurons convey information from sensory receptors at their peripheral endings to the CNS. The long part of their axon is outside the CNS and is part of the PNS. Afferent neurons are sometimes called primary afferents or firstorder neurons because they are the first cells entering the CNS in the synaptically linked chains of neurons that handle incoming information.  Efferent neurons carry signals out from the CNS to muscles, glands, and other tissues. The efferent division of the PNS is more complicated than the afferent, being subdivided into a somatic nervous system and an autonomic nervous system. These terms are somewhat misleading because they suggest the presence of additional nervous systems distinct from the central and peripheral systems. Keep in mind that these terms together make up the efferent division of the PNS.

The simplest distinction between the somatic and autonomic systems is that the neurons of the somatic division innervate skeletal muscle, whereas the autonomic neurons innervate smooth and cardiac muscle, glands, neurons in the gastrointestinal tract, and other tissues. The somatic portion of the efferent division of the PNS is made up of all the nerve fibers going from the CNS to skeletal muscle cells. The cell bodies of these neurons are located in groups in the brainstem or the ventral horn of the spinal cord. Their large-diameter, myelinated axons leave the CNS and pass without any synapses to skeletal muscle cells. The neurotransmitter these neurons release is acetylcholine. Because activity in the somatic neurons leads to contraction of the innervated skeletal muscle cells, these neurons are called motor neurons. Excitation of motor neurons leads only to the contraction of skeletal muscle cells; there are no somatic neurons that inhibit skeletal muscles. Muscle relaxation involves the inhibition of the motor neurons in the spinal cord.

Cranial nerves

THE SYNAPSE

Axons end close to, or in some cases at the point of contact with, another cell. Once action potentials reach the end of an axon, they directly or indirectly stimulate (or inhibit) the other cell. In specialized cases, action potentials can directly pass from one cell to another. In most

cases, however, the action potentials stop at the axon terminal, where they stimulate the release of a chemical neurotransmitter that affects the next cell. A synapse is the functional connection between a neuron and a second cell. In the CNS, this other cell is also a neuron. In the PNS, the other cell may be either a neuron or an effector cell within a muscle or gland. Although the physiology of neuron-neuron synapses and neuron-muscle synapses is similar, the latter synapses are often called myoneural, or neuromuscular, junctions.

Neuron-neuron synapses usually involve a connection between the axon of one neuron and the dendrites, cell body, or axon of a second neuron. These are called, respectively, axodendritic, axosomatic, and axoaxonic synapses. In almost all synapses, transmission is in one direction only—from the axon of the first (or presynaptic) neuron to the second (or postsynaptic) neuron. Most commonly, the synapse occurs between the axon of the presynaptic neuron and the dendrites or cell body of the postsynaptic neuron. In the early part of the twentieth century, most physiologists believed that synaptic transmission was electrical —that is, that action potentials were conducted directly from one cell to the next. This was a logical assumption, given that nerve endings appeared to touch the postsynaptic cells and that the delay in synaptic conduction was extremely short (about 0.5 msec). Improved histological techniques, however, revealed tiny gaps in the synapses, and experiments demonstrated that the actions of autonomic nerves could be duplicated by certain chemicals. This led to the   hypothesis that synaptic transmission might be chemical —that the presynaptic nerve endings might release chemicals called neurotransmitters that stimulated action potentials in the postsynaptic cells.

In 1921 a physiologist named Otto Loewi published the results of experiments suggesting that synaptic transmission was indeed chemical, at least at the junction between a branch of the vagus nerve and the heart. He had isolated the heart of a frog and, while stimulating the branch of the vagus that innervates the heart, perfused the heart with an isotonic salt solution. Stimulation of the vagus nerve was known to slow the heart rate. After stimulating the vagus nerve to this frog heart, Loewi collected the isotonic salt solution and then gave it to a second heart. The vagus nerve to this second heart was not stimulated, but the isotonic solution from the first heart caused the second heart to also slow its beat. Loewi concluded that the nerve endings of the vagus must have released a chemical—which he called Vagusstoff - that inhibited the heart rate. This chemical was subsequently identified as acetylcholine, or ACh. In the decades following Loewi’s discovery, many other examples of chemical synapses were discovered, and the theory of electrical synaptic transmission fell into disrepute. More recent evidence, ironically, has shown that electrical synapses do exist in the nervous system (though they are the exception), within smooth muscles, and between cardiac cells in the heart.

Electrical Synapses: Gap Junctions

In order for two cells to be electrically coupled, they must be approximately equal in size and they must be joined by areas of contact with low electrical resistance. In this way, impulses can be regenerated from one cell to the next without interruption. Adjacent cells that are electrically coupled are joined together by gap junctions. In gap junctions, the membranes of the two cells are separated by only 2 nanometers (1 nano meter = 10 − 9 meter). A surface view of gap junctions in the electron microscope reveals hexagonal arrays of particles that function as channels through which ions and molecules may pass from one cell to the next. Each gap junction is now known to be composed of 12 proteins known as connexins, which are arranged like staves of a barrel to form a water-filled pore.

Gap junctions are present in cardiac muscle, where they allow action potentials to spread from cell to cell, so that the myocardium can contract as a unit. Similarly, gap junctions in some smooth muscles allow many cells to be stimulated and contract together, producing a stronger contraction (as in the uterus during labor). The function of gap junctions in the nervous system is less well understood; nevertheless, gap junctions are found between neurons in the brain, where they can synchronize the firing of groups of neurons. Gap junctions are also found between neuroglial cells, where they are believed to allow the passage of Ca 2 + and perhaps other ions and molecules between the connected cells. The function of gap junctions is more complex than was once thought. Neurotransmitters and other stimuli, acting through second messengers such as cAMP or Ca 2 +, can lead to the phosphorylation or dephosphorylation of gap junction connexin proteins, causing the opening or closing of gap junction channels. For example, light causes the ion conductance through the gap junctions between neurons in the retina to increase in some neurons and decrease in others.

Chemical Synapses

Transmission across the majority of synapses in the nervous system is one-way and occurs through the release of chemical neurotransmitters from presynaptic axon endings. These presynaptic endings, called terminal boutons (from the Middle French bouton = button) because of their swollen appearance, are separated from the postsynaptic cell by a synaptic cleft so narrow (about 10 nm) that it can be seen clearly only with an electron microscope.

Chemical transmission requires that the synaptic cleft stay very narrow and that neurotransmitter molecules are released near their receptor proteins in the postsynaptic membrane. The physical association of the pre- and postsynaptic membranes at the chemical synapse is stabilized by the action of particular membrane proteins. Cell adhesion molecules (CAMs) are proteins in the pre- and postsynaptic membranes that project from these membranes into the synaptic cleft, where they bond to each other. This Velcro-like effect ensures that the pre- and postsynaptic membranes stay in close proximity for rapid chemical transmission.

Release of Neurotransmitter

Neurotransmitter molecules within the presynaptic neuron endings are contained within many small, membrane-enclosed synaptic vesicles. In order for the neurotransmitter within these vesicles to be released into the synaptic cleft, the vesicle membrane must fuse with the axon membrane in the process of exocytosis. Exocytosis of synaptic vesicles, and the consequent release of neurotransmitter molecules into the synaptic cleft, is triggered by action potentials that stimulate the entry of Ca²⁺ into the axon terminal through voltage-gated Ca²⁺ channels. When there is a greater frequency of action potentials at the axon terminal, there is a greater entry of Ca²⁺, and thus a larger number of synaptic vesicles undergoing exocytosis and releasing neurotransmitter molecules. As a result, a greater frequency of action potentials by the presynaptic axon will result in greater stimulation of the postsynaptic neuron. Ca²⁺ entering the axon terminal binds to a protein, believed to be synaptotagmin, which serves as a Ca²⁺ sensor, forming a Ca 2 + -synaptotagmin complex in the cytoplasm. This occurs close to the location where synaptic vesicles are already docked (attached) to the plasma membrane of the axon terminal. At this stage, the docked vesicles are bound to the plasma membrane of the presynaptic axon by complexes of three SNARE proteins that bridge the vesicles and plasma membrane. The complete fusion of the vesicle membrane and plasma membrane, and the formation of a pore that allows the release of neurotransmitter, occurs when the Ca²⁺ -synaptotagmin complex displaces a component of the SNARE, or fusion, complex. This process is very rapid: exocytosis of neurotransmitter occurs less than 100 microseconds after the intracellular Ca 2 + concentration rises (SNARE- Soluble NSF Attachment protein Receptor; NSF – N-ethyl maleimide Sensitive Factor).

Action of Neurotransmitter

Once the neurotransmitter molecules have been released from the presynaptic axon terminals, they diffuse rapidly across the synaptic cleft and reach the membrane of the postsynaptic cell. The neurotransmitters then bind to specific receptor proteins that are part of the postsynaptic membrane. Receptor proteins have high specificity for their neurotransmitter, which is the ligand of the receptor protein. The term ligand in this case refers to a smaller molecule (the neurotransmitter) that binds to and forms a complex with a larger protein molecule (the receptor). Binding of the neurotransmitter ligand to its receptor protein causes ion channels to open in the postsynaptic membrane. The gates that regulate these channels, therefore, can be called chemically regulated (or ligand-regulated) gates because they open in response to the binding of a chemical ligand to its receptor in the postsynaptic plasma membrane.

NEURONS AND SUPPORTING CELLS

The nervous system is composed of neurons, which produce and conduct electrochemical impulses, and supporting cells, which assist the functions of neurons. Neurons are classified functionally and structurally; the various types of supporting cells perform specialized functions.

Neurons

Although neurons vary considerably in size and shape, they generally have three principal regions: (1) a cell body, (2) dendrites, and (3) an axon. Dendrites and axons can be referred to generically as processes, or extensions from the cell body.  The cell body is the enlarged portion of the neuron that contains the nucleus. It is the “nutritional center” of the neuron where macromolecules are produced. The cell body and larger dendrites (but not axons) contain Nissl bodies, which are seen as dark-staining granules under the microscope. Nissl bodies are composed of large stacks of rough endoplasmic reticulum that are needed for the synthesis of membrane proteins. The cell bodies within the CNS are frequently clustered into groups called nuclei (not to be confused with the nucleus of a cell). Cell bodies in the PNS usually occur in clusters called ganglia.

Dendrites (from the Greek dendron = tree branch) are thin, branched processes that extend from the cytoplasm of the cell body. Dendrites provide a receptive area that transmits graded electrochemical impulses to the cell body. The axon is a longer process that conducts impulses, called action potentials, away from the cell body. Axons vary in length from only a millimeter long to up to a meter or more (for those that extend from the CNS to the foot). The origin of the axon near the cell body is an expanded region called the axon hillock; it is here that action potentials originate. Side branches called axon collaterals may extend from the axon. Because axons can be quite long, special mechanisms are required to transport organelles and proteins from the cell body to the axon terminals. This axonal transport is energy-dependent and is often divided into a fast component and two slow components. The fast component (at 200 to 400 mm/day) mainly transports membranous vesicles. One slow component (at 0.2 to 1 mm/day) transports microfilaments and microtubules of the cytoskeleton, while the other slow component (at 2 to 8 mm/day) transports over 200 different proteins, including those critical for synaptic function. The slow components appear to transport their cargo in fast bursts with frequent pauses, so that the overall rate of transport is much slower than that occurring in the fast component.  Axonal transport may occur from the cell body to the axon and dendrites. This direction is called anterograde transport, and involves molecular motors of kinesin proteins that move cargo along the microtubules of the cytoskeleton. For example, kinesin motors move synaptic vesicles, mitochondria, and ion channels from the cell body through the axon. Similar anterograde transport occurs in the dendrites, as kinesin moves postsynaptic receptors for neurotransmitters and ion channels along the microtubules in the dendrites.

By contrast, axonal transport in the opposite direction-that is, along the axon and dendrites toward the cell body-is known as retrograde transport and involves molecular motor proteins of dyneins. The dyneins move membranes, vesicles, and various molecules along microtubules of the cytoskeleton toward the cell body of the neuron. Retrograde transport can also be responsible for movement of herpes virus, rabies virus, and tetanus toxin from the nerve terminals into cell bodies.

Classification of Neurons and Nerves

Neurons may be classified according to their function or structure. The functional classification is based on the direction in which they conduct impulses. Sensory, or afferent, neurons conduct impulses from sensory receptors into the CNS. Motor, or efferent, neurons conduct impulses out of the CNS to effector organs (muscles and glands). Association neurons, or interneurons, are located entirely within the CNS and serve the associative, or integrative, functions of the nervous system. There are two types of motor neurons: somatic and autonomic. Somatic motor neurons are responsible for both reflex and voluntary control of skeletal muscles. Autonomic motor neurons innervate (send axons to) the involuntary effectors—smooth muscle, cardiac muscle, and glands. The cell bodies of the autonomic neurons that innervate these organs are located outside the CNS in autonomic ganglia. There are two subdivisions of autonomic neurons: sympathetic and parasympathetic. Autonomic motor neurons, together with their central control centers, constitute the autonomic nervous system. The structural classification of neurons is based on the number of processes that extend from the cell body of the neuron. Pseudounipolar neurons have a single short process that branches like a T to form a pair of longer processes. They are called pseudounipolar (from the Late Latin pseudo = false) because, although they originate with two processes, during early embryonic development their two processes converge and partially fuse. Sensory neurons are pseudounipolar—one of the branched processes receives sensory stimuli and produces nerve impulses; the other delivers these impulses to synapses within the brain or spinal cord. Anatomically, the part of the process that conducts impulses toward the cell body can be considered a dendrite, and the part that conducts impulses away from the cell body can be considered an axon. Functionally, however, the branched process behaves as a single, long axon that continuously conducts action potentials (nerve impulses). Only the small projections at the receptive end of the process function as typical dendrites, conducting graded electrochemical impulses rather than action potentials. Bipolar neurons have two processes, one at either end; this type is found in the retina of the eye. Multipolar neurons, the most common type, have several dendrites and one axon extending from the cell body; motor neurons are good examples of this type.

A nerve is a bundle of axons located outside the CNS. Most nerves are composed of both motor and sensory fibers and are thus called mixed nerves. Some of the cranial nerves, however, contain sensory fibers only. These are the nerves that serve the special senses of sight, hearing, taste, and smell. A bundle of axons in the CNS is called a tract.

Supporting Cells

Unlike other organs that are “packaged” in connective tissue derived from mesoderm (the middle layer of embryonic tissue), most of the supporting cells of the nervous system are derived from the same embryonic tissue layer (ectoderm) that produces neurons. The term neuroglia (or glia) traditionally refers to the supporting cells of the CNS, but in current usage the supporting cells of the PNS are often also called glial cells.

There are two types of supporting cells in the peripheral nervous system:

1. Schwann cells (also called neurolemmocytes), which form myelin sheaths around peripheral axons; and

2. Satellite cells, or ganglionic gliocytes, which support neuron cell bodies within the ganglia of the PNS.

There are four types of supporting cells in the central nervous system:

1. Oligodendrocytes, which form myelin sheaths around axons of the CNS;

2. Microglia, which migrate through the CNS and phagocytose foreign and degenerated material;

3. Astrocytes, which help to regulate the external environment of neurons in the CNS; and

4. Ependymal cells, which line the ventricles (cavities) of the brain and the central canal of the spinal cord.

Microglia are of hematopoietic (bone marrow) origin, and indeed can be replenished by monocytes (a type of leukocyte) from the blood. They remove toxic debris within the brain and secrete anti-inflammatory factors, functions that are essential for the health of neurons. Yet their actions have a negative side; overactive microglial cells can release free radicals that promote oxidative stress. and thereby contribute to neurodegenerative diseases.

Neurotransmitters and Neuromodulators

Neurons are often referred to using the suffix -ergic; the missing prefix is the type of neurotransmitter the neuron releases. For example, dopaminergic applies to neurons that release the neurotransmitter dopamine (EPSPs – Excitatory Post Synaptic Potentials or IPSPs – Inhibitory Post Synaptic Potentials). Neurotransmitters are the agents which are responsible for nerve impulse transmission.  Neuromodulators are the agents which are responsible for complex role as neurotransmitter, paracrine factor, and hormone etc.. They are acting both in sympathetic and parasympathetic neurons.

Acetylcholine

Acetylcholine (ACh) is a major neurotransmitter in the PNS at the neuromuscular junction and in the brain. Neurons that release ACh are called cholinergic neurons. The cell bodies of the brain’s cholinergic neurons are concentrated in relatively few areas, but their axons are widely distributed. Acetylcholine is synthesized from choline (a common nutrient found in many foods) and acetyl coenzyme A in the cytoplasm of synaptic terminals and stored in synaptic vesicles. After it is released and activates receptors on the postsynaptic membrane, the concentration of ACh at the postsynaptic membrane decreases (thereby stopping receptor activation) due to the action of the enzyme acetylcholinesterase. This enzyme is located on the presynaptic and postsynaptic membranes and rapidly destroys ACh, releasing choline and acetate. The choline is then transported back into the presynaptic axon terminals where it is reused in the synthesis of new ACh. Some chemical weapons, such as the nerve gas Sarin, inhibit acetylcholinesterase, causing a buildup of ACh in the synaptic cleft. This results in overstimulation of postsynaptic ACh receptors, initially causing uncontrolled muscle contractions but ultimately leading to receptor desensitization and paralysis.

There are two general types of ACh receptors, and they are distinguished by their responsiveness to two different chemicals. Nicotinic Acetylcholine Receptors Recall that although a receptor is considered specific for a given ligand, such as ACh, most receptors will recognize natural or synthetic compounds that exhibit some degree of chemical similarity to that ligand. Some ACh receptors respond not only to acetylcholine but to the compound nicotine and have therefore come to be known as nicotinic receptors. Nicotine is a plant alkaloid compound that constitutes 1% to 2% of tobacco products. It is also contained in treatments for smoking cessation, such as nasal sprays, chewing gums, and transdermal patches. Nicotine’s hydrophobic structure allows rapid absorption through lung capillaries, mucous membranes, skin, and the blood–brain barrier. The nicotinic acetylcholine receptor is an excellent example of a receptor that contains an ion channel (i.e., a ligand-gated ion channel). In this case, the channel is permeable to both sodium and potassium ions, but because Na⁺ has the larger electrochemical driving force, the net effect of opening these channels is depolarization. Nicotinic receptors are present at the neuromuscular junction and,  several nicotinic receptor antagonists are toxins that induce paralysis. Nicotinic receptors in the brain are important in cognitive functions and behavior. For example, one cholinergic system that employs nicotinic receptors has a major function in attention, learning, and memory by reinforcing the ability to detect and respond to meaningful stimuli. The presence of nicotinic receptors on presynaptic terminals in reward pathways of the brain explains why tobacco products are among the most highly addictive substances known.

Muscarinic Acetylcholine Receptors The other general type of cholinergic receptor is stimulated not only by acetylcholine but by muscarine, a poison contained in some mushrooms; therefore, these are called muscarinic receptors. These receptors are metabotropic and couple with G proteins, which then alter the activity of a number of different enzymes and ion channels. They are prevalent at some cholinergic synapses in the brain and at junctions where a major division of the PNS innervates peripheral glands, tissues, and organs, like salivary glands, smooth muscle cells, and the heart. Atropine is a naturally occuring antagonist of muscarinic receptors with many clinical uses, such as in eyedrops that relax the smooth muscles of the iris, thereby dilating the pupils for an eye exam.

Biogenic Amines

The biogenic amines are small, charged molecules that are synthesized from amino acids and contain an amino group (R}NH2). The most common biogenic amines are dopamine, norepinephrine, serotonin, and histamine. Epinephrine, another biogenic amine, is not a common neurotransmitter in the CNS but is the major hormone secreted by the adrenal medulla. Norepinephrine is an important neurotransmitter in both the central and peripheral components of the nervous system.

Catecholamines Dopamine (DA), norepinephrine (NE), and epinephrine all contain a catechol ring (a six-carbon ring with two adjacent hydroxyl groups) and an amine group, which is why they are called catecholamines. The catecholamines are formed from the amino acid tyrosine and share the same two initial steps in their synthetic pathway. Synthesis of catecholamines begins with the uptake of tyrosine by the axon terminals and its conversion to another precursor, L-dihydroxy-phenylalanine (L-dopa) by the rate-limiting enzyme in the pathway, tyrosine hydroxylase. Depending on the enzymes expressed in a given neuron, any one of the three catecholamines may ultimately be released. Autoreceptors on the presynaptic terminals strongly modulate synthesis and release of the catecholamines. After activation of the receptors on the postsynaptic cell, the catecholamine concentration in the synaptic cleft declines, mainly because a membrane transporter protein actively transports the catecholamine back into the axon terminal. The catecholamine neurotransmitters are also broken down in both the extracellular fluid and the axon terminal by enzymes such as monoamine oxidase (MAO). Drugs known as monoamine oxidase (MAO) inhibitors increase the amount of norepinephrine and dopamine in a synapse by slowing their metabolic degradation. Among other things, they are used in the treatment of mood disorders such as some types of depression.

Within the CNS, the cell bodies of the catecholamine releasing neurons lie in the brainstem and hypothalamus. Although these neurons are relatively few in number, their axons branch greatly and go to virtually all parts of the brain and spinal cord. These neurotransmitters have essential functions in states of consciousness, mood, motivation, directed attention, movement, blood pressure regulation, and hormone release. Epinephrine and norepinephrine are also synthesized in the adrenal glands. For historical reasons having to do with nineteenth-century physiologists referring to secretions of the adrenal gland as “adrenaline,” the adjective “adrenergic” is commonly used to describe neurons that release norepinephrine

or epinephrine and also to describe the receptors to which those neurotransmitters bind. There are two major classes of receptors for norepinephrine and epinephrine: alpha-adrenergic receptors (alpha-adrenoceptors) and beta-adrenergic receptors (betaadrenoceptors). All catecholamine receptors are metabotropic, and thus use second messengers to transfer a signal from the surface of the cell to the cytoplasm. Alpha-adrenoceptors exist in two subclasses, a1 and a2. They act presynaptically to inhibit norepinephrine release (a2) or postsynaptically to either stimulate or inhibit the activity of different types of K⁺ channels (a1). Betaadrenoceptors act via stimulatory G proteins to increase cAMP in the postsynaptic cell. There are three subclasses of beta-receptors, b1, b2, and b3, which function in different ways in different tissues. The subclasses of alpha- and beta-receptors are distinguished by the drugs that influence them and their second-messenger systems.

Serotonin:

Serotonin (5-hydroxytryptamine, or 5-HT) is produced from tryptophan, an essential amino acid. Its effects generally have a slow onset, indicating that it works as a neuromodulator. Serotonergic neurons innervate virtually every structure in the brain and spinal cord and operate via at least 16 different receptor subtypes. In general, serotonin has an excitatory effect on pathways that are involved in the control of muscles, and an inhibitory effect on pathways that mediate sensations. The activity of serotonergic neurons is lowest or absent during sleep and highest during states of alert wakefulness. In addition to their contributions to motor activity and sleep, serotonergic pathways also function in the regulation of food intake, reproductive behavior, and emotional states such as mood and anxiety.

Selective serotonin reuptake inhibitors such as paroxetine (Paxil) are thought to aid in the treatment of depression by inactivating the presynaptic membrane 5-HT transporter, which mediates the reuptake of serotonin into the presynaptic cell. This, in turn, increases the synaptic concentration of the neurotransmitter. Interestingly, such drugs are often associated with decreased appetite but paradoxically cause weight gain due to disruption of enzymatic pathways that regulate fuel metabolism. This is one example of how the use of reuptake inhibitors for a specific neurotransmitter—one with widespread actions—can cause unwanted side effects. Serotonin is found in both neural and nonneural cells, with the majority located outside of the CNS. In fact, approximately 90% of the body’s total serotonin is found in the digestive system, 8% is in blood platelets and immune cells, and only 1% to 2% is found in the brain. The drug lysergic acid diethylamide (LSD) stimulates the 5-HT2A subtype of serotonin receptor in the brain. Though the mechanism is not completely understood, alteration of this receptor complex produces the intense visual hallucinations that are produced by ingestion of LSD.

Amino Acid Neurotransmitters

In addition to the neurotransmitters that are synthesized from amino acids, several amino acids themselves function as neurotransmitters. Although the amino acid neurotransmitters chemically fit the category of biogenic amines, they are traditionally placed into a category of their own. The amino acid neurotransmitters are by far the most prevalent neurotransmitters in the CNS, and they affect virtually all neurons there.

Glutamate There are a number of excitatory amino acids, but the most common by far is glutamate, which is estimated to be the primary neurotransmitter at 50% of excitatory synapses in the CNS. As with other neurotransmitters, pharmacological manipulation of the receptors for glutamate has permitted identification of specific receptor subtypes by their ability to bind natural and synthetic ligands. Although metabotropic glutamate receptors do exist, the vast majority are ionotropic, with two important subtypes being found in postsynaptic membranes. They are designated as AMPA receptors (identified by their binding to a-amino-3 hydroxy-5 methyl-4 isoxazole propionic acid) and NMDA receptors (which bind N-methyl-D-aspartate). Cooperative activity of AMPA and NMDA receptors has been implicated in one type of a phenomenon called longterm potentiation (LTP). This mechanism couples frequent activity across a synapse with lasting changes in the strength of signaling across that synapse and is thus thought to be one of the major cellular processes involved in learning and memory.

When a presynaptic neuron fires action potentials (step 1), glutamate is released from presynaptic terminals (step 2) and binds to both AMPA and NMDA receptors on postsynaptic membranes (step 3). AMPA receptors function just like the excitatory postsynaptic receptors discussed earlier—when glutamate binds, the channel becomes permeable to both Na⁺ and K⁺, but the larger entry of Na⁺ creates a depolarizing EPSP of the postsynaptic cell (step 4). By contrast, NMDA-receptor channels also mediate a substantial Ca⁺ flux, but opening them requires more than just glutamate binding. A magnesium ion blocks NMDA channels when the membrane voltage is near the negative resting potential, and to drive it out of the way the membrane must be significantly depolarized by the current through AMPA channels (step 5). This explains why it requires a high frequency of presynaptic action potentials to complete the longterm potentiation mechanism. At low frequencies, there is insufficient temporal summation of AMPA-receptor EPSPs to provide the 20–30 mV of depolarization needed to move the magnesium ion, and so the NMDA receptors do not open. When the depolarization is sufficient, however, NMDA receptors do open, allowing Ca2⁺ to enter the postsynaptic cell (step 6). Calcium ions then activate a second-messenger cascade in the postsynaptic cell that includes persistent activation of multiple different protein kinases, stimulation of gene expression and protein synthesis, and ultimately a long-lasting increase in the sensitivity of the postsynaptic neuron to glutamate (step 7). This second-messenger system can also activate long-term enhancement of presynaptic glutamate release via retrograde signals that have not yet been identified (step 8). Each subsequent action potential arriving along this presynaptic cell will cause a greater depolarization of the postsynaptic membrane. Thus, repeatedly and intensely activating a particular pattern of synaptic firing (as you might when studying for an exam) causes chemical and structural changes that facilitate future activity along those same pathways (as might occur when recalling what you learned).

Prior to exocytosis, the synaptic vesicles are filled with neurotransmitter and translocate to the active zone, where they dock at morphologically defined sites on the target plasma membrane. The v-SNARE synaptobrevin/VAMP faces the target plasma membrane, which contains the v-SNAREs SNAP25 and syntaxin, which associates with MUNC18/n-Sec1. During the priming stage of vesicle fusion, the SNARE proteins partially zipper together and complexin clamps the SNARE complex in an activation-poised state to prevent membrane fusion. Action potential–induced calcium influx triggers calcium, phospholipid, and SNARE complex binding by synaptotagmin, which causes displacement of complexin and opening of the fusion pore. Vesicle/target membrane fusion allows neurotransmitter to enter the synaptic cleft and interact with the postsynaptic density of the partner neuron.  (vSNARE- Vesicle SNARE; t-SNARE – Target SNARE; Q-SNARE – Gln SNARE; R-SNARE-Arg SNARE; Munc18-Mammalian uncoordinated 18 protein)

During step 1, synaptic vesicles are primed for fusion; this step involves opening of the closed conformation of syntaxin, a switch of the Munc18-binding mode of syntaxin from the closed to the open conformation and partial assembly of trans-SNARE complexes. Step 1 is facilitated by recently discovered chaperones (cysteine string proteins (CSPs) and synucleins) that enhance SNARE complex assembly and whose dysfunction is related to neurodegeneration³. During step 2, the fusion pore opens, with full trans-SNARE complex assembly. During step 3, the fusion pore expands, converting trans-SNARE into cis-SNARE complexes. In step 4, NSF and SNAPs mediate disassembly of the SNARE complex, leading to vesicle recycling. The cycle shown here for synaptic vesicle fusion is paradigmatic for most cytoplasmic fusion reactions, although the details differ. In knockout experiments, deletion of the SM protein Munc18-1 produces the most severe phenotype²², possibly because loss of SNARE components of the fusion machinery is better compensated for than loss of SM proteins. SNAREs are generally classified into four types (R, Qa, Qb and Qc) that assemble into SNARE complexes in an obligatory R-Qa-Qb-Qc combination.

NMDA receptors have also been implicated in mediating excitotoxicity. This is a phenomenon in which the injury or death of some brain cells (due, for example, to blocked or ruptured blood vessels) rapidly spreads to adjacent regions. When glutamate-containing cells die and their membranes rupture, the flood of glutamate excessively stimulates AMPA and NMDA receptors on nearby neurons. The excessive stimulation of those neurons causes the accumulation of toxic concentrations of intracellular Ca2⁺, which in turn kills those neurons and causes them to rupture, and the wave of damage progressively spreads. Recent experiments and clinical trials suggest that administering NMDA receptor antagonists may help minimize the spread of cell death following injuries to the brain.

GABA GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in the brain. Although it is not one of the 20 amino acids used to build proteins, it is classified with the amino acid neurotransmitters because it is a modified form of glutamate. With few exceptions, GABA neurons in the brain are small interneurons that dampen activity within neural circuits. Postsynaptically, GABA may bind to ionotropic or metabotropic receptors. The ionotropic receptor increases Cl2 flux into the cell, resulting in hyperpolarization (an IPSP) of the postsynaptic membrane. In addition to the GABA binding site, this receptor has several additional binding sites for other compounds, including steroids, barbiturates, and benzodiazepines. Benzodiazepine drugs such as alprazolam (Xanax) and diazepam (Valium) reduce anxiety, guard against seizures, and induce sleep by increasing Cl2 flux through the GABA receptor. Synapses that use GABA are also among the many targets of the ethanol (ethyl alcohol) found in alcoholic beverages. Ethanol stimulates GABA synapses and simultaneously inhibits excitatory glutamate synapses, with the overall effect being global depression of the electrical activity of the brain. Thus, as a person’s blood alcohol content increases, there is a progressive reduction in overall cognitive ability, along with sensory perception inhibition (hearing and balance, in particular), loss of motor coordination, impaired judgment, memory loss, and unconsciousness. Very high doses of ethanol are sometimes fatal, due to suppression of brainstem centers responsible for regulating the circulatory and respiratory systems. Dopaminergic and endogenous opioid signaling pathways (discussed in the next section) are also affected by ethanol, which results in short-term mood elevation or euphoria. The involvement of these pathways underlies the development of long-term alcohol dependence in some people.

Glycine Glycine is the major neurotransmitter released from inhibitory interneurons in the spinal cord and brainstem. It binds to ionotropic receptors on postsynaptic cells that allow Cl₂ to enter, thus preventing them from approaching the threshold for firing action potentials. Normal function of glycinergic neurons is essential for maintaining a balance of excitatory and inhibitory activity in spinal cord integrating centers that regulate skeletal muscle contraction. This becomes apparent in cases of poisoning with the neurotoxin strychnine, an antagonist of glycine receptors sometimes used to kill rodents. Victims experience hyperexcitability throughout the nervous system, which leads to convulsions, spastic contraction of skeletal muscles, and ultimately death due to impairment of the muscles of respiration.

Neuropeptides

The neuropeptides are composed of two or more amino acids linked together by peptide bonds. About 100 neuropeptides have been identified, but their physiological functions are not all known. It seems that evolution has favored the same chemical messengers for use in widely differing circumstances, and many of the neuropeptides have been previously identified in nonneural tissue where they function as hormones or paracrine substances. They generally retain the name they were given when first discovered in the nonneural tissue. The neuropeptides are formed differently than other neurotransmitters, which are synthesized in the axon terminals by very few enzyme-mediated steps. The neuropeptides, in contrast, are derived from large precursor proteins, which in themselves have little, if any, inherent biological activity. The synthesis of these precursors, directed by mRNA, occurs on ribosomes, which exist only in the cell body and large dendrites of the neuron, often a considerable distance from axon terminals or varicosities where the peptides are released. In the cell body, the precursor protein is packaged into vesicles, which are then moved by axonal transport into the terminals or varicosities, where the protein is cleaved by specific peptidases. Many of the precursor proteins contain multiple peptides, which may be different or be copies of one peptide. Neurons that release one or more of the peptide neurotransmitters

are collectively called peptidergic. In many cases, neuropeptides are cosecreted with another type of neurotransmitter and act as neuromodulators. The amount of neuropeptide released from vesicles at synapses is significantly less than the amount of nonpeptidergic neurotransmitters such as catecholamines. In addition, neuropeptides can diffuse away from the synapse and affect other neurons at some distance, in which case they are referred to as neuromodulators.

The actions of these neuromodulators are longer lasting (on the order of several hundred milliseconds) than when neuropeptides or other molecules act as neurotransmitters. After release, neuropeptides can interact with either ionotropic or metabotropic receptors. They are eventually broken down by peptidases located in neuronal membranes. Endogenous opioids—a group of neuropeptides that includes beta-endorphin, the dynorphins, and the enkephalins— have attracted much interest because their receptors are the sites of action of opiate drugs such as morphine and codeine. The opiate drugs are powerful analgesics (that is, they relieve pain without loss of consciousness), and the endogenous opioids undoubtedly have a function in regulating pain. There is also evidence that the opioids function in regulating eating and drinking behavior, circulatory system function, and mood and emotion.

Gases

Certain very short-lived gases also serve as neurotransmitters. Nitric oxide is the best understood, but recent research indicates that carbon monoxide and hydrogen sulfide are also emitted by neurons as signals. Gases are not released by exocytosis of presynaptic vesicles, nor do they bind to postsynaptic plasma membrane receptors. They are produced by enzymes in axon terminals (in response to Ca21 entry) and simply diffuse from their sites of origin in one cell into the intracellular fluid of other neurons or effector cells, where they bind to and activate proteins. For example, nitric oxide released from neurons activates guanylyl cyclase in recipient cells. This enzyme increases the concentration of the second-messenger cyclic GMP, which in turn can alter ion channel activity in the postsynaptic cell.

Nitric oxide functions in a bewildering array of neutrally mediated events—learning, development, drug tolerance, penile and clitoral erection, and sensory and motor modulation, to name a few. Paradoxically, it is also implicated in neural damage that results, for example, from the stoppage of blood flow to the brain or from a head injury. In later chapters, we will see that nitric oxide is produced not only in the central and peripheral nervous systems but also by a variety of nonneural cells; for example, it has important paracrine functions in the circulatory and immune systems, among others.

Purines

Other nontraditional neurotransmitters include the purines, ATP and adenosine, which act principally as neuromodulators. ATP is present in all presynaptic vesicles and is coreleased with one or more other neurotransmitters in response to Ca2⁺ influx into the terminal. Adenosine is derived from ATP via enzyme activity occurring in the extracellular compartment. Both presynaptic and postsynaptic receptors have been described for adenosine, and the functions these substances have in the nervous system and other tissues are active areas of research.

Neuroeffector Communication

Many neurons of the PNS end, however, not at synapses on other neurons but at neuroeffector junctions on muscle, gland, and other cells. The neurotransmitters released by these efferent neurons’ terminals or varicosities provide the link by which electrical activity of the nervous system regulates effector cell activity. The events that occur at neuroeffector junctions are similar to those at synapses between neurons. The neurotransmitter is released from the efferent neuron upon the arrival of an action potential at the neuron’s axon terminals or varicosities. The neurotransmitter then diffuses to the surface of the effector cell, where it binds to receptors on that cell’s plasma membrane. The receptors may be directly under the axon terminal or varicosity, or they may be some distance away so that the diffusion path the neurotransmitter follows is long. The receptors on the effector cell may be either ionotropic or metabotropic.

Nerve impulse

The changes in Na+ and K+ diffusion and the resulting changes in the membrane potential they produce constitute an event called the action potential, or nerve impulse. The electrochemical wave that travels along nerve fiber and stimulates muscles, glands or other nerve cells is called as nerve impulse.

Spike Potential

The periodic rise of depolarization wave and rapid fall of repolarization wave are known as spike potential.

All-or-None Law

Once a region of axon membrane has been depolarized to a threshold value, the positive feedback effect of depolarization on Na+ permeability and of Na+ permeability on depolarization causes the membrane potential to shoot toward about +30 mV. It does not normally become more positive than +30 mV because the Na+ channels quickly close and the K+ channels open. The length of time that the Na+ and K+ channels stay open is independent of the strength of the depolarization stimulus.  The amplitude (size) of action potentials is therefore all or none. When depolarization is below a threshold value, the voltage-regulated gates are closed; when depolarization reaches threshold, a maximum potential change (the action potential) is produced. Because the change from −70 mV to +30 mV and back to −70 mV lasts only about 3 msec, the image of an action potential on an oscilloscope screen looks like a spike. Action potentials are therefore sometimes called spike potentials. The channels are open only for a fixed period of time because they are soon inactivated, a process different from simply closing the gates. Inactivation occurs automatically and lasts until the membrane has repolarized. Because of this automatic inactivation, all action potentials have about the same duration. Likewise, since the concentration gradient for Na+ is relatively constant, the amplitudes of the action potentials are about equal in all axons at all times (from −70 mV to +30 mV, or about 100 mV in total amplitude).

Conduction of Nerve Impulses

When stimulating electrodes artificially depolarize one point of an axon membrane to a threshold level, voltage-regulated channels open and an action potential is produced at that small region of axon membrane containing those channels. For about the first millisecond of the action potential, when the membrane voltage changes from −70 mV to +30 mV, a current of Na+ enters the cell by diffusion because of the opening of the Na+ gates. Each action potential thus “injects” positive charges (sodium ions) into the axon. These positively charged sodium ions are conducted, by the cable properties of the axon, to an adjacent region that still has a membrane potential of −70 mV. Within the limits of the cable properties of the axon (1 to 2 mm), this helps to depolarize the adjacent region of axon membrane. When this adjacent region of membrane reaches a threshold level of depolarization, it too produces the action potential as its voltage-regulated gates open. The action potential produced at the first location in the axon membrane (usually at the axon hillock) thus serves as the depolarization stimulus for the next region of the axon membrane, which can then produce the action potential. The action potential in this second region, in turn, serves as a depolarization stimulus for the production of the action potential in a third region, and so on. This explains how the action potential is produced at all regions of the axon beyond the initial segment at the axon hillock.

Conduction in an Unmyelinated Axon

In an unmyelinated axon, every patch of membrane that contains Na+ and K+ channels can produce an action potential. Action potentials are thus produced along the entire length of the axon. The cablelike spread of depolarization induced by the influx of Na + during one action potential helps to depolarize the adjacent regions of membrane—a process that is also aided by movements of ions on the outer surface of the axon membrane. This process would depolarize the adjacent membranes on each side of the region to produce the action potential, but the area that had previously produced one cannot produce another at this time because it is still in its refractory period. It is important to recognize that action potentials are not really “conducted,” although it is convenient to use that word. Each action potential is a separate, complete event that is repeated, or regenerated, along the axon’s length. This is analogous to the “wave” performed by spectators in a stadium.  One person after another gets up (depolarization) and then sits down (repolarization). It is thus the “wave” that travels (the repeated action potential at different locations along the axon membrane), not the people.

The action potential produced at the end of the axon is thus a completely new event that was produced in response to depolarization from the previous region of the axon membrane. The action potential produced at the last region of the axon has the same amplitude as the action potential produced at the first region. Action potentials are thus said to be conducted without decrement (without decreasing in amplitude). The spread of depolarization by the cable properties of an axon is fast compared to the time it takes to produce an action potential. Thus, the more action potentials along a given stretch of axon that have to be produced, the slower the conduction. Because action potentials must be produced at every fraction of a micrometer in an unmyelinated axon, the conduction rate is relatively slow. This conduction rate is somewhat faster if the unmyelinated axon is thicker, because thicker axons have less resistance to the flow of charges (so conduction of charges by cable properties is faster). The conduction rate is substantially faster if the axon is myelinated, because fewer action potentials are produced along a given length of myelinated axon.

Conduction in a Myelinated Axon

The myelin sheath provides insulation for the axon, preventing movements of Na+ and K+ through the membrane. If the myelin sheath were continuous, therefore, action potentials could not be produced. The myelin thus has interruptions-the nodes of Ranvier, as previously described. Because the cable properties of axons can conduct depolarizations over only a very short distance (1 to 2 mm), the nodes of Ranvier cannot be separated by more than this distance. Studies have shown that Na+ channels are highly concentrated at the nodes (estimated at 10,000 per square micrometer) and almost absent in the regions of axon membrane between the nodes. Action potentials, therefore, occur only at the nodes of Ranvier and seem to “leap” from node to node—a process called saltatory conduction (from the Latin saltario = leap). The leaping is, of course, just a metaphor; the action potential at one node depolarizes the membrane at the next node to threshold, so that a new action potential is produced at the next node of Ranvier.

Myelinated axons conduct the action potential faster than unmyelinated axons. This is because myelinated axons have voltage-gated channels only at the nodes of Ranvier, which are about 1 mm apart, whereas unmyelinated axons have these channels along their entire length. Because myelinated axons have more cablelike spread of depolarization (which is faster), and fewer sites at which the action potential is produced (which is slower) than unmyelinated axons, the conduction is faster in a myelinated axon. Conduction rates in the human nervous system vary from 1.0 m/sec—in thin, unmyelinated fibers that mediate slow, visceral responses-to faster than 100 m/sec (225 miles per hour)—in thick, myelinated fibers involved in quick stretch reflexes in skeletal muscles.

In summary, the speed of action potential conduction is increased by (1) increased diameter of the axon, because this reduces the resistance to the spread of charges by cable properties; and (2) myelination, because the myelin sheath results in saltatory conduction of action potentials. These methods of affecting conduction speed are generally combined in the nervous system: the thinnest axons tend to be unmyelinated and the thickest tend to be myelinated.

AUTONOMIC NERVOUS SYSTEM (ANS)

The autonomic nervous system (ANS) is the part of the nervous system that is responsible for homeostasis. Except for skeletal muscle, which gets its innervation from the somatomotor nervous system, innervation to all other organs is supplied by the ANS. Nerve terminals are located in smooth muscle (eg, blood vessels, the wall of the gastrointestinal tract, and urinary bladder), cardiac muscle, and glands (eg, sweat glands and salivary glands). Although survival is possible without an ANS, the ability to adapt to environmental stressors and other challenges is severely compromised. The importance of understanding the functions of the ANS is underscored by the fact that so many drugs used to treat a vast array of diseases exert their actions on elements of the ANS. Also, many neurologic diseases or disorders result directly from a loss of preganglionic sympathetic neurons (eg, multiple system atrophy and Shy–Drager syndrome) and other common diseases (eg, Parkinson disease and diabetes) are associated with autonomic dysfunction.

The ANS has two major and anatomically distinct divisions: the sympathetic and parasympathetic nervous systems. As will be described, some target organs are innervated by both divisions and others are controlled by only one. In addition, the ANS includes the enteric nervous system within the gastrointestinal tract. The classic definition of the ANS is the preganglionic and postganglionic neurons within the sympathetic and parasympathetic divisions. This would be equivalent to defining the somatomotor nervous system as the cranial and spinal motor neurons. A modern definition of the ANS takes into account the descending pathways from several forebrain and brainstem regions as well as visceral afferent pathways that set the level of activity in sympathetic and parasympathetic nerves. This is analogous to including the many descending and ascending pathways that influence the activity of somatic motor neurons as elements of the somatomotor nervous system. The sympathetic divisions responsible for showing, expressing and feeling like fight-flight-fright response.  The parasympathetic divisions responsible for rest state and digestion. It is contrary to sympathetic nervous system function.

SYMPATHETIC DIVISION

In contrast to α-motor neurons, which are located at all spi­nal segments, sympathetic preganglionic neurons are located in the IML of only the first thoracic to the third or fourth lumbar segments. This is why the sympathetic nervous sys­tem is sometimes called the thoracolumbar division of the ANS. The axons of the sympathetic preganglionic neurons leave the spinal cord at the level at which their cell bodies are located and exit via the ventral root along with axons of α- and γ-motor neurons. They then separate from the ventral root via the white rami communicans and project to the adjacent sympathetic paravertebral ganglion, where some of them end on the cell bodies of the postgan­glionic neurons. Paravertebral ganglia are located adjacent to each thoracic and upper lumbar spinal segment; in addi­tion, there are a few ganglia adjacent to the cervical and sacral spinal segments. The ganglia are connected to each other via the axons of preganglionic neurons that travel rostrally or caudally to terminate on postganglionic neurons located at some distance. Together these ganglia and axons form the sympathetic chain bilaterally. Some preganglionic neurons pass through the paraver­tebral ganglion chain and end on postganglionic neurons located in prevertebral (or collateral) ganglia close to the viscera, including the celiac, superior mesenteric, and inferior mesenteric ganglia. There are also preganglionic neurons whose axons terminate directly on the effector organ, the adrenal gland.  The axons of some of the postganglionic neurons leave the chain ganglia and reenter the spinal nerves via the gray rami communicans and are distributed to autonomic effec­tors in the areas supplied by these spinal nerves. These postganglionic sympathetic nerves terminate mainly on smooth muscle (eg, blood vessels and hair follicles) and on sweat glands in the limbs. Other postganglionic fibers leave the chain ganglia to enter the thoracic cavity to terminate in visceral organs. Postganglionic fibers from prevertebral gan­glia also terminate in visceral targets.

PARASYMPATHETIC DIVISION

The parasympathetic nervous system is sometimes called the craniosacral division of the ANS because of the location of its preganglionic neurons; preganglionic neurons are located in several cranial nerve nuclei (III, VII, IX, and X) and in the IML of the sacral spinal cord. The cell bodies in the Edinger–Westphal nucleus of the oculomotor nerve project to the ciliary ganglia to innervate the sphincter (con­strictor) muscle of the iris and the ciliary muscle. Neurons in the superior salivatory nucleus of the facial nerve proj­ect to the sphenopalatine ganglia to innervate the lacrimal glands and nasal and palatine mucous membranes and to the submandibular ganglia to innervate the submandibu­lar (also called submaxillary) and sublingual glands. The cell bodies in the inferior salivatory nucleus of the glos­sopharyngeal nerve project to the otic ganglion to inner­vate the parotid salivary gland. Vagal preganglionic fibers synapse on ganglia cells clustered within the walls of visceral organs; thus these parasympathetic postganglionic fibers are very short. Neurons in the nucleus ambiguus innervate the sinoatrial (SA) and atrioventricular (AV) nodes in the heart; and neurons in the dorsal motor vagal nucleus innervate the esophagus, trachea, lungs, and gastrointestinal tract. The parasympathetic sacral outflow (pelvic nerve) supplies the pelvic viscera via branches of the second to fourth sacral spi­nal nerves.

The parasympathetic (at left) and sympathetic (at right) divisions of the autonomic nervous system. Although single nerves are shown exiting the brainstem and spinal cord, all represent paired (left and right) nerves. Only one sympathetic trunk is indicated, although there are two, one on each side of the spinal cord. The celiac, superior mesenteric, and inferior mesenteric ganglia are collateral ganglia. Not shown are the fibers passing to the liver, blood vessels, genitalia, and skin glands.

GENERAL PROPERTIES OF REFLEXES

The basic unit of integrated reflex activity is the reflex arc. This arc consists of a sense organ, an afferent neuron, one or more synapses within a central integrating station, an effer­ent neuron, and an effector. The afferent neurons enter via the dorsal roots or cranial nerves and have their cell bodies in the dorsal root ganglia or in the homologous ganglia of the cranial nerves. The efferent fibers leave via the ventral roots or cor­responding motor cranial nerves.  Activity in the reflex arc starts in a sensory receptor with a receptor potential whose magnitude is proportional to the strength of the stimulus. This generates all-or-none action potentials in the afferent nerve, the number of action potentials being proportional to the size of the receptor potential. In the central nervous system (CNS), the responses are again graded in terms of excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) at the synaptic junctions. All-or-none responses (action potentials) are generated in the efferent nerve. When these reach the effector, they again set up a graded response. When the effec­tor is smooth muscle, responses summate to produce action potentials in the smooth muscle. In contrast, when the effector is skeletal muscle, the graded response is adequate to produce action potentials that bring about muscle contraction. The connection between the afferent and efferent neurons is in the CNS, and activity in the reflex arc is modified by the multiple inputs converging on the efferent neurons or at any synaptic station within the reflex arc.  The stimulus that triggers a reflex is generally very pre­cise. This stimulus is called the adequate stimulus for the par­ticular reflex. A dramatic example is the scratch reflex in the dog. This spinal reflex is adequately stimulated by multiple lin­ear touch stimuli such as those produced by an insect crawling across the skin. The response is vigorous scratching of the area stimulated. If the multiple touch stimuli are widely separated or not in a line, the adequate stimulus is not produced and no scratching occurs. Fleas crawl, but they also jump from place to place. This jumping separates the touch stimuli so that an adequate stimulus for the scratch reflex is not produced.

MONOSYNAPTIC REFLEXES: THE STRETCH REFLEX

The simplest reflex arc is one with a single synapse between the afferent and efferent neurons, and reflexes occurring in them are called monosynaptic reflexes. Reflex arcs in which interneurons are interposed between the afferent and efferent neurons are called polysynaptic reflexes. There can be any­where from two to hundreds of synapses in a polysynaptic reflex arc.  When a skeletal muscle with an intact nerve supply is stretched, it contracts. This response is called the stretch reflex or myotatic reflex. The stimulus that initiates this reflex is stretch of the muscle, and the response is contrac­tion of the muscle being stretched. The sense organ is a small encapsulated spindlelike or fusiform-shaped structure called the muscle spindle, located within the fleshy part of the muscle. The impulses originating from the spindle are transmitted to the CNS by fast sensory fibers that pass directly to the motor neurons that supply the same muscle. The neurotransmitter at the central synapse is glutamate. The stretch reflex is the best known and studied monosyn­aptic reflex and is typified by the knee jerk reflex.

MUSCLE SYSTEM

Muscle cells, like neurons, can be excited chemically, electrically, and mechanically to produce an action potential that is transmitted along their cell membranes. Unlike neurons, they respond to stimuli by activating a contractile mechanism. The contractile protein myosin and the cytoskeletal protein actin are abundant in muscle, where they are the primary structural components that bring about contraction.  Muscle is generally divided into three types: skeletal, cardiac, and smooth, although smooth muscle is not a homogeneous single category. Skeletal muscle makes up the great mass of the somatic musculature. It has well-developed cross-striations, does not normally contract in the absence of nervous stimulation, lacks anatomic and functional connections between individual muscle fibers, and is generally under voluntary control. Cardiac muscle also has cross-striations, but it is functionally syncytial and, although it can be modulated via the autonomic nervous system, it can contract rhythmically in the absence of external innervation owing to the presence in the myocardium of pacemaker cells that discharge spontaneously. Smooth muscle lacks cross-striations and can be further subdivided into two broad types: unitary (or visceral) smooth muscle and multiunit smooth muscle. The type found in most hollow viscera is functionally syncytial and contains pacemakers that discharge irregularly. The multiunit type found in the eye and in some other locations is not spontaneously active and resembles skeletal muscle in graded contractile ability.

SKELETAL MUSCLE MORPHOLOGY

Skeletal muscle is made up of individual muscle fibers that are the “building blocks” of the muscular system in the same sense that the neurons are the building blocks of the nervous system. Most skeletal muscles begin and end in tendons, and the muscle fibers are arranged in parallel between the tendinous ends, so that the force of contraction of the units is additive. Each muscle fiber is a single cell that is multinucleated, long, cylindrical, and surrounded by a cell membrane, the sarcolemma. There are no syncytial bridges between cells. The muscle fibers are made up of myofibrils, which are divisible into individual filaments. These myofilaments contain several proteins that together make up the contractile machinery of the skeletal muscle. 

The contractile mechanism in skeletal muscle largely depends on the proteins myosin-II, actin, tropomyosin, and troponin. Troponin is made up of three subunits: troponin I, troponin T, and troponin C. Other important proteins in mus­cle are involved in maintaining the proteins that participate in contraction in appropriate structural relation to one another and to the extracellular matrix.  microscope. The parts of the cross-striations are frequently identified by letters. The light I band is divided by the dark Z line, and the dark A band has the lighter H band in its center. A transverse M line is seen in the middle of the H band, and this line plus the narrow light areas on either side of it are sometimes called the pseudo-H zone. The area between two adjacent Z lines is called a sarcomere. The orderly arrangement of actin, myosin, and related proteins that pro­duces this pattern. The thick filaments, which are about twice the diameter of the thin filaments, are made up of myosin; the thin filaments are made up of actin, tropomyosin, and troponin. The thick filaments are lined up to form the A bands, whereas the array of thin filaments extends out of the A band and into the less dense staining I bands. The lighter H bands in the center of the A bands are the regions where, when the muscle is relaxed, the thin filaments do not overlap the thick filaments. The Z lines allow for anchoring of the thin filaments. If a transverse section through the A band is examined under the electron microscope, each thick filament is seen to be surrounded by six thin filaments in a regular hexagonal pattern.

The form of myosin found in muscle is myosin-II, with two globular heads and a long tail. The heads of the myosin molecules form cross-bridges with actin. Myosin contains heavy chains and light chains, and its heads are made up of the light chains and the amino terminal portions of the heavy chains. These heads contain an actin-binding site and a catalytic site that hydrolyzes adenosine triphosphate (ATP). The myosin molecules are arranged symmetrically on either side of the cen­ter of the sarcomere, and it is this arrangement that creates the light areas in the pseudo-H zone. The M line is the site of the reversal of polarity of the myosin molecules in each of the thick filaments. At these points, there are slender cross-connections that hold the thick filaments in proper array. Each thick filament contains several hundred myosin molecules.  The thin filaments are polymers made up of two chains of actin that form a long double helix. Tropomyosin molecules are long filaments located in the groove between the two chains in the actin. Each thin filament contains 300–400 actin molecules and 40–60 tropomyosin molecules. Troponin molecules are small globular units located at intervals along the tropomyosin molecules. Each of the three troponin subunits has a unique function: Troponin T binds the troponin components to tropomyosin, troponin I inhibits the interaction of myosin with actin, and troponin C contains the binding sites for the Ca2+ that helps initiate contraction.

Some additional structural proteins that are important in skeletal muscle function include actinin, titin, and desmin. Actinin binds actin to the Z lines. Titin, the largest known protein (with a molecular mass near 3,000,000 Da), connects the Z lines to the M lines and provides scaffolding for the sarcomere. It contains two kinds of folded domains that provide muscle with its elasticity. At first when the muscle is stretched there is relatively little resistance as the domains unfold, but with further stretch there is a rapid increase in resistance that protects the structure of the sarcomere. Desmin adds structure to the Z lines in part by binding the Z lines to the plasma membrane. It should be noted that although these proteins are important in muscle structure/function, by no means do they represent an exhaustive list.

SARCOTUBULAR SYSTEM

The muscle fibrils are surrounded by structures made up of membranes that appear in electron micrographs as vesicles and tubules. These structures form the sarcotubular system, which is made up of a T system and a sarcoplasmic reticulum. The T system of transverse tubules, which is continuous with the sar­colemma of the muscle fiber, forms a grid perforated by the indi­vidual muscle fibrils. The space between the two layers of the T system is an extension of the extracellular space. The sarcoplasmic reticulum, which forms an irregular curtain around each of the fibrils, has enlarged terminal cisterns in close contact with the T system at the junctions between the A and I bands. At these points of contact, the arrangement of the central T system with a cistern of the sarcoplasmic reticulum on either side has led to the use of the term triads to describe the system. The T system, which is continuous with the sarco­lemma, provides a path for the rapid transmission of the action potential from the cell membrane to all the fibrils in the muscle. The sarcoplasmic reticulum is an important store of Ca2+ and also participates in muscle metabolism.

DYSTROPHIN–GLYCOPROTEIN COMPLEX

The large dystrophin protein (molecular mass 427,000 Da) forms a rod that connects the thin actin filaments to the trans­membrane protein β-dystroglycan in the sarcolemma by smaller proteins in the cytoplasm, syntrophins. β-dystroglycan is connected to merosin (merosin refers to laminins that con­tain the α2 subunit in their trimeric makeup) in the extracellu­lar matrix by α-dystroglycan. The dystroglycans are in turn associated with a complex of four transmembrane glycoproteins: α-, β-, γ-, and δ-sarcoglycan. This dystrophin–glycoprotein complex adds strength to the muscle by pro­viding a scaffolding for the fibrils and connecting them to the extracellular environment. Disruption of these important structural features can result in several different muscular dys­trophies.

MYOFIBRIL
When muscle cells are viewed in the electron microscope, which can produce images at several thousand times the magnification possible in an ordinary light microscope, each cell is seen to be composed of many subunits known as myofibrils (fibrils = little fibers). These myofibrils are approximately 1 micrometer (1 μ m) in diameter and extend in parallel rows from one end of the muscle fiber to the other. The myofibrils are so densely packed that other organelles, such as mitochondria and intracellular membranes, are restricted to the narrow cytoplasmic spaces that remain between adjacent myofibrils. When a muscle fiber is seen with an electron microscope, its striations do not extend all the way across its width. Rather, the dark A bands and light I bands that produce the striations are seen within each myofibril. Because the dark and light bands of different myofibrils are stacked in register (aligned vertically) from one side of the muscle fiber to the other, and the individual myofibrils are not visible with an ordinary light microscope, the entire muscle fiber seems to be striated under a light microscope.

Each myofibril contains even smaller structures called myofilaments. When a myofibril is observed at high magnification in longitudinal section (side view), the A bands are seen to contain thick filaments. These are about 110 angstroms thick (110 Å, where 1 Å = 10 − 10 m) and are stacked in register. It is these thick filaments that give the A band its dark appearance. The lighter I band, by contrast, contains thin filaments (from 50 to 60 Å thick). The thick filaments are primarily composed of the protein myosin, and the thin filaments are primarily composed of the protein actin. The I bands within a myofibril are the lighter areas that extend from the edge of one stack of thick filaments to the edge of the next stack of thick filaments. They are light in appearance because they contain only thin filaments. The thin filaments, however, do not end at the edges of the I bands. Instead, each thin filament extends partway into the A bands on each side (between the stack of thick filaments on each side of an I band). Because thick and thin filaments overlap at the edges of each A band, the edges of the A band are darker in appearance than the central region. These central lighter regions of the A bands are called the H bands (for helle, a German word meaning “bright”). The central H bands thus contain only thick filaments that are not overlapped by thin filaments. In the center of each I band is a thin dark Z line. The arrangement of thick and thin filaments between a pair of Z lines forms a repeating pattern that serves as the basic subunit of striated muscle contraction. These subunits, from Z to Z, are known as sarcomeres. A longitudinal section of a myofibril thus presents a side view of successive sarcomeres. This side view is, in a sense, misleading; there are numerous sarcomeres within each myofibril that are out of the plane of the section (and out of the picture). A better appreciation of the three-dimensional structure of a myofibril can be obtained by viewing the myofibril in cross section. In this view, it can be seen that the Z lines are actually Z discs, and that the thin filaments that penetrate these Z discs surround the thick filaments in a hexagonal arrangement.  If we concentrate on a single row of dark thick filaments in this cross section, the alternating pattern of thick and thin filaments seen in longitudinal section becomes apparent. The M lines are produced by protein filaments located at the center of the thick filaments (and thus the A band) in a sarcomere. These serve to anchor the thick filaments, helping them to stay together during a contraction.  Also shown are filaments of titin, a type of elastic protein that runs through the thick filaments from the M lines to the Z discs. Because of its elastic properties, titin is believed to contribute to the elastic recoil of muscles that helps them to return to their resting length during muscle relaxation.

Sliding theory events:

1. A myofiber, together with all its myofibrils, shortens by movement of the insertion toward the origin of the muscle.

2. Shortening of the myofibrils is caused by shortening of the sarcomeres—the distance between Z lines (or discs) is reduced.

3. Shortening of the sarcomeres is accomplished by sliding of the myofilaments—the length of each filament remains the same during contraction.

4. Sliding of the filaments is produced by asynchronous power strokes of myosin cross bridges, which pull the thin filaments (actin) over the thick filaments (myosin).

5. The A bands remain the same length during contraction, but are pulled toward the origin of the muscle.

6. Adjacent A bands are pulled closer together as the I bands between them shorten.

7. The H bands shorten during contraction as the thin filaments on the sides of the sarcomeres are pulled toward the middle.

SLIDING FILAMENT THEORY OF CONTRACTION

When a muscle contracts it decreases in length as a result of the shortening of its individual fibers. Shortening of the muscle fibers, in turn, is produced by shortening of their myofibrils, which occurs as a result of the shortening of the distance from Z disc to Z disc. As the sarcomeres shorten in length, however, the A bands do not shorten but instead move closer together. The I bands—which represent the distance between A bands of successive sarcomeres—decrease in length. The thin filaments composing the I band, however, do not shorten. Close examination reveals that the thick and thin filaments remain the same length during muscle contraction. Shortening of the sarcomeres is produced not by shortening of the filaments, but rather by the sliding of thin filaments over and between the thick filaments. In the process of contraction, the thin filaments on either side of each A band slide deeper and deeper toward the center, producing increasing amounts of overlap with the thick filaments. The I bands (containing only thin filaments) and H bands (containing only thick filaments) thus get shorter during contraction.

Cross Bridges

Sliding of the filaments is produced by the action of numerous cross bridges that extend out from the myosin toward the actin. These cross bridges are part of the myosin proteins that extend from the axis of the thick filaments to form “arms” that terminate in globular “heads”. A myosin protein has two globular heads that serve as cross bridges. The orientation of the myosin heads on one side of a sarcomere is opposite to that of the other side, so that, when the myosin heads form cross bridges by attaching to actin on each side of the sarcomere, they can pull the actin from each side toward the center. Isolated muscles are easily stretched (although this is opposed in the body by the stretch reflex, described in a later section), demonstrating that the myosin heads are not attached to actin when the muscle is at rest. Each globular myosin head of a cross bridge contains an ATP-binding site closely associated with an actin-binding site. The globular heads function as myosin ATPase enzymes, splitting ATP into ADP and Pi. This reaction must occur before the myosin heads can bind to actin. When ATP is hydrolyzed to ADP and Pi, the phosphate binds to the myosin head, phosphorylating it and causing it to change its conformation so that it becomes “cocked” (by analogy to the hammer of a gun). The position of the myosin head has changed and it now has the potential energy required for contraction. Perhaps a more apt analogy is with a bow and arrow: The energized myosin head is like a pulled bowstring; it is now in position to bind to actin, right) so that its stored energy can be released in the next step. Once the myosin head binds to actin, forming a cross bridge, the bound Pi is released (the myosin head becomes dephosphorylated). This results in a conformational change in the myosin, causing the cross bridge to produce a power stroke. This is the force that pulls the thin filaments toward the center of the A band. After the power stroke, with the myosin head now in its flexed position, the bound ADP is released as a new ATP molecule binds to the myosin head. This release of ADP and binding to a new ATP is required for the myosin head to break its bond with actin after the power stroke is completed. The myosin head will then split ATP to ADP and Pi, and—if nothing prevents the binding of the myosin head to the actin—a new cross-bridge cycle will occur.

Note that the splitting of ATP is required before a cross bridge can attach to actin and undergo a power stroke, and that the attachment of a new ATP is needed for the cross bridge to release from actin at the end of a power stroke.  A single cross-bridge power stroke pulls the actin filament a distance of 6 nanometers (6 nm), and all of the cross bridges acting together in a single cycle will shorten the muscle by less than 1% of its resting length. Muscles can shorten up to 60% of their resting lengths, so the contraction cycles must be repeated many times. For this to occur the cross bridges must detach from the actin at the end of a power stroke, reassume their resting orientation, and then reattach to the actin and repeat the cycle. During normal contraction, however, only a portion of the cross bridges are attached at any given time. The power strokes are thus not in synchrony, as the strokes of a competitive rowing team would be. Rather, they are like the actions of a team engaged in tug-of-war, where the pulling action of the members is asynchronous. Some cross bridges are engaged in power strokes at all times during the contraction. The force produced by each power stroke is constant, but when the muscle’s load is greater, the number of cross bridges engaged in power strokes is increased to generate more force.

Regulation of Contraction

When the cross bridges attach to actin, they undergo power strokes and cause muscle contraction. In order for a muscle to relax, therefore, the attachment of myosin cross bridges to actin must be prevented. The regulation of cross-bridge attachment to actin is a function of two proteins that are associated with actin in the thin filaments. The actin filament—or F-actin —is a polymer formed of 300 to 400 globular subunits (G-actin), arranged in a double row and twisted to form a helix. A different type of protein, known as tropomyosin, lies within the groove between the double row of G-actin monomers. There are 40 to 60 tropomyosin molecules per thin filament, with each tropomyosin spanning a distance of approximately seven actin subunits.

Attached to the tropomyosin, rather than directly to the actin, is a third type of protein called troponin. Troponin is actually a complex of three proteins. These are troponin I (which inhibits the binding of the cross bridges to actin), troponin T (which binds to tropomyosin), and troponin C (which binds Ca²⁺). Troponin and tropomyosin work together to regulate the attachment of cross bridges to actin, and thus serve as a switch for muscle contraction and relaxation. In a relaxed muscle, the position of the tropomyosin in the thin filaments is such that it physically blocks the cross bridges from bonding to specific attachment sites in the actin. Thus, in order for the myosin cross bridges to attach to actin, the tropomyosin must be moved. This requires the interaction of troponin with Ca²⁺.

Twitch, Summation, and Tetanus

Contractions of isolated muscles in response to electrical shocks mimic the behavior of muscles when they contract within the body. When the muscle is stimulated with a single electric shock of sufficient voltage, it quickly contracts and relaxes. This response is called a twitch. Increasing the stimulus voltage increases the strength of the twitch, up to a maximum. The strength of a muscle contraction can thus be graded, or varied—an obvious requirement for the proper control of skeletal movements. If a second electric shock is delivered immediately after the first, it will produce a second twitch that may partially “ride piggyback” on the first. This response is called summation. Stimulation of fibers within a muscle in vitro with an electric stimulator, or in vivo by motor axons, usually results in the full contraction of the individual fibers. Stronger muscle contractions are produced by the stimulation of greater numbers of muscle fibers. Skeletal muscles can thus produce graded contractions, the strength of which depends on the number of fibers stimulated rather than on the strength of the contractions of individual muscle fibers. If the stimulator is set to deliver an increasing frequency of electric shocks automatically, the relaxation time between successive twitches will get shorter and shorter as the strength of contraction increases in amplitude. This effect is known as incomplete tetanus. Finally, at a particular “fusion frequency” of stimulation, there is no visible relaxation between successive twitches. Contraction is smooth and sustained, as it is during normal muscle contraction in vivo. This smooth, sustained contraction is called complete tetanus. The term tetanus should not be confused with the disease of the same name, which is accompanied by a painful state of muscle contracture, or tetany.

Muscle Fatigue: If a muscle repeatedly performs maximal acute or chronic submaximal work, the force of the contractions gradually decreases.  It is called as muscle fatigue.

Role of Ca²⁺ in Muscle Contraction

Scientists long thought that Ca 2 + only served to form the calcium phosphate crystals that hardened bone, enamel, and dentin. In 1883, Sidney Ringer published the results of a surprisingly simple experiment that changed that idea. He isolated rat hearts and found that they beat well when placed in isotonic solutions made with the hard water from a London tap. When he made the isotonic solutions with distilled water, however, the hearts gradually stopped beating. This could be reversed, he found, if he added Ca²⁺ to the solutions. This demonstrated a role for Ca²⁺ in muscle contraction, a role that scientists now understand in some detail.  In a relaxed muscle, when tropomyosin blocks the attachment of cross bridges to actin, the concentration of Ca²⁺ in the sarcoplasm (cytoplasm of muscle cells) is very low. When the muscle cell is stimulated to contract, mechanisms that will be discussed shortly cause the concentration of Ca²⁺ in the sarcoplasm to quickly rise. Some of this Ca²⁺ attaches to troponin, causing a conformational change that moves the troponin complex and its attached tropomyosin out of the way so that the cross bridges can attach to actin. Once the attachment sites on the actin are exposed, the cross bridges can bind to actin, undergo power strokes, and produce muscle contraction.

The position of the troponin-tropomyosin complexes in the thin filaments is thus adjustable. When Ca 2 + is not attached to troponin, the tropomyosin is in a position that inhibits attachment of myosin heads to actin, preventing muscle contraction. When Ca²⁺ attaches to troponin, the troponin-tropomyosin complexes shift position. The myosin heads can then attach to actin, produce a power stroke, and detach from actin. These contraction cycles can continue as long as Ca²⁺ is attached to troponin.

CARDIAC MUSCLE MORPHOLOGY

The striations in cardiac muscle are similar to those in skeletal muscle, and Z lines are present. Large numbers of elongated mitochondria are in close contact with the muscle fibrils. The muscle fibers branch and interdigitate, but each is a complete unit surrounded by a cell membrane. Where the end of one muscle fiber abuts on another, the membranes of both fibers parallel each other through an extensive series of folds. These areas, which always occur at Z lines, are called intercalated disks. They provide a strong union between fibers, maintaining cell-to-cell cohesion, so that the pull of one contractile cell can be transmitted along its axis to the next. Along the sides of the muscle fibers next to the disks, the cell membranes of adjacent fibers fuse for considerable distances, forming gap junctions. These junctions provide low-resistance bridges for the spread of excitation from one fiber to another. They permit cardiac muscle to function as if it were a syncytium, even though no protoplasmic bridges are present between cells. The T system in cardiac muscle is located at the Z lines rather than at the A–I junction, where it is located in mammalian skeletal muscle.

CONTRACTILE RESPONSE

The contractile response of cardiac muscle begins just after the start of depolarization and lasts about 1.5 times as long as the action potential. The role of Ca2+ in excitation—contraction coupling is similar to its role in skeletal muscle. However, it is the influx of extracellular Ca2+ through the voltage-sensitive DHPR (Dihydropyridine receptor) in the T system that trig­gers calcium-induced calcium release through the RyR (Ryanodine Receptor) at the sarcoplasmic reticulum. Because there is a net influx of Ca2+ during activation, there is also a more prominent role for plasma membrane Ca2+ ATPases and the Na+/Ca2+ exchanger in recovery of intracellular Ca2+ concentrations. During phases 0 to 2 and about half of phase 3 (until the membrane potential reaches approximately –50 mV during repolarization), cardiac muscle cannot be excited again; that is, it is in its absolute refractory period. It remains relatively refractory until phase 4. Therefore, tetanus of the type seen in skeletal muscle cannot occur. Of course, tetanization of cardiac muscle for any length of time would have lethal consequences, and in this sense, the fact that cardiac muscle cannot be tetanized is a safety feature [Ryanodine drug from Ryania speisosa which act as insecticide].

SMOOTH MUSCLE MORPHOLOGY

Smooth muscle is distinguished anatomically from skeletal and cardiac muscle because it lacks visible cross-striations. Actin and myosin-II are present, and they slide on each other to produce contraction. However, they are not arranged in regular arrays, as in skeletal and cardiac muscle, and so the striations are absent. Instead of Z lines, there are dense bodies in the cytoplasm and attached to the cell membrane, and these are bound by α-actinin to actin filaments. Smooth muscle also contains tropomyosin, but troponin appears to be absent. The isoforms of actin and myosin differ from those in skeletal mus­cle. A sarcoplasmic reticulum is present, but it is less extensive than those observed in skeletal or cardiac muscle. In general, smooth muscles contain few mitochondria and depend, to a large extent, on glycolysis for their metabolic needs.

TYPES

There is considerable variation in the structure and function of smooth muscle in different parts of the body. In general, smooth muscle can be divided into unitary (or visceral) smooth muscle and multiunit smooth muscle. Unitary smooth muscle occurs in large sheets, has many low-resistance gap junctional connections between individual muscle cells, and functions in a syncytial fashion. Unitary smooth muscle is found primarily in the walls of hollow viscera. The muscula­ture of the intestine, the uterus, and the ureters are examples. Multiunit smooth muscle is made up of individual units with few (or no) gap junctional bridges. It is found in structures such as the iris of the eye, in which fine, graded contractions occur. It is not under voluntary control, but it has many func­tional similarities to skeletal muscle. Each multiunit smooth muscle cell has en passant endings of nerve fibers, but in uni­tary smooth muscle there are en passant junctions on fewer cells, with excitation spreading to other cells by gap junctions. In addition, these cells respond to hormones and other circu­lating substances. Blood vessels have both unitary and multi­unit smooth muscle in their walls.

MOLECULAR BASIS OF CONTRACTION

As in skeletal and cardiac muscle, Ca2+ plays a prominent role in the initiation of contraction of smooth muscle. However, the source of Ca2+ increase can be quite different in unitary smooth muscle. Depending on the activating stimulus, Ca2+ increase can be due to influx through voltage- or ligand-gated plasma membrane channels, efflux from intracellular stores through the RyR, efflux from intracellular stores through the inositol trisphosphate receptor (IP3R) Ca2+ channel, or via a combi­nation of these channels. In addition, the lack of troponin in smooth muscle prevents Ca2+ activation via troponin binding. Rather, myosin in smooth muscle must be phosphorylated for activation of the myosin ATPase. Phosphorylation and dephosphorylation of myosin also occur in skeletal muscle, but phosphorylation is not necessary for activation of the ATPase. In smooth muscle, Ca2+ binds to calmodulin, and the result­ing complex activates calmodulin-dependent myosin light chain kinase. This enzyme catalyzes the phosphorylation of the myosin light chain on serine at position 19, increasing its ATPase activity.

Myosin is dephosphorylated by myosin light chain phosphatase in the cell. However, dephosphorylation of myosin light chain kinase does not necessarily lead to relaxation of the smooth muscle. Various mechanisms are involved. One appears to be a latch bridge mechanism by which myosin cross-bridges remain attached to actin for some time after the cytoplasmic Ca2+ concentration falls. This produces sustained contraction with little expenditure of energy, which is especially important in vascular smooth muscle. Relaxation of the muscle presumably occurs when the Ca2+-calmodulin complex finally dissociates or when some other mechanism comes into play. The events in multiunit smooth muscle are generally similar.  Unitary smooth muscle is unique in that, unlike other types of muscle, it contracts when stretched in the absence of any extrinsic innervation. Stretch is followed by a decline in membrane potential, an increase in the frequency of spikes, and a general increase in tone.  If epinephrine or norepinephrine is added to a preparation of intestinal smooth muscle arranged for recording of intra­cellular potentials in vitro, the membrane potential usually becomes larger, the spikes decrease in frequency, and the muscle relaxes. Acetylcholine has an effect opposite to that of norepinephrine on the membrane potential and con­tractile activity of intestinal smooth muscle.

TYPES OF CONTRACTION

Muscular contraction involves shortening of the contractile elements, but because muscles have elastic and viscous elements in series with the contractile mechanism, it is possible for contraction to occur without an appreciable decrease in the length of the whole muscle. Such a contraction is called isometric (“same measure” or length). Contraction against a constant load with a decrease in muscle length is isotonic (“same tension”). Note that because work is the product of force times distance, isotonic contractions do work, whereas isometric contractions do not. In other situations, muscle can do negative work while lengthening against a constant weight.