BIOLOGY WRITE-UP - BIOLOGY ARTICLES: GENERAL PHYSIOLOGY OF NERVOUS SYSTEM: central and peripheral nervous system, histology of nervous tissue (neuron, neuroglia, astrocyte, oligodendrites, microglia, ependymal cells, schwann cells, satellite cells, myelin sheath), elecrtical signals in neurons (ion channels, voltage gated channels, generation of action potential, propagation of action potential), neurotransmitters and neuropeptides.

General physiology: Nervous System

OBJECTIVES

• Describe the organization of the nervous system.

• Describe the three basic functions of the nervous system.

Organization of the Nervous System

The nervous system is one of the smallest and yet the most complex of the 11 body systems. This intricate network of billions of neurons and even more neuroglia is organized into two main subdivisions: the central nervous system and the peripheral nervous system.

Central Nervous System:

The central nervous system (CNS) consists of the brain and spinal cord .The brain is the part of the CNS that is located in the skull and contains about 100 billion (1011) neurons. The spinal cord is connected to the brain through the foramen magnum of the occipital bone and is encircled by the bones of the vertebral column. The spinal cord contains about 100 million neurons. The CNS processes many different kinds of incoming sensory information. It is also the source of thoughts, emotions, and memories. Most signals that stimulate muscles to contract and glands to secrete originate in the CNS.

Note: CNS has two parts brain and spinal cord. Axon tracts of pathways run longitudinally through the spinal cord. Some run down wards and some up wards. Afferent nerve fibers enter from the dorsal side of spinal cord and are called dorsal root, and form clumps called as dorsal groove ganglia. The efferent nerve fibers leave the spinal cord on the ventral side and make ventral roots. They come together and make a pair of spinal nerves.

Brain has three parts: fore brain, mid brain and hind brain. Fore brain has cerebrum and diencephalon. The mid brain, Pons and the medulla forms the brain stem which extends as the spinal cord. Hind brain has cerebellum. Along the brain stem, longitudinally relays the nerve fibers (both afferent and efferent). The small hyaline branched neurons of the core tissue of the brain forms the reticular formation which cluster and form the brain stem nuclei which is a integrating center has both ascending system and the descending system. The ascending system influences the afferent fibers while the descending system influences the efferent and sometimes also the afferent.

Peripheral Nervous System:

The peripheral nervous system (PNS) (pe-RIF-e-ral) consists of all nervous tissue outside the CNS. Components of the PNS include nerves, ganglia, enteric plexuses, and sensory receptors. A nerve is a bundle of hundreds to thousands of axons plus associated connective tissue and blood vessels that lays out- side the brain and spinal cord. Twelve pairs of cranial nerves emerge from the brain and thirty-one pairs of spinal nerves emerge from the spinal cord. Each nerve follows a deﬁned path and serves a speciﬁc region of the body. Ganglia (GANG-gle¯-a swelling or knot; singular is ganglion) are small masses of nervous tissue, consisting primarily of neuron cell bodies, that are located outside of the brain and spinal cord. Ganglia are closely associated with cranial and spinal nerves. Enteric plexuses (PLEK-sus-ez) are extensive networks of neurons located in the walls of organs of the gastrointestinal tract. The neurons of these plexuses help regulate the digestive system. The term sensory receptor refers to a structure of the nervous system that monitors changes in the external or internal environment. Examples of sensory receptors include touch receptors in the skin, photoreceptors in the eye, and olfactory receptors in the nose. The PNS is divided into a somatic nervous system (SNS) (so¯- MAT-ik; soma body), an autonomic nervous system (ANS) (aw-to¯-NOM-ik; auto- self; -nomic law), and an enteric nervous system (ENS) (en-TER-ik; enteron intestines). The SNS consists of (1) sensory neurons that convey information from somatic receptors in the head, body wall, and limbs and from receptors for the special senses of vision, hearing, taste, and smell to the CNS and (2) motor neurons that conduct impulses from the CNS to skeletal muscles only. Because these motor responses can be consciously controlled, the action of this part of the PNS is voluntary. The ANS consists of (1) sensory neurons that convey information from autonomic sensory receptors, located primarily in visceral organs such as the stomach and lungs, to the CNS and (2) motor neurons that conduct nerve impulses from the CNS to smooth muscle, cardiac muscle, and glands. Because its motor responses are not normally under conscious control, the action of the ANS is involuntary. The motor part of the ANS consists of two branches, the sympathetic division and the parasympathetic division. With a few exceptions, effectors receive nerves from both divisions, and usually the two divisions have opposing actions. For example, sympathetic neurons increase heart rate, and parasympathetic neurons slow it down. In general, the sympathetic division helps support exercise of emergency actions, the “ﬁght-or-ﬂight” responses, and the parasympathetic division takes care of “rest-and-digest” activities. The operation of the ENS, the “brain of the gut,” is involuntary. Once considered part of the ANS, the ENS consists of over 100 million neurons in enteric plexuses that extend most of the length of the gastrointestinal (GI) tract. Many of the neurons of the enteric plexuses function independently of the ANS and CNS to some extent, although they also communicate with the CNS via sympathetic and parasympathetic neurons. Sensory neurons of the ENS monitor chemical changes within the GI tract as well as the stretching of its walls. Enteric motor neurons govern contraction of GI tract smooth muscle to propel food through the GI tract, secretions of the GI tract organs such as acid from the stomach, and activity of GI tract endocrine cells, which secrete hormones.

The neurons of the PNS lie outside of the CNS and their clusters are called as the ganglia. Somatic system controls the skeletal muscles and their axon terminals release the neurotransmitters into the neuro muscular junction. These neuro transmitters are generally acetyl choline.

Functions of the Nervous System

The nervous system carries out a complex array of tasks. It allows us to sense various smells, produce speech, and remember past events; in addition, it provides signals that control body movements and regulates the operation of internal organs. These diverse activities can be grouped into three basic functions: sensory (input), integrative (process), and motor (output).

• Sensory function. Sensory receptors detect internal stimuli, such as an increase in blood pressure, or external stimuli (for example, a raindrop landing on your arm). This sensory information is then carried into the brain and spinal cord through cranial and spinal nerves.

• Integrative function. The nervous system processes sensory information by analyzing it and making decisions for appropriate responses—an activity known as integration.

• Motor function. Once sensory information is integrated, the nervous system may elicit an appropriate motor response by activating effectors (muscles and glands) through cranial and spinal nerves. Stimulation of the effectors causes muscles to contract and glands to secrete.

The three basic functions of the nervous system occur, for example, when you answer your cell phone after hearing it ring. The sound of the ringing cell phone stimulates sensory receptors in your ears (sensory function). This auditory information is subsequently relayed into your brain where it is processed and the decision to answer the phone is made (integrative function). The brain then stimulates the contraction of speciﬁc muscles that will allow you to grab the phone and press the appropriate button to answer it (motor function).

HISTOLOGY OF NERVOUS TISSUE

OBJECTIVES

• Contrast the histological characteristics and the functions of neurons and neuroglia.

• Distinguish between gray matter and white matter.

Nervous tissue comprises two types of cells—neurons and neuroglia. These cells combine in a variety of ways in different regions of the nervous system. In addition to forming the complex processing networks within the brain and spinal cord, neurons also connect all regions of the body to the brain and spinal cord. As highly specialized cells capable of reaching great lengths and making extremely intricate connections with other cells, neurons provide most of the unique functions of the nervous system, such as sensing, thinking, remembering, controlling muscle activity, and regulating glandular secretions. As a result of their specialization, they have lost the ability to undergo mitotic divisions. Neuroglia are smaller cells but they greatly outnumber neurons, perhaps by as much as 25 times. Neuroglia supports, nourishes, and protects neurons, and maintain the interstitial ﬂuid that bathes them. Unlike neurons, neuroglia continue to divide throughout an individual’s lifetime. Both neurons and neuroglia differ structurally depending on whether they are located in the central nervous system or the peripheral nervous system. These differences in structure correlate with the differences in function of the central nervous system and the peripheral nervous system.

Neurons

Like muscle cells, neurons (nerve cells) (NOO-rons) possess electrical excitability (ek-s¯ıt-a-BIL-i-te¯), the ability to respond to a stimulus and convert it into an action potential. A stimulus is any change in the environment that is strong enough to initiate an action potential. An action potential (nerve impulse) is an electrical signal that propagates (travels) along the surface of the membrane of a neuron. It begins and travels due to the movement of ions (such as sodium and potassium) between interstitial ﬂuid and the inside of a neuron through speciﬁc ion channels in its plasma membrane. Once begun, a nerve impulse travels rapidly and at a constant strength. Some neurons are tiny and propagate impulses over a short distance (less than 1 mm) within the CNS. Others are the longest cells in the body. The neurons that enable you to wiggle your toes, for example, extend from the lumbar region of your spinal cord (just above waist level) to the muscles in your foot. Some neurons are even longer. Those that allow you to feel a feather tickling your toes stretch all the way from your foot to the lower portion of your brain. Nerve impulses travel these great distances at speeds ranging from 0.5 to 130 meters per second (1 to 290 mi/hr).

Parts of Neuron Most neurons have three parts:

(1) a cell body, (2) dendrites, and (3) an axon the cell body, also known as the perikaryon (per-i-KAR-e¯-on) or soma, contains a nucleus surrounded by cytoplasm that includes typical cellular organelles such as lysosomes, mitochondria, and a Golgi complex. Neuronal cell bodies also contain free ribosomes and prominent clusters of rough endoplasmic reticulum, termed Nissl bodies (NIS-el). The ribosomes are the sites of protein synthesis. Newly synthesized proteins produced by Nissl bodies are used to replace cellular components, as material for growth of neurons, and to regenerate damaged axons in the PNS. The cytoskeleton includes both neuroﬁbrils (noo-ro¯-FI ¯-brils), composed of bundles of intermediate ﬁlaments that provide the cell shape and support, and microtubules (mı¯-kro¯-TOO-bu¯ls), which assist in moving materials between the cell body and axon. Aging neurons also contain lipofuscin (l¯ıp-o-FYU ¯S-¯ın), a pigment that occurs as clumps of yellowish brown granules in the cytoplasm. Lipofuscin is a product of neuronal lysosomes that accumulates as the neuron ages, but does not seem to harm the neuron as it ages. A nerve ﬁber is a general term for any neuronal process (extension) that emerges from the cell body of a neuron. Most neurons have two kinds of processes: multiple dendrites and a single axon. Dendrites (DEN-dr¯ıts little trees) are the receiving or input portions of a neuron. The plasma membranes of dendrites (and cell bodies) contain numerous receptor sites for binding chemical messengers from other cells. Dendrites usually are short, tapering, and highly branched. In many neurons the dendrites form a tree- shaped array of processes extending from the cell body. Their cytoplasm contains Nissl bodies, mitochondria, and other organelles. The single axon (axis) of a neuron propagates nerve impulses toward another neuron, a muscle ﬁber, or a gland cell. An axon is a long, thin, cylindrical projection that often joins to the cell body at a cone-shaped elevation called the axon hillock (HIL- lok small hill). The part of the axon closest to the axon hillock is the initial segment. In most neurons, nerve impulses arise at the junction of the axon hillock and the initial segment, an area called the trigger zone, from which they travel along the axon to their destination. An axon contains mitochondria, microtubules, and neuroﬁbrils. Because rough endoplasmic reticulum is not present, protein synthesis does not occur in the axon. The cytoplasm of an axon, called axoplasm, is surrounded by a plasma membrane known as the axolemma (lemma sheath or husk). Along the length of an axon, side branches called axon collaterals may branch off, typically at a right angle to the axon. The axon and its collaterals end by dividing into many ﬁne processes called axon terminals (telodendria) (te¯l-o¯-DEN-dre¯-a). The site of communication between two neurons or between a neuron and an effector cell is called a synapse (SIN-aps). The tips of some axon terminals swell into bulb-shaped structures called synaptic end bulbs; others exhibit a string of swollen bumps called varicosities (var-i-KOS-i-te¯z). Both synaptic end bulbs and varicosities contain many tiny membrane-enclosed sacs called synaptic vesicles that store a chemical called a neurotransmitter (noo-ro¯- trans-MIT-ter). A neurotransmitter is a molecule released from a synaptic vesicle that excites or inhibits another neuron, muscle ﬁber, or gland cell. Many neurons contain two or even three types of neurotransmitters, each with different effects on the postsynaptic cell. Because some substances synthesized or recycled in the neuron cell body are needed in the axon or at the axon terminals, two types of transport systems carry materials from the cell body to the axon terminals and back. The slower system, which moves materials about 1–5 mm per day, is called slow axonal transport. It conveys axoplasm in one direction only—from the cell body toward the axon terminals. Slow axonal transport supplies new axoplasm to developing or regenerating axons and replenishes axoplasm in growing and mature axons. Fast axonal transport, which is capable of moving materials a distance of 200–400 mm per day, uses proteins that function as “motors” to move materials along the surfaces of microtubules of the neuron’s cytoskeleton. Fast axonal transport moves materials in both directions—away from and toward the cell body. Fast axonal transport that occurs in an anterograde (forward) direction moves organelles and synaptic vesicles from the cell body to the axon terminals. Fast axonal transport that occurs in a retrograde (backward) direction moves membrane vesicles and other cellular materials from the axon terminals to the cell body to be degraded or recycled. Substances that enter the neuron at the axon terminals are also moved to the cell body by fast retrograde transport. These substances include trophic chemicals such as nerve growth factor and harmful agents such as tetanus toxin and the viruses that cause rabies, herpes simplex, and polio.

Note:

Dendrites conduct impulse form other neurons meant for reception of the signal. They are just the branched outgrowths of cell/membrane. Surface area gets increased so as to receive max. Amount of the impulse.

Axon has got some divisions: the initial segment:- True electrical signals are generated here. The axon branches out and they are called as axon collaterals ; which further branch out and end up as axon terminals.

Chemical linkage: communication between the neurons occurs by the chemical linkage and not by physical linkage. Through the axon terminals the neuro transmitters are released into the synaptic cleft or the junction from where these neuro transmitters are taken up by the dendrites of other neurons having particular receptors.

The neuro transmitters are synthesized by the cell body of the neuron.

Axons also have some bulges which are called as vericosities.

Neuro filaments are the cytoskeletal materials which are responsible for the transportation of the impulse from cell body to the axon. Depending on the situation and the environment the neuron is exposed it may conduct the opposite signals and transport it, which changes the metabolic activity of the neuron.

Structural Diversity in Neurons displays great diversity in size and shape. For example, their cell bodies range in diameter from 5 micrometers (m) (slightly smaller than a red blood cell) up to 135 m (barely large enough to see with the unaided eye). The pattern of dendritic branching is varied and distinctive for neurons in different parts of the nervous system. A few small neurons lack an axon, and many others have very short axons. As we have already discussed, the longest axons are almost as long as a person is tall, extending from the toes to the lowest part of the brain.

Classiﬁcation of Neurons: Both structural and functional features are used to classify the various neurons in the body.

Based on the functional features of the neurons they are classified as follows:-

1). afferent neuron: those neurons which carry the signal from the peripheral organs to the CNS. Also called as sensory neurons. They either contain sensory receptors at their distal ends (dendrites) or are located just after sensory receptors that are separate cells. Once an appropriate stimulus activates a sensory receptor, the sensory neuron forms an action potential in its axon and the action potential is conveyed into the CNS through cranial or spinal nerves.

2). Efferent neurons: those neurons which carry the signal from the CNS to the peripheral organs. Also called as motor neurons. They convey action potentials away from the CNS to effectors (muscles and glands) in the periphery (PNS) through cranial or spinal nerves

3). Inter neurons: these neurons interlinks between the afferent and efferent neurons. 99% of the total neurons in our body are inter neurons. Also called as association neurons. Inter neurons integrate (process) incoming sensory information from sensory neurons and then elicit a motor response by activating the appropriate motor neurons. Most interneurons are multipolar in structure

Analogy: For every afferent neuron there will be 10 efferent neurons and 200,000 inter neurons.

Note: the first neuron is called as the pre synaptic neuron. The second neuron which carries the impulse away from the synapse is called as the post synaptic neuron. The post synaptic neuron may have 1000”s of junctions to receive impulse from multiple neurons. Not all the junctions are permanent they may be changing and not all the junctions are active at a time.

Neuroglia

Neuroglia or glia make up about half the volume of the CNS. Their name derives from the idea of early histologists that they were the “glue” that held nervous tissue together. We now know that neuroglia are not merely passive bystanders but rather actively participate in the activities of nervous tissue. Generally, neuroglia are smaller than neurons, and they are 5 to 25 times more numerous. In contrast to neurons, glia do not generate or propagate action potentials, and they can multiply and divide in the mature nervous system. In cases of injury or disease, neuroglia multiply to ﬁll in the spaces formerly occupied by neurons. Brain tumors derived from glia, called gliomas (gle¯-O ¯-mas), tend to be highly malignant and to grow rapidly. Of the six types of neuroglia, four—astrocytes, oligodendrocytes, microglia, and ependymal cells—are found only in the CNS. The remaining two types—Schwann cells and satellite cells—are present in the PNS.

Neuroglia of the CNS Neuroglia of the CNS can be classiﬁed on the basis of size, cytoplasmic processes, and intracellular organization into four types: astrocytes, oligodendrocytes, microglia, and ependymal cells.

ASTROCYTES

These star- shaped cells have many processes and are the largest and most numerous of the neuroglia. There are two types of astrocytes. Protoplasmic astrocytes have many short branching processes and are found in gray matter (described shortly). Fibrous astrocytes have many long unbranched processes and are located mainly in white matter (also described shortly). The processes of astrocytes make contact with blood capillaries, neurons, and the pia mater (a thin membrane around the brain and spinal cord). The functions of astrocytes include the following:

(1) Astrocytes contain microﬁlaments that give them considerable strength, which enables them to support neurons.

(2) Processes of astrocytes wrapped around blood capillaries isolate neurons of the CNS from various potentially harmful substances in blood by secreting chemicals that maintain the unique selective permeability characteristics of the endothelial cells of the capillaries. In effect, the endothelial cells create a blood–brain barrier, which restricts the movement of substances between the blood and interstitial ﬂuid of the CNS. Details of the blood–brain barrier. In the embryo, astrocytes secrete chemicals that appear to regulate the growth, migration, and interconnection among neurons in the brain. (4) Astrocytes help to maintain the appropriate chemical environment for the generation of nerve impulses. For example, they regulate the concentration of important ions such as k take up excess neurotransmitters; and serve as a conduit for the passage of nutrients and other substances between blood capillaries and neurons.

(5) Astrocytes may also play a role in learning and memory by inﬂuencing the formation of neural synapses.

OLIGODENDROCYTES

These resemble astrocytes but are smaller and contain fewer processes. Oligodendrocyte processes are responsible for forming and maintaining the myelin sheath around CNS axons. As you will see shortly, the myelin sheath is a multilayered lipid and protein covering around some axons that insulates them and increases the speed of nerve impulse conduction. Such axons are said to be myelinated.

MICROGLIA

these neuroglia are small cells with slender processes that give off numerous spine like projections. Microglia function as phagocytes. Like tissue macrophages, they remove cellular debris formed during normal development of the nervous system and phagocytize microbes and damaged nervous tissue

EPENDYMAL CELLS

Ependymal cells are cuboidal to columnar cells arranged in a single layer that possess microvilli and cilia. These cells line the ventricles of the brain and central canal of the spinal cord (spaces ﬁlled with cerebrospinal ﬂuid, which protects and nourishes the brain and spinal cord). Functionally, ependymal cells produce, possibly monitor, and assist in the circulation of cerebrospinal ﬂuid. They also form the blood–cerebrospinal ﬂuid barrier.

Neuroglia of the PNS: Neuroglia of the PNS completely surround axons and cell bodies. The two types of glial cells in the PNS are Schwann cells and satellite cells.

SCHWANN CELLS (SCHVON or SCHWON)

these cells encircle PNS axons. Like oligodendrocytes, they form the myelin sheath around axons. However, a single oligodendrocyte myelinates several axons, but each Schwann cell myelinates a single axon c). A single Schwann cell can also enclose as many as 20 or more unmyelinated axons (axons that lack a myelin sheath). Schwann cells participate in axon regeneration, which is more easily accomplished in the PNS than in the CNS.

SATELLITE CELLS

These ﬂat cells surround the cell bodies of neurons of PNS ganglia. Besides pro- viding structural support, satellite cells regulate the exchanges of materials between neuronal cell bodies and interstitial -ﬂuid.

Myelination As you have already learned, axons surrounded by a multilayered lipid and protein covering, called the myelin sheath, are said to be myelinated. The sheath electrically insulates the axon of a neuron and increases the speed of nerve impulse conduction. Axons without such a covering are said to be unmyelinated. Two types of neuroglia produce myelin sheaths: Schwann cells (in the PNS) and oligodendrocytes (in the CNS). Schwann cells begin to form myelin sheaths around axons during fetal development. Each Schwann cell wraps about 1 millimeter (1 mm 0.04 in.) of a single axon’s length by spiraling many times around the axon. Eventually, multiple layers of glial plasma membrane surround the axon, with the Schwann cell’s cytoplasm and nucleus forming the outermost layer. The inner portion, consisting of up to 100 layers of Schwann cell membrane, is the myelin sheath. The outer nucleated cytoplasmic layer of the Schwann cell, which encloses the myelin sheath, is the neurolemma (sheath of Schwann). A neurolemma is found only around axons in the PNS. When an axon is injured, the neurolemma aids regeneration by forming a regeneration tube that guides and stimulates regrowth of the axon. Gaps in the myelin sheath, called nodes of Ranvier appear at intervals along the axon. Each Schwann cell wraps one axon segment between two nodes. In the CNS, an oligodendrocyte myelinates parts of several axons. Each oligodendrocyte puts forth about 15 broad, ﬂat processes that spiral around CNS axons, forming a myelin sheath. A neurolemma is not present, however, because the oligodendrocyte cell body and nucleus do not envelop the axon. Nodes of Ranvier are present, but they are fewer in number. Axons in the CNS display little regrowth after injury. This is thought to be due, in part, to the absence of a neurolemma, and in part to an inhibitory inﬂuence exerted by the oligodendrocytes on axon regrowth. The amount of myelin increases from birth to maturity, and its presence greatly increases the speed of nerve impulse conduction. An infant’s responses to stimuli are neither as rapid nor as coordinated as those of an older child or an adult, in part because myelination is still in progress during infancy.

Clusters of Neuronal Cell Bodies Recall that a ganglion (plural is ganglia) refers to a cluster of neuronal cell bodies located in the PNS. As mentioned earlier, ganglia are closely associated with cranial and spinal nerves. By contrast, a nucleus is a cluster of neuronal cell bodies located in the CNS.

Composition and function of myelin sheath

Myelin is a dielectric (electrically insulating) material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. It is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination. In humans, the production of myelin begins in the 14th week of fetal development, although little myelin exists in the brain at the time of birth. During infancy, myelination occurs quickly and continues through the adolescent stages of life.

Schwann cells supply the myelin for peripheral neurons, whereas oligodendrocytes, specifically of the interfascicular type, myelinate the axons of the central nervous system. Myelin is considered a defining characteristic of the (gnathostome) vertebrates, but myelin-like sheaths have also arisen by parallel evolution in some invertebrates, although they are quite different from vertebrate myelin at the molecular level. Myelin was discovered in 1854 by Rudolf Virchow.

Myelin is made up by different cell types, and varies in chemical composition and configuration, but performs the same insulating function. Myelinated axons are white in appearance, hence the "white matter" of the brain. The fat helps to insulate the axons from electrically charged atoms and molecules. These charged particles (ions) are found in the fluid surrounding the entire nervous system. Under a microscope, myelin looks like strings of sausages. Myelin is also a part of the maturation process leading to a child's fast development, including crawling and walking in the first year.

Myelin is about 40% water; the dry mass is about 70 - 85% lipids and about 15 - 30% proteins. Some of the proteins are myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein. The primary lipid of myelin is a glycolipid called galactocerebroside. The intertwining hydrocarbon chains of sphingomyelin serve to strengthen the myelin sheath.

The main purpose of a myelin layer (or sheath) is to increase the speed at which impulses propagate along the myelinated fiber. Along unmyelinated fibers, impulses move continuously as waves, but in myelinated fibers, they hop or "propagate by saltation." Myelin decreases capacitance across the cell membrane, and increases electrical resistance. Thus, myelination helps prevent the electrical current from leaving the axon. It has been suggested that myelin permits larger body size by maintaining agile communication between distant body parts.

When a peripheral fiber is severed, the myelin sheath provides a track along which regrowth can occur. Unfortunately, the myelin layer does not ensure a perfect regeneration of the nerve fiber. Some regenerated nerve fibers do not find the correct muscle fibers and some damaged motor neurons of the peripheral nervous system die without regrowth. Damage to the myelin sheath and nerve fiber is often associated with increased functional insufficiency.

Unmyelinated fibers and myelinated axons of the mammalian central nervous system do not regenerate.

Some studies have revealed optic nerve fibers can be regenerated in postnatal rats. This regeneration depends upon two conditions: axonal die-back has to be prevented with appropriate neurotrophic factors and neurite growth inhibitory components have to be inactivated. These studies may lead to further understanding of nerve fiber regeneration in the central nervous system.

Review:

Overview of the Nervous System

1. The central nervous system (CNS) consists of the brain and spinal cord.

2. The peripheral nervous system (PNS) consists of all nervous tissue outside the CNS. Components of the PNS include nerves, ganglia, enteric plexuses, and sensory receptors.

3. The PNS is divided into a somatic nervous system (SNS), autonomic nervous system (ANS), and enteric nervous system (ENS).

4. The SNS consists of sensory neurons that conduct impulses from somatic and special sense receptors to the CNS and motor neurons from the CNS to skeletal muscles.

5. The ANS contains sensory neurons from visceral organs and motor neurons that convey impulses from the CNS to smooth muscle tissue, cardiac muscle tissue, and glands.

6. The ENS consists of neurons in enteric plexuses in the gastrointestinal (GI) tract that function some- what independently of the ANS and CNS. The ENS monitors chemical changes within the GI tract and stretching of its walls; the ENS also controls contraction of GI tract smooth muscle.

7. The nervous system helps maintain homeostasis and integrates all body activities by sensing changes (sensory function), interpreting them (integrative function), and reacting to them (motor function).

Histology of Nervous Tissue .

Nervous tissue consists of neurons (nerve cells) and neuroglia. Neurons have the property of electrical excitability and are responsible for most unique functions of the nervous system:

1. sensing, thinking, remembering, controlling muscle activity, and regulating glandular secretions.

2. Most neurons have three parts. The dendrites are the main receiving or input region. Integration occurs in the cell body, which includes typical cellular organelles. The output part typically is a single axon, which propagates nerve impulses toward another neuron, a muscle ﬁber, or a gland cell.

3. Synapses are the site of functional contact between two excitable cells. Axon terminals contain synaptic vesicles ﬁlled with neurotransmitter molecules.

4. Slow axonal transport and fast axonal transport are systems for conveying materials to and from the cell body and axon terminals.

5. On the basis of their structure, neurons are classiﬁed as multipolar, bipolar, or unipolar.

6. Neurons are functionally classiﬁed as sensory (afferent) neurons, motor (efferent) neurons, and interneurons. Sensory neurons carry sensory information into the CNS. Motor neurons carry information out of the CNS to effectors (muscles and glands). Interneurons are located within the CNS between sensory and motor neurons.

7. Neuroglia support, nurture, and protect neurons and maintain the interstitial ﬂuid that bathes them. Neuroglia in the CNS include astrocytes, oligodendrocytes, microglia, and ependymal cells. Neuroglia in the PNS include Schwann cells and satellite cells.

8. Two types of neuroglia produce myelin sheaths: Oligodendrocytes myelinate axons in the CNS, and Schwann cells myelinate axons in the PNS.

9. White matter consists of aggregates of myelinated axons; gray matter contains cell bodies, dendrites, and axon terminals of neurons, unmyelinated axons, and neuroglia.

10. In the spinal cord, gray matter forms an H-shaped inner core that is surrounded by white matter in the brain, a thin; superﬁcial shell of gray matter covers the cerebral and cerebellar hemispheres.

ELECTRICAL SIGNALS IN NEURONS

OBJECTIVES

• Describe the cellular properties that permit communication among neurons and effectors.

• Compare the basic types of ion channels, and explain how they relate to graded potentials and action potentials.

• Describe the factors that maintain a resting membrane potential.

• List the sequence of events that generate an action potential.

Like muscle ﬁbers, neurons are electrically excitable. They communicate with one another using two types of electrical signals: (1) Graded potentials are used for short-distance communication only.

(2) Action potentials allow communication over long distances within the body. Recall that an action potential in a muscle ﬁber is called a muscle action potential.

When an action potential occurs in a neuron (nerve cell), it is called a nerve action potential (nerve impulse).

The production of graded potentials and action potentials depends on two basic features of the plasma membrane of excitable cells: the existence of a resting membrane potential and the presence of speciﬁc types of ion channels. Like most other cells in the body, the plasma membrane of excitable cells exhibits a membrane potential, an electrical potential difference (voltage) across the membrane. In excitable cells, this voltage is termed the resting membrane potential. The membrane potential is like voltage stored in a battery. If you connect the positive and negative terminals of a battery with a piece of wire, electrons will ﬂow along the wire. This ﬂow of charged particles is called current. In living cells, the ﬂow of ions (rather than electrons) constitutes the electrical current.

Graded potentials and action potentials occur because the membranes of neurons contain many different kinds of ion channels that open or close in response to speciﬁc stimuli. Because the lipid bilayer of the plasma membrane is a good electrical insulator, the main paths for current to ﬂow across the membrane are through the ion channels.

Ion Channels When ion channels are open, they allow speciﬁc ions to move across the plasma membrane, down their electrochemical gradient—a concentration (chemical) difference plus an electrical difference. Recall that ions move from areas of higher concentration to areas of lower concentration (the chemical part of the gradient). Also, positively charged cations move toward a negatively charged area, and negatively charged anions move toward a positively charged area (the electrical aspect of the gradient). As ions move, they create a ﬂow of electrical current that can change the membrane potential. Ion channels open and close due to the presence of “gates.” The gate is a part of the channel protein that can seal the channel pore shut or move aside to open the pore. The electrical signals produced by neurons and muscle ﬁbers rely on four types of ion channels: leakage channels, ligand-gated channels, mechanically gated channels, and voltage-gated channels.

1. The gates of leakage channels randomly alternate between open and closed positions. Typically, plasma membranes have many more potassium ion (K) leakage channels than sodium ion (Na) leakage channels, and the potassium ion leakage channels are leakier than the sodium ion leakage channels. Thus, the membrane’s permeability to K is much higher than its permeability to Na.

2. A ligand-gated channel opens and closes in response to a speciﬁc chemical stimulus. A wide variety of chemical ligands— including neurotransmitters, hormones, and particular ions—can open or close ligand-gated channels. The neurotransmitter acetyl- choline, for example, opens cation channels that allow Na and Ca2 to diffuse inward and K to diffuse outward

3. A mechanically gated channel opens or closes in response to mechanical stimulation in the form of vibration (such as sound waves), touch, pressure, or tissue stretching. The force distorts the channel from its resting position, opening the gate. Examples of mechanically gated channels are those found in auditory receptors in the ears, in receptors that monitor stretching of internal organs, and in touch receptors and pressure receptors in the skin.

4. A voltage-gated channel opens in response to a change in membrane potential (voltage). Voltage-gated channels participate in the generation and conduction of action potentials.

Resting Membrane Potential

The resting membrane potential exists because of a small buildup of negative ions in the cytosol along the inside of the membrane, and an equal buildup of positive ions in the extra- cellular ﬂuid along the outside surface of the membrane. Such a separation of positive and negative electrical charges is a form of potential energy, which is measured in mili volts (1 mV 0.001 V). The greater the difference in charge across the membrane, the larger the membrane potential (voltage). The buildup of charge occurs only very close to the membrane. The cytosol or extracellular ﬂuid elsewhere in the cell contains equal numbers of positive and negative charges and is electrically neutral. The resting membrane potential of a cell can be measured in the following way: The tip of a recording microelectrode is inserted inside the cell, and a reference electrode is placed outside the cell in the extracellular ﬂuid. Electrodes are devices that con- duct electrical charges. The recording microelectrode and the reference electrode are connected to an instrument known as a voltmeter, which detects the electrical difference (voltage) across the plasma membrane. In neurons, the resting membrane potential ranges from 40 to 90 mV. A typical value is 70 mV. The minus sign indicates that the inside of the cell is negative relative to the outside. A cell that exhibits a membrane potential is said to be polarized. Most body cells are polarized; the membrane potential varies from 5 mV to 100 mV in different types of cells. The resting membrane potential arises from three major factors: 1. Unequal distribution of ions in the ECF and cytosol. A major factor that contributes to the resting membrane potential is the unequal distribution of various ions in extracellular ﬂuid and cytosol. Extracellular ﬂuid is rich in Na and chloride ions (Cl). In cytosol, however, the main cation is K and the two dominant anions are phosphates attached to molecules, such as the three phosphates in ATP, and amino acids in proteins. Because the plasma membrane typically has more K leakage channels than Na leakage channels, the number of potassium ions that diffuse down their concentration gradient out of the cell into the ECF is greater than the number of sodium ions that diffuse down their concentration gradient from the ECF into the cell. As more and more positive potassium ions exit, the in- side of the membrane becomes increasingly negative, and the outside of the membrane becomes increasingly positive. 2. Inability of most anions to leave the cell. Another factor contributes to the inside-negative resting membrane potential: Most anions inside the cell are not free to leave. They cannot follow the K out of the cell because they are attached to non-diffusible molecules such as ATP and large proteins. 3. Electrogenic nature of the Na K ATPases. Membrane permeability to Na is very low because there are only a few sodium leakage channels. Nevertheless, sodium ions do slowly diffuse inward, down their concentration gradient. Left unchecked, such inward leakage of Na would eventually destroy the resting membrane potential. The small inward Na leak and outward K leak are offset by the Na K ATPases (sodium–potassium pumps). These pumps help maintain the resting membrane potential by pumping out Na as fast as it leaks in. At the same time, the Na/K ATPases bring in K However, the potassium ions eventually leak back out of the cell as they move down their concentration gradient. Recall that the Na/K ATPases expel three Na for each two K imported. Since these pumps remove more positive charges from the cell than they bring into the cell, they are electrogenic, which means they contribute to the negativity of the resting membrane potential. Their total contribution, however, is very small: only 3 mV of the total 70 mV resting membrane potential in a typical neuron.

Graded Potentials

A graded potential is a small deviation from the membrane potential that makes the membrane either more polarized (inside more negative) or less polarized (inside less negative). When the response makes the membrane more polarized (inside more negative), it is termed a hyperpolarizing graded potential. When the response makes the membrane less polarized (inside less negative), it is termed a depolarizing graded potential. A graded potential occurs when a stimulus causes mechanically gated or ligand-gated channels to open or close in an excitable cell’s plasma membrane. Typically, mechanically gated channels and ligand-gated channels can be present in the dendrites of sensory neurons, and ligand-gated channels are numerous in the dendrites and cell bodies of inter neurons and motor neurons. Hence, graded potentials occur mainly in the dendrites and cell body of a neuron. To say that these electrical signals are graded means that they vary in amplitude (size), depending on the strength of the stimulus. They are larger or smaller depending on how many ligand-gated or mechanically gated channels have opened (or closed) and how long each remains open. The opening or closing of these ion channels alters the ﬂow of speciﬁc ions across the membrane, producing a ﬂow of current that is localized, which means that it spreads to adjacent regions along the plasma membrane in either direction from the stimulus source for a short distance and then gradually dies out as the charges are lost across the membrane through leakage channels. This mode of travel by which graded potentials die out as they spread along the membrane is known as decremental conduction. Because they die out within a few millimeters of their point of origin, graded potentials are useful for short-distance communication only. Although an individual graded potential undergoes decremental conduction, it can become stronger and last longer by sum- mating with other graded potentials. Summation is the process by which graded potentials add together. If two depolarizing graded potentials summate, the net result is a larger depolarizing graded potential. If two hyperpolarizing graded potentials summate, the net result is a larger hyperpolarizing graded potential. If two equal but opposite graded potentials summate (one depolarizing and the other hyperpolarizing), then they cancel each other out and the overall graded potential disappears. You will learn more about the process of summation later in this chapter. Graded potentials have different names depending on which type of stimulus causes them and where they occur. For example, when a graded potential occurs in the dendrites or cell body of a neuron in response to a neurotransmitter, it is called a post- synaptic potential (explained shortly). On the other hand, the graded potentials that occur in sensory receptors and sensory neurons are termed receptor potentials and generator potentials.

Generation of Action Potentials

An action potential (AP) or impulse is a sequence of rapidly occurring events that decrease and reverse the membrane potential and then eventually restore it to the resting state. An action potential has two main phases: a depolarizing phase and a repolarizing phase. During the depolarizing phase, the negative membrane potential becomes less negative, reaches zero, and then becomes positive. During the repolarizing phase, the membrane potential is restored to the resting state of 70 mV. Following the repolarizing phase there may be an after-hyperpolarizing phase, during which the membrane potential temporarily becomes more negative than the resting level. Two types of voltage-gated channels open and then close during an action potential. These channels are present mainly in the axon plasma membrane and axon terminals. The ﬁrst channels that open, the voltage-gated Na channels, allow Na to rush into the cell, which causes the depolarizing phase. Then voltage-gated K channels open, allowing K to ﬂow out, which produces the repolarizing phase. The after-hyperpolarizing phase occurs when the voltage-gated K channels remain open after the repolarizing phase ends. An action potential occurs in the membrane of the axon of a neuron when depolarization reaches a certain level termed the threshold (about 55 mV in many neurons). Different neurons may have different thresholds for generation of an action potential, but the threshold in a particular neuron usually is constant. The generation of an action potential depends on whether a particular stimulus is able to bring the membrane potential to threshold. An action potential will not occur in response to a sub- threshold stimulus, a stimulus that is a weak depolarization that cannot bring the membrane potential to threshold. However, an action potential will occur in response to a threshold stimulus, a stimulus that is just strong enough to de- polarize the membrane to threshold. Several action potentials will form in response to a supra threshold stimulus, a stimulus that is strong enough to depolarize the membrane above threshold. Each of the action potentials caused by a supra threshold stimulus has the same amplitude (size) as an action potential caused by a threshold stimulus. Therefore, once an action potential is generated, the amplitude of an action potential is always the same and does not depend on stimulus intensity. Instead, the greater the stimulus strength above threshold, the greater the frequency of the action potentials until a maximum frequency is reached as determined by the absolute refractory period (described shortly). As you have just learned, an action potential is generated in response to a threshold stimulus, but does not form when there is a sub threshold stimulus. In other words, an action potential either occurs completely or it does not occur at all. This characteristic of an action potential is known as the all-or-none principle. The all-or-none principle of the action potential is similar to pushing the ﬁrst domino in a long row of standing dominoes. When the push on the ﬁrst domino is strong enough (when depolarization reaches threshold), that domino falls against the second domino, and the entire row topples (an action potential occurs). Stronger pushes on the ﬁrst domino produce the identical effect—toppling of the entire row. Thus, pushing on the ﬁrst domino produces an all-or-none event: The dominoes all fall or none fall.

Depolarizing Phase: When a depolarizing graded potential or some other stimulus causes the membrane of the axon to depolarize to threshold, voltage-gated Na channels open rapidly. Both the electrical and the chemical gradients favor inward movement of Na and the resulting in rush of Na causes the depolarizing phase of the action potential. The inﬂow of Na changes the membrane potential from 55 mV to 30 mV. At the peak of the action potential, the inside of the membrane is 30 mV more positive than the outside. Each voltage-gated Na channel has two separate gates, an activation gate and an inactivation gate. In the resting state of a voltage-gated Na channel, the inactivation gate is open, but the activation gate is closed. As a result, Na cannot move into the cell through these channels. At thresh- old, voltage-gated Na channels are activated. In the activated state of a voltage-gated Na channel, both the activation and in- activation gates in the channel are open and Na inﬂow begins. As more channels open, Na inﬂow in- creases, the membrane depolarizes further, and more Na channels open. This is an example of a positive feedback mechanism. During the few ten-thousandths of a second that the voltage- gated Na channel is open, about 20,000 Na ﬂow across the membrane and change the membrane potential considerably. But the concentration of Na hardly changes because of the millions of Na present in the extracellular ﬂuid. The sodium–potassium pumps easily bail out the 20,000 or so Na that enter the cell during a single action potential and maintain the low concentration of Na inside the cell.

Repolarizing Phase: Shortly after the activation gates of the voltage-gated Na channels open, the inactivation gates close. Now the voltage-gated Na channel is in an inactivated state. In addition to opening voltage-gated Na channels, a threshold- level depolarization also opens voltage-gated K channels. Because the voltage-gated K channels open more slowly, their opening occurs at about the same time the voltage-gated Na channels are closing. The slower opening of voltage-gated K channels and the closing of previously open voltage-gated Na channels produce the repolarizing phase of the action potential. As the Na channels are inactivated, Na inﬂow slows. At the same time, the K channels are opening, accelerating K outﬂow. Slowing of Na inﬂow and acceleration of K outﬂow causes the membrane potential to change from 30 mV to 70 mV. Repolarization also allows inactivated Na channels to revert to the resting state.

After-hyperpolarizing Phase While the voltage-gated K channels are open, outﬂow of K may be large enough to cause an after-hyperpolarizing phase of the action potential. During this phase, the voltage-gated K channels remain open and the membrane potential becomes even more negative (about 90 mV). As the voltage-gated K channels close, the membrane potential returns to the resting level of 70 mV. Unlike voltage-gated Na channels, most voltage-gated K channels do not exhibit an inactivated state. Instead, they alternate between closed (resting) and open (activated) states.

Refractory Period: The period of time after an action potential begins during which an excitable cell cannot generate another action potential in response to a normal threshold stimulus is called the refractory period. During the absolute refractory period, even a very strong stimulus cannot initiate a second action potential. This period coincides with the period of Na channel activation and inactivation. Inactivated Na channels cannot reopen; they ﬁrst must return to the resting state. In contrast to action potentials, graded potentials do not exhibit a refractory period. Large-diameter axons have a larger surface area and have a brief absolute refractory period of about 0.4 msec. Because a second nerve impulse can arise very quickly, up to 1000 impulses per second are possible. Small-diameter axons have absolute refractory periods as long as 4 msec, enabling them to transmit a maximum of 250 impulses per second. Under normal body conditions, the maximum frequency of nerve impulses in different axons ranges between 10 and 1000 per second. The relative refractory period is the period of time during which a second action potential can be initiated, but only by a larger-than-normal stimulus. It coincides with the period when the voltage-gated K channels are still open after inactivated Na channels have returned to their resting state.

SIGNAL TRANSMISSION AT SYNAPSES

Synapses are essential for homeostasis because they allow information to be ﬁltered and integrated. During learning, the structure and function of particular synapses change. The changes may allow some signals to be transmitted while others are blocked. For example, the changes in your synapses from studying will determine how well you do on your anatomy and physiology tests! Synapses are also important because some diseases and neurological disorders result from disruptions of synaptic communication, and many therapeutic and addictive chemicals affect the body at these junctions. At a synapse between neurons, the neuron sending the signal is called the presynaptic neuron, and the neuron receiving the message is called the postsynaptic neuron. Most synapses are either axodendritic (from axon to dendrite), axosomatic (from axon to cell body), or axoaxonic (from axon to axon). The two types of synapses—electrical and chemical—differ both structurally and functionally.

Electrical Synapses: At an electrical synapse, action potentials (impulses) conduct directly between adjacent cells through structures called gap junctions. Each gap junction contains a hundred or so tubular connexons, which act like tunnels to connect the cytosol of the two cells directly. As ions ﬂow from one cell to the next through the connexons, the action potential spreads from cell to cell. Gap junctions are common in visceral smooth muscle, cardiac muscle, and the developing embryo. They also occur in the CNS. Electrical synapses have two main advantages: 1. faster communication. Because action potentials conduct directly through gap junctions, electrical synapses are faster than chemical synapses. At an electrical synapse, the action potential passes directly from the presynaptic cell to the postsynaptic cell. The events that occur at a chemical synapse take some time and delay communication slightly. 2. Synchronization. Electrical synapses can synchronize (coordinate) the activity of a group of neurons or muscle ﬁbers. In other words, a large number of neurons or muscle ﬁbers can produce action potentials in unison if they are connected by gap junctions. The value of synchronized action potentials in the heart or in visceral smooth muscle is coordinated contraction of these ﬁbers to produce a heartbeat or move food through the gastrointestinal tract.

Chemical Synapses: Although the plasma membranes of presynaptic and postsynaptic neurons in a chemical synapse are close, they do not touch. They are separated by the synaptic cleft, a space of 20–50 nm* that is ﬁlled with interstitial ﬂuid. Nerve impulses cannot conduct across the synaptic cleft, so an alternative, indirect form of communication occurs. In response to a nerve impulse, the presynaptic neuron releases a neurotransmitter that diffuses through the ﬂuid in the synaptic cleft and binds to receptors in the plasma membrane of the postsynaptic neuron. The postsynaptic neuron receives the chemical signal and in turn produces a postsynaptic potential, a type of graded potential. Thus, the presynaptic neuron converts an electrical signal (nerve impulse) into a chemical signal (released neurotransmitter). The postsynaptic neuron receives the chemical signal and in turn generates an electrical signal (postsynaptic potential). The time required for these processes at a chemical synapse, a synaptic delay of about 0.5 msec, is the reason that chemical synapses relay signals more slowly than electrical synapses. A typical chemical synapse transmits a signal as follows:

● A nerve impulse arrives at a synaptic end bulb (or at a varicosity) of a presynaptic axon.

● The depolarizing phase of the nerve impulse opens voltage- gated Ca2 channels, which are present in the membrane of synaptic end bulbs. Because calcium ions are more concentrated in the extracellular ﬂuid, Ca2 ﬂows inward through the opened channels.

● An increase in the concentration of Ca2 inside the presynaptic neuron serves as a signal that triggers exocytosis of the synaptic vesicles. As vesicle membranes merge with the plasma membrane, neurotransmitter molecules within the vesicles are released into the synaptic cleft. Each synaptic vesicle contains several thousand molecules of neurotransmitter.

● The neurotransmitter molecules diffuse across the synaptic cleft and bind to neurotransmitter receptors in the postsynaptic neuron’s plasma membrane. Not all neurotransmitters bind to ionotropic receptors; some bind to metabotropic receptors (described shortly).

● Binding of neurotransmitter molecules to their receptors on ligand-gated channels opens the channels and allows particular ions to ﬂow across the membrane.

● As ions ﬂow through the opened channels, the voltage across the membrane changes. This change in membrane voltage is a postsynaptic potential. Depending on which ions the channels admit, the postsynaptic potential may be a depolarization or a hyperpolarization. For example, opening of Na channels allows inﬂow of Na which causes de- polarization. However, opening of Cl or K channels causes hyperpolarization. Opening Cl channels permits Cl to move into the cell, while opening the K channels allows K to move out—in either event, the inside of the cell becomes more negative.

● When a depolarizing postsynaptic potential reaches threshold, it triggers an action potential in the axon of the post- synaptic neuron. At most chemical synapses, only one-way information transfer can occur—from a presynaptic neuron to a postsynaptic neuron or an effector, such as a muscle ﬁber or a gland cell. For ex- ample, synaptic transmission at a neuromuscular junction (NMJ) proceeds from a somatic motor neuron to a skeletal muscle ﬁber (but not in the opposite direction). Only synaptic end bulbs of presynaptic neurons can release neurotransmitter, and only the postsynaptic neuron’s membrane has the receptor proteins that can recognize and bind that neurotransmitter. As a result, action potentials move in one direction.

Excitatory and Inhibitory Postsynaptic Potentials:

A neurotransmitter causes either an excitatory or an inhibitory graded potential. A neurotransmitter that depolarizes the postsynaptic membrane is excitatory because it brings the membrane closer to threshold. A depolarizing postsynaptic potential is called an excitatory postsynaptic potential (EPSP). Although a single EPSP normally does not initiate a nerve impulse, the postsynaptic cell does become more excitable. Because it is partially depolarized, it is more likely to reach threshold when the next EPSP occurs. A neurotransmitter that causes hyperpolarization of the post- synaptic membrane is inhibitory. During hyperpolarization, generation of an action potential is more difﬁcult than usual because the membrane potential becomes inside more negative and thus even farther from threshold than in its resting state. A hyperpolarizing postsynaptic potential is termed an inhibitory postsynaptic potential (IPSP).

Neurotransmitters

About 100 substances are either known or suspected neurotransmitters. Some neurotransmitters bind to their receptors and act quickly to open or close ion channels in the membrane. Others act more slowly via second-messenger systems to inﬂuence chemical reactions inside cells. The result of either process can be excitation or inhibition of postsynaptic neurons. Many neurotransmitters are also hormones released into the bloodstream by endocrine cells in organs throughout the body. Within the brain, certain neurons, called neurosecretory cells, also secrete hormones. Neurotransmitters can be divided into two classes based on size: small-molecule neurotransmitters and neuropeptides.

Small-Molecule Neurotransmitters

The small-molecule neurotransmitters include acetylcholine, amino acids, biogenic amines, ATP and other purines, and nitric oxide.

Acetylcholine The best-studied neurotransmitter is acetylcholine (ACh), which is released by many PNS neurons and by some CNS neurons. ACh is an excitatory neurotransmitter at some synapses, such as the neuromuscular junction, where the binding of ACh to ionotropic receptors opens cation channels. It is also an inhibitory neurotransmitter at other synapses, where it binds to metabotropic receptors coupled to G proteins that open K channels. For example, ACh slows heart rate at inhibitory synapses made by parasympathetic neurons of the vagus (X) nerve. The enzyme acetylcholinesterase (AChE) inactivates ACh by splitting it into acetate and choline fragments.

Amino Acids: Several amino acids are neurotransmitters in the CNS. Glutamate (glutamic acid) and aspartate (aspartic acid) have powerful excitatory effects. Most excitatory neurons in the CNS and perhaps half of the synapses in the brain communicate via glutamate. At some glutamate synapses, binding of the neuro- transmitter to ionotropic receptors opens cation channels. The consequent inﬂow of cations (mainly Na ions) produces an EPSP. Inactivation of glutamate occurs via reuptake. Glutamate transporters actively transport glutamate back into the synaptic end bulbs and neighboring neuroglia. Gamma amino butyric acid (GABA) and glycine are important inhibitory neurotransmitters. At many synapses, the binding of GABA to ionotropic receptors opens Cl channels. GABA is found only in the CNS, where it is the most common inhibitory neurotransmitter. As many as one-third of all brain synapses use GABA. Antianxiety drugs such as diazepam enhance the action of GABA. Like GABA, the binding of glycine to ionotropic receptors opens Cl channels. About half of the inhibitory synapses in the spinal cord use the amino acid glycine; the rest use GABA.

Biogenic Amines: Certain amino acids are modiﬁed and decarboxylated (carboxyl group removed) to produce biogenic amines. Those that are prevalent in the nervous system include norepinephrine, epinephrine, dopamine, and serotonin. Most biogenic amines bind to metabotropic receptors; there are many different types of metabotropic receptors for each biogenic amine. Biogenic amines may cause either excitation or inhibition, depending on the type of metabotropic receptor at the synapse. Norepinephrine (NE) plays roles in arousal (awakening from deep sleep), dreaming, and regulating mood. A smaller number of neurons in the brain use epinephrine as a neurotransmitter. Both epinephrine and norepinephrine also serve as hormones. Cells of the adrenal medulla, the inner portion of the adrenal gland, release them into the blood. Brain neurons containing the neurotransmitter dopamine (DA) are active during emotional responses, addictive behaviors, and pleasurable experiences. In addition, dopamine-releasing neurons help regulate skeletal muscle tone and some aspects of movement due to contraction of skeletal muscles. The muscular stiffness that occurs in Parkinson disease is due to degeneration of neurons that release dopamine. One form of schizophrenia is due to accumulation of excess dopamine. Norepinephrine, dopamine, and epinephrine are classiﬁed chemically as catecholamines. They all include an amino group (-NH2) and a catechol ring composed of six carbons and two adjacent hydroxyl (-OH) groups. Catecholamines are synthesized from the amino acid tyrosine. Inactivation of catecholamines occurs via reuptake into synaptic end bulbs. Then they are either recycled back into the synaptic vesicles or destroyed by the enzymes. The two enzymes that break down catecholamines are catechol-O-methyltransferase or COMT, and monoamine oxidase or MAO. Serotonin, also known as 5-hydroxytryptamine (5-HT), is concentrated in the neurons in a part of the brain called the raphe nucleus. It is thought to be involved in sensory perception, temperature regulation, control of mood, appetite, and the induction of sleep

ATP and Other Purines: The characteristic ring structure of the adenosine portion of ATP is called a purine ring. Adenosine itself, as well as its triphosphate, diphosphate, and monophosphate derivatives (ATP, ADP, and AMP), is an excitatory neurotransmitter in both the CNS and the PNS. Most of the synaptic vesicles that contain ATP also contain another neurotransmitter. In the PNS, ATP and norepinephrine are released together from some sympathetic neurons; some parasympathetic neurons release ATP and acetylcholine in the same vesicles.

Nitric Oxide: The simple gas nitric oxide (NO) is an important neurotransmitter that has widespread effects throughout the body. NO contains a single nitrogen atom, in contrast to nitrous oxide (N2O), or laughing gas, which has two nitrogen atoms. N2O is sometimes used as an anesthetic during dental procedures. The enzyme nitric oxide synthase (NOS) catalyzes formation of NO from the amino acid arginine. Based on the presence of NOS, it is estimated that more than 2% of the neurons in the brain produce NO. Unlike all previously known neurotransmitters, NO is not synthesized in advance and packaged into synaptic vesicles. Rather, it is formed on demand and acts immediately. Its action is brief because NO is a highly reactive free radical. It exists for less than 10 seconds before it combines with oxygen and water to form inactive nitrates and nitrites. Because NO is lipid-soluble, it diffuses from cells that produce it into neighboring cells, where it activates an enzyme for production of a second messenger called cyclic GMP. Some research suggests that NO plays a role in memory and learning. The ﬁrst recognition of NO as a regulatory molecule was the discovery in 1987 that a chemical called EDRF (endothelium- derived relaxing factor) was actually NO. Endothelial cells in blood vessel walls release NO, which diffuses into neighboring smooth muscle cells and causes relaxation. The result is vasodilation, an increase in blood vessel diameter. The effects of such vasodilation range from a lowering of blood pressure to erection of the penis in males. Sildenaﬁl alleviates erectile dysfunction (impotence) by enhancing the effect of NO. In larger quantities, NO is highly toxic. Phagocytic cells, such as macrophages and certain white blood cells, produce NO to kill microbes and tumor cells.

Neuropeptides: Neurotransmitters consisting of 3 to 40 amino acids linked by peptide bonds called neuropeptides are numerous and widespread in both the CNS and the PNS. Neuropeptides bind to metabotropic receptors and have excitatory or inhibitory actions, depending on the type of metabotropic receptor at the synapse. Neuropeptides are formed in the neuron cell body, packaged into vesicles, and transported to axon terminals. Besides their role as neurotransmitters, many neuropeptides serve as hormones that regulate physiological responses elsewhere in the body. Scientists discovered that certain brain neurons have plasma membrane receptors for opiate drugs such as morphine and heroin. The quest to ﬁnd the naturally occurring substances that use these receptors brought to light the ﬁrst neuropeptides: two molecules, each a chain of ﬁve amino acids, named enkephalins. Their potent analgesic (pain-relieving) effect is 200 times stronger than morphine. Other so called opioid pep- tides include the endorphins and dynorphins. It is thought that opioid peptides are the body’s natural painkillers. Acupuncture may produce analgesia (loss of pain sensation) by increasing the release of opioids. These neuropeptides have also been linked to improved memory and learning; feelings of pleasure or euphoria; control of body temperature; regulation of hormones that affect the onset of puberty, sexual drive, and reproduction; and mental illnesses such as depression and schizophrenia. Another neuropeptide, substance P, is released by neurons that transmit pain-related input from peripheral pain receptors into the central nervous system, enhancing the perception of pain. Enkephalin and endorphin suppress the release of sub- stance P, thus decreasing the number of nerve impulses being relayed to the brain for pain sensations. Substance P has also been shown to counter the effects of certain nerve-damaging chemicals, prompting speculation that it might prove useful as a treatment for nerve degeneration.

Structure of Neurotransmitter Receptors

As you have already learned, neurotransmitters released from a presynaptic neuron bind to neurotransmitter receptors in the plasma membrane of a postsynaptic cell. Each type of neuro- transmitter receptor has one or more neurotransmitter binding sites where its speciﬁc neurotransmitter binds. When a neuro- transmitter binds to the correct neurotransmitter receptor, an ion channel opens and a postsynaptic potential (either an EPSP or IPSP) forms in the membrane of the postsynaptic cell. Neuro- transmitter receptors are classiﬁed as either ionotropic receptors or metabotropic receptors based on whether the neurotransmitter binding site and the ion channel are components of the same protein or are components of different proteins.

Ionotropic Receptors: An ionotropic receptor is a type of neurotransmitter receptor that contains a neurotransmitter binding site and an ion channel. In other words, the neurotransmitter binding site and the ion channel are components of the same protein. An ionotropic receptor is a type of ligand-gated channel. In the absence of neurotransmitter (the ligand), the ion channel component of the ionotropic receptor is closed. When the correct neurotransmitter binds to the ionotropic receptor, the ion channel opens, and an EPSP or IPSP occurs in the postsynaptic cell. Many excitatory neurotransmitters bind to ionotropic receptors that contain cation channels. EPSPs result from opening these cation channels. When cation channels open, they allow passage of the three most plentiful cations (Na K and Ca2 through the postsynaptic cell membrane, but Na inﬂow is greater than either Ca2 inﬂow or K outﬂow and the inside of the postsynaptic cell becomes less negative (de- polarized). Many inhibitory neurotransmitters bind to ionotropic receptors that contain chloride channels. IPSPs result from opening these Cl channels. When Cl channels open, a larger number of chloride ions diffuse inward. The inward ﬂow of Cl ions causes the inside of the postsynaptic cell to become more negative (hyperpolarized).

Metabotropic Receptors: A metabotropic receptor is a type of neurotransmitter receptor that contains a neurotransmitter binding site, but lacks an ion channel as part of its structure. However, a metabotropic receptor is coupled to a separate ion channel by a type of membrane protein called a G protein. When a neurotransmitter binds to a metabotropic receptor, the G protein either directly opens (or closes) the ion channel or it may act indirectly by activating an- other molecule, a “second messenger,” in the cytosol, which in turn opens (or closes) the ion channel (see Chapter 18 for a detailed discussion of G proteins). Thus, a metabotropic receptor differs from an ionotropic receptor in that the neurotransmitter binding site and the ion channel are components of different proteins. Some inhibitory neurotransmitters bind to metabotropic receptors that are linked to K channels IPSPs result from the opening of these K channels. When K channels open, a larger number of potassium ions diffuses outward. The outward ﬂow of K ions causes the inside of the postsynaptic cell to become more negative (hyperpolarized).

Different Postsynaptic Effects for the Same Neurotransmitter The same neurotransmitter can be excitatory at some synapses and inhibitory at other synapses, depending on the structure of the neurotransmitter receptor to which it binds. For example, at some excitatory synapses acetylcholine (ACh) binds to ionotropic receptors that contains cation channels that open and subsequently generate EPSPs in the postsynaptic cell. By contrast, at some inhibitory synapses ACh binds to metabotropic receptors coupled to G proteins that open K channels, resulting in the formation of IPSPs in the postsynaptic cell.

Removal of Neurotransmitter

Removal of the neurotransmitter from the synaptic cleft is essential for normal synaptic function. If a neurotransmitter could linger in the synaptic cleft, it would inﬂuence the postsynaptic neuron, muscle ﬁber, or gland cell indeﬁnitely. Neurotransmitter is removed in three ways: 1. Diffusion. Some of the released neurotransmitter molecules diffuse away from the synaptic cleft. Once a neurotransmitter molecule is out of reach of its receptors, it can no longer exert an effect. 2. Enzymatic degradation. Certain neurotransmitters are inactivated through enzymatic degradation. For example, the enzyme acetylcholinesterase breaks down acetylcholine in the synaptic cleft. 3. Uptake by cells. Many neurotransmitters are actively trans- ported back into the neuron that released them (reuptake). Others are transported into neighboring neuroglia (uptake). The neurons that release norepinephrine, for example, rapidly take up the norepinephrine and recycle it into new synaptic vesicles. The membrane proteins that accomplish such uptake are called neurotransmitter transporters.

Spatial and Temporal Summation of Postsynaptic Potentials

A typical neuron in the CNS receives input from 1000 to 10,000 synapses. Integration of these inputs involves summation of the postsynaptic potentials that form in the postsynaptic neuron. Recall that summation is the process by which graded potentials add together. The greater the summation of EPSPs, the greater the chance that threshold will be reached. At threshold, one or more nerve impulses (action potentials) arise. There are two types of summation: spatial summation and temporal summation. Spatial summation is summation of postsynaptic potentials in response to stimuli that occur at different locations in the membrane of a postsynaptic cell at the same time. For example, spatial summation results from the buildup of neurotransmitter released simultaneously by several presynaptic end bulbs. Temporal summation is summation of postsynaptic potentials in response to stimuli that occur at the same location in the membrane of the postsynaptic cell but at different times. For example, temporal summation results from buildup of neurotransmitter released by a single presynaptic end bulb two or more times in rapid succession. Because a typical EPSP lasts about 15msec, the second (and subsequent) release of neurotransmitter must occur soon after the ﬁrst one if temporal summation is to occur. Summation is rather like a vote on the Internet. Many people voting “yes” or “no” on an issue at the same time can be compared to spatial summation. One person voting repeatedly and rapidly is like temporal summation. Most of the time, spatial and temporal summations are acting together to inﬂuence the chance that a neuron ﬁres an action potential.

A single postsynaptic neuron receives input from many pre- synaptic neurons, some of which release excitatory neurotransmitters and some of which release inhibitory neurotransmitters. The sum of all the excitatory and inhibitory effects at any given time determines the effect on the postsynaptic neuron, which may respond in the following ways: 1. EPSP. If the total excitatory effects are greater than the total inhibitory effects but less than the threshold level of stimulation, the result is an EPSP that does not reach threshold. Following an EPSP, subsequent stimuli can more easily generate a nerve impulse through summation because the neuron is partially depolarized. 2. Nerve impulse(s). If the total excitatory effects are greater than the total inhibitory effects and threshold is reached, one or more nerve impulses (action potentials) will be triggered. Impulses continue to be generated as long as the EPSP is at or above the threshold level. 3. IPSP. If the total inhibitory effects are greater than the excitatory effects, the membrane hyperpolarizes (IPSP). The result is inhibition of the postsynaptic neuron and an inability to generate a nerve impulse.

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