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49 The Autonomic and the

Susan Iversen Leslie Iversen Clifford B. Saper

WHEN WE ARE FRIGHTENED our races, our breathing becomes rapid and shallow, our mouth becomes dry, our muscles tense, our palms become sweaty, and we may want to run. These bodily changes are mediated by the , which controls heart muscle, , and exocrine . The autonomic nervous system is distinct from the , which controls . As we shall learn in the next chapter, even though the neural control of involves several regions, including the amygdala and the limbic association areas of the cerebral cortex, they all work through the hypothalamus to control the autonomic nervous system. The hypothalamus coordinates behavioral response to insure bodily , the constancy of the internal environment. The hypothalamus, in turn, acts on three major systems: the autonomic nervous system, the , and an ill-defined neural system concerned with motivation. In this chapter we shall first examine the autonomic nervous system and then go on to consider the hypothalamus. In the next two chapters, we shall examine emotion and motivation, behavioral states that depend greatly on autonomic and hypothalamic mechanisms.

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The Autonomic Nervous System Is a Visceral and Largely Involuntary Sensory and Motor System

In contrast to the somatic sensory and motor systems, which we considered in Parts IV and V of this book, the autonomic nervous system is a visceral sensory and motor system. Virtually all visceral are mediated by local circuits in the stem or . Although these reflexes are regulated by a network of central autonomic control nuclei in the brain stem, hypothalamus, and , these visceral reflexes are not under voluntary control, nor do they impinge on consciousness, with few exceptions. The autonomic nervous system is thus also referred to as the involuntary motor system, in contrast to the voluntary (somatic) motor system.

The autonomic nervous system has three major divisions: sympathetic, parasympathetic, and enteric. The sympathetic and parasympathetic divisions innervate , smooth muscle, and glandular tissues and mediate a variety of visceral reflexes. These two divisions include the sensory associated with spinal and cranial , the preganglionic and postganglionic motor neurons, and the circuitry that connects with and modulates the sensory and motor neurons. The enteric division has greater autonomy than the other two divisions and comprises a largely self-contained system, with only minimal connections to the rest of the nervous system. It consists of sensory and motor neurons in the that mediate digestive reflexes.

The American physiologist Walter B. Cannon first proposed that the sympathetic and parasympathetic divisions have distinctly different functions. He argued that the parasympathetic nervous system is responsible for rest and digest, maintaining basal , respiration, and under normal conditions. The sympathetic nervous system, on the other hand, governs the emergency reaction, or fight-or-flight reaction. In an emergency the body needs to respond to sudden changes in the external or internal environment, be it emotional , combat, athletic competition, severe change in temperature, or blood loss. For a person to respond effectively, the sympathetic nervous system increases output to the heart and other viscera, the peripheral vasculature and sweat glands, and the piloerector and certain ocular muscles. An animal whose sympathetic nervous system has been experimentally eliminated can only survive if sheltered, kept warm, and not exposed to stress or emotional stimuli. Such an animal cannot, however, carry out strenuous work or fend for itself; it cannot mobilize blood sugar from the quickly and does not react to cold with normal or elevation of body heat.

Figure 49-1 Anatomical organization of the somatic and autonomic motor pathways.

A. In the somatic motor system, effector motor neurons in the central nervous system project directly to skeletal muscles.

B. In the autonomic motor system, the effector motor neurons are located in ganglia outside the central nervous system and are controlled by preganglionic central neurons.

The relationship between the sympathetic and parasympathetic pathways is not as simple and as independent as suggested by Cannon, however. Both divisions are tonically active and operate in conjunction with each other and with the somatic motor system to regulate most behavior, be it normal or emergency. Although several visceral functions are controlled predominantly by one or the other division, and although both the sympathetic and parasympathetic divisions often exert opposing effects on innervated target tissues, it is the balance of activity between the two that helps maintain an internal stable environment in the face of changing external conditions.

The idea of a stable internal environment in the face of changing external conditions was first proposed in the nineteenth century by the French physiologist Claude Bernard. This idea was developed further by Cannon, who put forward the concept of homeostasis as the complex P.962 physiological mechanisms that maintain the internal milieu. In his classic book The Wisdom of the Body published in 1932, Cannon introduced the concept of regulation as a key homeostatic mechanism and outlined much of our current understanding of the functions of the autonomic nervous system.

Figure 49-2 Anatomical organization of the sympathetic preganglionic and postganglionic . (Adapted from Loewy and Spyer 1990.)

If a state remains steady, it does so because any change is automatically met by increased effectiveness of the factor or factors that resist the change. Consider, for example, when the body lacks ; the discharge of , which liberates sugar from the liver when the concentration of sugar in the blood falls below a critical point; and increased breathing, which reduces carbonic acid when the blood tends to shift toward acidity.

Cannon further proposed that the autonomic nervous system, under the control of the hypothalamus, is an important part of this feedback regulation. The hypothalamus regulates many of the neural circuits that mediate the peripheral components of emotional states: changes in heart rate, , temperature, and water and food intake. It also controls the pituitary and thereby regulates the endocrine system.

Each of the Three Divisions of the Autonomic Nervous System Has a Distinctive Anatomical Organization

The Motor Neurons of the Autonomic Nervous System Lie Outside the Central Nervous System

In the somatic motor system the motor neurons are part of the central nervous system: They are located in the spinal cord and brain stem and project directly to skeletal muscle. In contrast, the motor neurons of the sympathetic and parasympathetic motor systems are located outside the spinal cord in the autonomic ganglia. The autonomic motor neurons (also known as postganglionic neurons) are activated by the axons of central neurons (the preganglionic neurons) whose cell bodies are located in the spinal cord or brain stem, much as are the somatic motor neurons. Thus, in the visceral motor system a (in the autonomic ) is interposed between the efferent in the central nervous system and the peripheral target (Figure 49-1).

The sympathetic and parasympathetic nervous systems have clearly defined sensory components that provide input to the central nervous system and play an important role in autonomic reflexes. In addition, some sensory fibers that project to the spinal cord also send a branch to autonomic ganglia, thus forming circuits that control some visceral autonomic functions.

The innervation of target tissues by autonomic nerves also differs markedly from that of skeletal muscle by somatic motor nerves. Unlike skeletal muscle, which has specialized postsynaptic regions (the end-plates; see Chapter 14), target cells of the autonomic fibers have no specialized postsynaptic sites. Nor do the postganglionic nerve endings have presynaptic specializations such as the active zones of somatic motor neurons. Instead, the nerve endings have several swellings (varicosities) where vesicles containing transmitter substances accumulate (see Chapter 15).

Synaptic transmission therefore occurs at multiple sites along the highly branched terminals of autonomic nerves. The may diffuse for distances P.963 as great as several hundred nanometers to reach its targets. In contrast to the point-to-point contacts made in the somatic motor system, neurons in the autonomic motor system exert a more diffuse control over target tissues, so that a relatively small number of highly branched motor fibers can regulate the function of large masses of smooth muscle or glandular tissue.

Sympathetic Pathways Convey Thoracolumbar Outputs to Ganglia Alongside the Spinal Cord

Preganglionic sympathetic neurons form a column in the intermediolateral horn of the spinal cord extending from the first thoracic spinal segment to rostral lumbar segments. The axons of these neurons leave the spinal cord in the ventral root and initially run together in the . They then separate from the somatic motor axons and project (in small bundles called white myelinated rami) to the ganglia of the sympathetic chains, which lie along each side of the spinal cord (Figure 49-2).

Axons of preganglionic neurons exit the spinal cord at the level at which their cell bodies are located, but they may innervate situated either more rostrally or more caudally by traveling in the sympathetic nerve trunk that connects the ganglia (Figure 49-2). Most of the preganglionic axons are relatively slow-conducting, small-diameter myelinated fibers. Each preganglionic fiber forms with many postganglionic neurons in different ganglia. Overall, the ratio of preganglionic fibers to postganglionic fibers in the sympathetic nervous system is about 1:10. This divergence permits coordinated activity in sympathetic neurons at several different spinal levels. The axons of postganglionic neurons are largely unmyelinated and exit the ganglia in the gray unmyelinated rami. The postganglionic cells that innervate structures in the head are located in the superior cervical ganglion, which is a rostral extension of the sympathetic chain. The axons of these cells travel along branches of the carotid to their targets in the head. The postganglionic fibers innervating the rest of the body travel in spinal nerves to their targets; in an average spinal nerve about 8% of the fibers are sympathetic postganglionic axons. Some neurons of the cervical and upper innervate cranial blood vessels, sweat glands, and hair follicles; others innervate the glands and visceral organs of the head and chest, including the lacrimal and salivary glands, heart, , and blood vessels. Neurons in the lower thoracic and lumbar paravertebral ganglia innervate peripheral blood vessels, sweat glands, and pilomotor smooth muscle (Figure 49- 3).

Some preganglionic fibers pass through the sympathetic ganglia and branches of the to synapse on neurons of the prevertebral ganglia, which include the coeliac ganglion and the superior and inferior mesenteric ganglia (Figure 49-3). Neurons in these ganglia innervate the gastrointestinal system and the accessory gastrointestinal organs, including the and liver, and also provide sympathetic innervation of the kidneys, bladder, and genitalia. Another group of preganglionic axons runs in the thoracic splanchnic nerve into the and innervates the , which is an , secreting both and into circulation. The cells of the adrenal medulla are developmentally and functionally related to postganglionic sympathetic neurons.

Parasympathetic Pathways Convey Outputs From the Brain Stem Nuclei and Sacral Spinal Cord to Widely Dispersed Ganglia

The central, preganglionic cells of the parasympathetic nervous system are located in several brain stem nuclei and in segments S2-S4 of the sacral spinal cord (Figure 49-3). The axons of these cells are quite long because lie close to or are actually embedded in visceral target organs. In contrast, sympathetic ganglia are located at some distance from their targets.

The preganglionic parasympathetic nuclei in the brain stem include the Edinger-Westphal nucleus (associated with cranial nerve III), the superior and inferior salivary nuclei (associated with VII and IX, respectively), and the dorsal vagal nucleus and the nucleus ambiguus (both associated with cranial nerve X). Preganglionic axons exiting the brain stem through cranial nerves III, VII, and IX and project to postganglionic neurons in the ciliary, pterygopalatine, submandibular, and otic ganglia (Figure 49-3). Parasympathetic preganglionic fibers from the dorsal vagal nucleus project via nerve X to postganglionic neurons embedded in thoracic and abdominal targets—the , liver, gall bladder, pancreas, and upper intestinal tract (Figure 49-3). Neurons of the ventrolateral nucleus ambiguus provide the principal parasympathetic innervation of the cardiac ganglia, which innervate the heart, , and respiratory airways.

In the sacral spinal cord the parasympathetic preganglionic neurons occupy the intermediolateral column. Axons of spinal parasympathetic neurons leave the spinal cord through the ventral roots and project in the pelvic nerve to the pelvic ganglion plexus. Pelvic ganglion neurons innervate the descending colon, bladder, and external genitalia (Figure 49-3).

Figure 49-3 Sympathetic and parasympathetic divisions of the autonomic nervous system. Sympathetic preganglionic neurons are clustered in ganglia in the sympathetic chain alongside the spinal cord extending from the first thoracic spinal segment to upper lumbar segments. Parasympathetic preganglionic neurons are located within the brain stem and in segments S2-S4 of the spinal cord. The major targets of autonomic control are shown here.

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The sympathetic nervous system innervates tissues throughout the body, but the parasympathetic distribution is more restricted. There is also less divergence, with an average ratio of preganglionic to postganglionic fibers of about 1:3; in some tissues the numbers may be nearly equal. The Is Largely Autonomous

The enteric nervous system controls the function of the gastrointestinal tract, pancreas, and . It contains local sensory neurons and as well as motor neurons and is responsive to alterations in the tension of gut walls and changes in the chemical environment in the gut. The enteric motor neurons control smooth muscle of the gut, local blood vessels, and secretion by the mucosa. The enteric nervous system has 80-100 million neurons, approximately as many as are found in the spinal cord.

Two major plexuses of nerve cell bodies and fibers extend continuously along the entire length of the gastrointestinal tract (Figure 49-4). These are the myenteric (Auerbach's) plexus, between the outer longitudinal and inner circular smooth muscle layers, and the submucous (Meissner's) plexus between the circular muscle layer and the mucosa. In general, the submucous plexus is concerned P.965 with control of the secretory functions of the gut, while the controls gut motility. The two plexuses are interconnected, and they contain motor neurons that innervate both smooth muscle and secretory cells in the mucosa, as well as sensory neurons that respond to stretch, tonicity, and specific chemical signals.

Figure 49-4 The locations of the mucosal, submucous, and myenteric plexuses between the layers of intestinal wall are shown in three dimensions (A) and in cross-section (B). (Adapted from Furness and Costa 1980.)

The enteric nervous system is relatively independent of the central nervous system. Although it does have both sympathetic and parasympathetic inputs, these are relatively sparse in relation to the large numbers of enteric neurons. Parasympathetic preganglionic fibers project to enteric ganglia in the stomach, colon, and through the vagus, pelvic, and splanchnic nerves. The sympathetic fibers originate primarily in paravertebral ganglia, although some originate in the prevertebral ganglia, and project mainly to the myenteric and submucous plexuses.

Disruption of enteric connections to the central nervous system results in little or no impairment in function of the small and large bowels; the esophagus and stomach, however, appear to be more dependent on sympathetic and parasympathetic innervation for normal function. The innervation of parts of the gastrointestinal system by the sympathetic and parasympathetic systems may be a way that the other divisions of the autonomic nervous system can override the local nervous control of gut function.

Sensory Inputs Produce a Wide Range of Visceral Reflexes

To maintain homeostasis the autonomic nervous system responds to many different types of sensory inputs. Some of these are somatosensory. For example, a noxious stimulus activates sympathetic neurons that regulate local vasoconstriction (necessary to reduce bleeding when the is broken). At the same time, the stimulus activates nociceptive afferents in the with axon collaterals to an area in the rostral ventrolateral medulla that coordinates reflexes. These inputs cause widespread sympathetic activation that increases blood pressure and heart rate to protect arterial perfusion pressure and prepares the individual for vigorous defense.

Homeostasis also requires important information about the internal state of the body. Much of this information from the thoracic and abdominal cavities reaches the brain via the . The glossopharyngeal nerve also conveys visceral sensory information from the head and . Both of these nerves and the relay special visceral sensory information about taste (a visceral chemosensory function) from the oral cavity. All of these visceral sensory afferents synapse in a topographic fashion in the nucleus of the solitary tract. Taste information is represented most anteriorly; gastrointestinal information, in an intermediate P.966 position; cardiovascular inputs, caudomedially; and respiratory inputs, in the caudolateral part of the nucleus.

Box 49-1 First Isolation of a Chemical Transmitter The existence of chemical messengers was first postulated by John Langley and Henry Dale and their students on the basis of their pharmacological studies dating from the beginning of the century. However, convincing evidence for a neurotransmitter was not provided until 1920, when Otto Loewi, in a simple but decisive experiment, examined the autonomic innervation of two isolated, beating frog . In his own words: The night before Easter Sunday of that year I awoke, turned on the light, and jotted down a few notes on a tiny slip of paper. Then I fell asleep again. It occurred to me at six o'clock in the morning that during the night I had written down something most important, but I was unable to decipher the scrawl. The next night, at three o'clock, the idea returned. It was the design of an experiment to determine whether or not the hypothesis of chemical transmission that I had uttered seventeen years ago was correct. I got up immediately, went to the laboratory, and performed a simple experiment on a frog heart according to the nocturnal design. I have to describe briefly this experiment since its results became the foundation of the theory of chemical transmission of the nervous impulse. The hearts of two frogs were isolated, the first with its nerves, the second without. Both hearts were attached to Straub cannulas filled with a little Ringer solution. The vagus nerve of the first heart was stimulated for a few minutes. Then the Ringer solution that had been in the first heart during the stimulation of the vagus was transferred to the second heart. It slowed and its beat diminished just as if its vagus had been stimulated. Similarly, when the accelerator nerve was stimulated and the Ringer from this period transferred, the second heart speeded up and its beat increased. These results unequivocally proved that the nerves do not influence the heart directly but liberate from their terminals specific chemical substances which, in their turn, cause the well-known modifications of the function of the heart characteristic of the stimulation of its nerves. Loewi called this substance (vagus substance). Soon after, Vagusstoff was identified chemically as .

The nucleus of the solitary tract distributes visceral sensory information within the brain along three main pathways. Some neurons in the nucleus of the solitary tract directly innervate preganglionic neurons in the medulla and spinal cord, triggering direct autonomic reflexes. For example, there are direct inputs from the nucleus of the solitary tract to vagal motor neurons controlling esophageal and gastric motility, which are important for ingesting food. Also, projections from the nucleus of the solitary tract to the spinal cord are involved in respiratory reflex responses to inflation.

Other neurons in the nucleus project to the lateral medullary reticular formation, where they engage populations of premotor neurons that organize more complex, patterned autonomic reflexes. For example, groups of neurons in the rostral ventrolateral medulla control blood pressure by regulating both blood flow to different vascular beds and in the heart to modulate heart rate. Other groups of neurons control complex responses such as and respiratory rhythm (a somatic motor response that has an important autonomic component and that depends critically on visceral sensory information).

The third main projection from the nucleus of the solitary tract provides visceral sensory input to a network of cell groups that extend from the and up through the hypothalamus, amygdala, and cerebral cortex. This network coordinates autonomic responses and integrates them into ongoing patterns of behavior. These will be described in more detail after we consider more elementary autonomic reflexes.

Discrete Autonomic Reflexes Produce Both Slow and Rapid Visceral Responses

The usual role of the autonomic nervous system is to control a variety of visceral and ocular reflexes. Some of these reflexes are relatively fast, for example, adjustment of size in response to light. Others, such as glandular secretion or gastrointestinal responses to food, are slow. Some bodily functions are under the dual control of the autonomic and somatic motor systems.

Ocular Reflexes

The autonomic nervous system controls two movements of the eye: opening the and focusing the lens. Pupil size determines the amount of light impinging on the . Sympathetic fibers from the superior cervical ganglion innervate the muscles of the iris that dilate the pupil, while parasympathetic fibers innervate circular muscle fibers of the iris that constrict the pupil. Ordinarily, the parasympathetic and sympathetic controls P.967 are balanced to achieve the appropriate pupillary opening, although fine-tuning of pupil size may be largely under parasympathetic control. Under conditions of excitement or alarm there is a shift in this balance, inhibiting pupillary constriction and increasing tone in the pupillodilator muscle of the iris. Focusing of the lens is regulated almost entirely by parasympathetic control of ciliary muscles, whereas Muller's muscle, which retracts the eyelids, is under sympathetic control.

Figure 49-5 Acetylcholine (ACh) and norepinephrine (NE) acting on the same cells produce different firing patterns in cardiocytes in the sinoatrial node.

A. Stimulation of the cholinergic vagal nerve slows firing and shortens the amplitude of the action potential in the target cell. (Adapted from Toda and West 1967.)

B. Stimulation of the adrenergic sympathetic nerve of the frog sinus venosus increases the rate of firing of the cardiac cell. (Adapted from Hutter and Trautwein 1956.)

Cardiovascular Reflexes

Arterial blood pressure is determined by the rate of output of blood from the heart and the resistance to blood flow through the blood vessels. The sympathetic system increases heart rate and strength of contraction; the parasympathetic slows the heart. Sympathetic stimulation increases blood pressure by increasing cardiac output and peripheral resistance (by constricting small ). Parasympathetic stimulation has a smaller effect on peripheral resistance, although some vasodilatory responses occur, as in blushing. Parasympathetic may involve unconventional chemical messengers such as . Under resting conditions almost all systemic arterioles are constricted to approximately half maximal diameter by ongoing sympathetic tonic activity. A decrease in sympathetic output leads to vasodilation; an increase, to further constriction. Without ongoing tonic activity of the sympathetic system, sympathetic output could only increase and thus control only constriction.

Sympathetic vasoconstrictor tone results from continuous firing of mainly adrenergic neurons in the rostral ventrolateral medulla, which innervate sympathetic vasoconstrictor preganglionic neurons. Activation of pressure-sensitive () neurons that innervate the aortic arch and the carotid sinus signal an increase in blood pressure to the nucleus of the solitary tract. Neurons of this nucleus excite interneurons in the caudal ventrolateral medulla, which in turn both inhibit the tonic neurons and excite vagal cardiomotor neurons. The result, the baroreceptor reflex, is a fall in both arterial blood pressure and heart rate.

The actions of norepinephrine and acetylcholine (ACh) on the heart are worth considering in detail as examples of the complex cellular regulatory systems involved in autonomic control. Norepinephrine acts on cardiac muscle to stimulate heart rate and force of contraction. It increases the force of contraction by acting on β- adrenergic receptors that activate the cyclic adenosine monophosphate (cAMP) second-messenger system, which in turn increases the long-lasting (L-type) Ca2+ channel current in the muscle (Chapter 14). Activation of the β-adrenergic receptors also decreases the threshold for firing the cells in the sinoatrial node, thereby increasing heart rate. These effects of norepinephrine can be potently reinforced by circulating epinephrine released from the adrenal medulla.

ACh is released from parasympathetic nerve terminals, as first shown by Otto Loewi in his classic experiment proving the existence of chemical (Box 49-1). ACh slows the heart by acting on muscarinic receptors in the cardiocytes of the sinoatrial and atrioventricular nodes of cardiac muscle, thus increasing a resting K+ conductance in these cells. The P.968 increase in K+ conductance hyperpolarizes sinoatrial cells, thus slowing conductance through the atrioventricular node. Hyperpolarization of the sinoatrial cells appears to involve direct gating of a K+ channel by a G protein activated by the muscarinic receptor. ACh also decreases heart rate by increasing the threshold for firing the pacemaker cells in a manner opposite to that of norepinephrine, thereby slowing the heart rate (Figure 49-5). ACh also reduces the force of contraction by decreasing intracellular cAMP, thus reducing the L-type Ca2+ current.

Glandular Reflexes

Nasal, lacrimal, and many gastrointestinal glands are strongly stimulated by parasympathetic inputs. The enteric glands most strongly stimulated by the parasympathetic system are in the upper alimentary tract, particularly in the mouth and stomach. Glandular secretion in lower parts of the alimentary tract is mostly under the autonomous control of the enteric nervous system. Salivary glands respond to both parasympathetic and sympathetic stimulation with secretion. Sympathetic stimulation elicits viscous secretion with a high amylase content, and parasympathetic stimulation elicits a more copious, watery saliva.

Sympathetic activity generally reduces glandular secretion because it causes vasoconstriction, whereas parasympathetic stimulation increases local blood flow, promoting secretion. Sweat glands are an exception to this rule, as sympathetic stimulation increases sweating. Most of the sympathetic fibers are cholinergic rather than adrenergic, but in many sympathetic fibers to sweat glands are under {α}-adrenergic control.

Gastrointestinal Reflexes

Gastrointestinal function is controlled by many autonomic reflexes. Some depend on input from the parasympathetic or sympathetic nervous systems (eg, control of secretion in the stomach), while others are mainly under local control of the enteric nervous system. For example, intestinal —the wave of muscle contractions along the length of the intestine that propels intestinal contents toward the anus—is controlled entirely by the enteric nervous system.

As food enters the intestine it pushes the intestinal wall outward, thus stretching sensory neurons in the wall. When sufficiently stretched, these neurons activate interneurons and motor neurons in the myenteric plexus to move the food forward. Peristalsis starts with the activation of excitatory motor neurons whose fibers project orally, causing the circular muscle at the oral end of the intestinal distention to contract. At the same time, reflex activation of inhibitory motor neurons, whose fibers project anally, relaxes the circular smooth muscle at the anal end of the distention. The waves of contraction and relaxation of the intestinal wall propel the food through the intestines. During peristalsis, parasympathetic nerves excite enteric neurons through nicotinic receptors and contracts smooth muscle through muscarinic receptors. Nitric oxide is thought to mediate smooth muscle relaxation in peristalsis.

Urogenital Reflexes

The control of bladder emptying is unusual because it involves both involuntary autonomic reflexes and some voluntary control. The excitatory input to the bladder wall that causes contraction and promotes emptying is parasympathetic. Activation of parasympathetic postganglionic neurons in the pelvic ganglion plexus near to and within the bladder wall contracts the bladder's smooth muscle. These neurons are quiet when the bladder begins to fill but are activated reflexly by visceral afferents when the bladder is distended.

The sympathetic nervous system relaxes the bladder smooth muscle. Axons of preganglionic sympathetic neurons project from the thoracic and upper lumbar spinal cord to the inferior mesenteric ganglion. From there, postganglionic fibers travel to the bladder in the hypogastric nerve. When the sympathetic system is activated by low-frequency firing in sensory afferents that respond to tension in the bladder wall, the parasympathetic neurons in the pelvic ganglion are inhibited, relaxing bladder smooth muscle and exciting the internal muscle. Thus, during bladder filling the sympathetic system promotes relaxation of the bladder wall directly while maintaining closure of the internal sphincter.

Somatic motor neurons in the ventral horn of the sacral spinal cord innervate striated muscle fibers in the external urethral sphincter, causing it to contract. These motor neurons are stimulated by visceral afferents that are activated when the bladder is partially full. As the bladder fills, spinal sensory afferents relay this information to a region in the pons that coordinates micturition. This pontine area, sometimes called Barrington's nucleus after the British neurophysiologist who first described it, also receives important descending inputs from the forebrain concerning behavioral cues for emptying the bladder. Descending pathways from Barrington's nucleus cause coordinated inhibition of sympathetic and somatic systems, relaxing both . The onset of urinary flow through the causes reflex contraction P.969 of the bladder that is under parasympathetic control. Figure 49-6 Both acetylcholine (ACh) and a luteinizing -releasing hormone (LHRH)-like peptide are released by presynaptic cells at synapses in the sympathetic chain ganglia in the bullfrog. The two transmitters produce different types of postsynaptic potentials in different postganglionic neurons because of their actions on different receptors. (Adapted from Jan and Jan 1983.)

A. In one type of postganglionic neuron a single presynaptic stimulus evokes a fast excitatory postsynaptic potential (fast EPSP) at a nicotinic ACh receptor. Repetitive stimulation evokes a slow inhibitory postsynaptic potential (slow IPSP) at a muscarinic ACh receptor and a slow EPSP at a peptidergic receptor.

B. In another class of postganglionic neurons a single presynaptic stimulus also evokes a fast EPSP at the nicotinic ACh receptor but repetitive stimulation leads to a slow EPSP at the muscarinic ACh receptor. This class of neurons also evokes the slow peptidergic EPSP, but only in response to stimulation of the preganglionic fibers shown in A. The peptide diffuses from these terminals to distant receptors.

In patients with spinal cord injuries at the cervical or thoracic levels, the spinal reflex control of micturition remains intact, but the connections with the pons are severed. As a result, micturition cannot be voluntarily controlled. When it does occur as a spinal reflex resulting from bladder overfilling, is incomplete. As a result, urinary tract infections are common, and it may be necessary to empty the bladder mechanically by catheterization

Sexual reflexes are organized in a pattern that is analogous to those controlling bladder function. Erectile tissue is controlled largely by the parasympathetic nervous system, involving neurons that produce nitrous oxide as their main mediator. Glandular secretion is also parasympathetically mediated. Ejaculation in males is caused by sympathetic control of the and vas deferens, and emission involves control of striated muscles in the pelvic floor as well. Supraspinal inputs play an important role in producing the coordinated pattern of sexual response, although some simple sexual reflexes can be activated even after spinal transection (eg, penile can be elicited by local sensory stimuli).

Autonomic Neurons Use a Variety of Chemical Transmitters

Autonomic ganglion cells receive and integrate inputs from both the central nervous system (through preganglionic nerve terminals) and the periphery (through branches of sensory nerves that terminate in the ganglia). Most of the sensory fibers are nonmyelinated and may release neuropeptides, such as substance P and gene-related peptide (CGRP), onto ganglion cells. Preganglionic fibers primarily use ACh and norepinephrine as transmitters.

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Ganglionic Transmission Involves Both Fast and Slow Synaptic Potentials

Preganglionic activity induces both brief and prolonged responses from postganglionic neurons. ACh released from preganglionic terminals evokes fast excitatory postsynaptic potentials (EPSPs) mediated by nicotinic ACh receptors. The fast EPSP is often large enough to generate an action potential in the postganglionic neuron, and it is thus regarded as the principal synaptic pathway for ganglionic transmission in both the sympathetic and parasympathetic systems.

ACh also evokes slow EPSPs and inhibitory postsynaptic potentials (IPSPs) in postganglionic neurons. These slow potentials can modulate the excitability of these cells. They have been most often studied in sympathetic ganglia but are also known to occur in some parasympathetic ganglia. Slow EPSPs or IPSPs are mediated by muscarinic ACh receptors (Figure 49-6). The slow excitatory potential results when Na+ and Ca2+ channels open and M-type K+ channels close. The M-type channels are normally active at the resting membrane potential, so their closure leads to membrane depolarization (Chapter 13). The slow inhibitory potential results from the opening of K+ channels, allowing K+ ions to flow out of the nerve terminals, resulting in hyperpolarization.

The fast cholinergic EPSP reaches a maximum within 10-20 ms; the slow cholinergic synaptic potentials take up to half a second to reach their maximum and last for a second or more (Figure 49-6). Even slower synaptic potentials, lasting up to a minute, are evoked by neuropeptides, a variety of which are present in the terminals of preganglionic neurons and endings. The actions of one peptide have been studied in detail and reveal important features of peptidergic transmission.

In some, but not all, preganglionic nerve terminals in bullfrog sympathetic ganglia, ACh is colocalized with a -releasing hormone (LHRH)-like peptide. High-frequency stimulation of the preganglionic nerves causes the peptide to be released, evoking a slow, long-lasting EPSP in all postganglionic neurons (Figure 49-6), even those not directly innervated by the peptidergic fibers. The peptide must diffuse over considerable distances to influence distant receptive neurons. The slow peptidergic EPSP, like the slow cholinergic excitatory potential, also results from the closure of M-type channels and the opening of Na+ and Ca2+ channels. The peptidergic excitatory potential alters the excitability of cells for long periods after intense activation of preganglionic inputs. No mammalian equivalent of the actions of the LHRH-like peptide in has yet been identified, but the neuropeptide substance P released from sensory afferent terminals in evokes a similar slow, long-lasting EPSP.

Norepinephrine and Acetylcholine Are the Predominant Transmitters in the Autonomic Nervous System

Most postganglionic sympathetic neurons release norepinephrine, which acts on a variety of different adrenergic receptors. There are five major types of adrenergic receptors, and these are the target for several medically important drugs (Table 49-1).

ATP and Adenosine Have Potent Extracellular Actions

Adenosine triphosphate (ATP) is an important cotransmitter with norepinephrine in many postganglionic sympathetic neurons. By acting on ATP-gated ion channels

(P2 purinergic receptors), it is responsible for some of the fast responses seen in target tissues (Table 49-1). The proportion of ATP to norepinephrine varies considerably in different sympathetic nerves. The ATP component is relatively minor in nerves to blood vessels in the rat tail and rabbit , while the responses of guinea pig submucosal arterioles to sympathetic stimulation appear to be mediated solely by ATP.

The nucleotide adenosine is formed from the hydrolysis of ATP and is recognized by P1 purinergic receptors (Table 49-1) located both pre- and postjunctionally. It is thought to play a modulatory role in autonomic transmission, particularly in the sympathetic system. Adenosine may dampen sympathetic function after intense sympathetic activation by activating receptors on sympathetic nerve endings that inhibit further norepinephrine and ATP release. Adenosine also has inhibitory actions in cardiac and smooth muscle that tend to oppose the excitatory actions of norepinephrine.

Many Different Neuropeptides Are Present in Autonomic Neurons

Neuropeptides are colocalized with norepinephrine and ACh in autonomic neurons. Cholinergic preganglionic neurons in the spinal cord and brain stem and their terminals in autonomic ganglia may contain enkephalins, neurotensin, , or substance P. Noradrenergic postganglionic sympathetic neurons may also express a variety of neuropeptides. Neuropeptide Y is present in as many as 90% of the cells and modulates sympathetic transmission. In tissues in which the nerve endings are distant from their targets (more than 60 nm, as for the rabbit ear ), P.971

P.972 neuropeptide Y potentiates both the purinergic and adrenergic components of the tissue response, probably by acting postsynaptically. In contrast, in tissues with dense sympathetic innervation and where the target is closer (20 nm, such as the vas deferens), neuropeptide Y acts presynaptically to inhibit release of ATP and norepinephrine, thus dampening the tissue response. The peptides galanin and dynorphin are often found with neuropeptide Y in sympathetic neurons, which can contain several neuropeptides. Cholinergic postganglionic sympathetic neurons commonly contain CGRP and vasoactive intestinal polypeptide (VIP) (Figure 49-7).

Table 49-1 Pharmacology of the Autonomic Nervous System Receptor category Functional roles1 Drugs that act selectively at these Medical use receptors Norepinephrine

Adrenergic α1 Contractile effects of NE on smooth muscle, especially Prazosin (antagonist) blood vessels, urogenital, and sphincter muscles

Adrenergic α2 Presynaptic control (inhibitory) of release of NE, ATP, Yohimbine (antagonist) Delay ejaculation and ACh from nerve terminals

Adrenergic β1 Stimulatory effects of NE and circulating epinephrine Atenolol (antagonist) Hypertension on heart

Adrenergic β2 Relaxant effects of NE on smooth muscle in Salbutamol (agonist) Bronchodilator for asthma gastrointestinal tract, urinogenital system, and airways

Adrenergic β3 Stimulate release of free fatty acids from adipose None Potential in obesity tissue Acetylcholine Cholinergic-nicotinic (ganglionic type) Fast excitation of postganglionic neurons in autonomic Hexamethonium (antagonist) Hypertension (formerly) ganglia

Cholinergic-muscarinic M1 Inhibit ACh and NE release from Pirenzepine (antagonist) Anti-ulcerogenic terminals

Cholinergic-muscarinic M2 Effects of ACh on heart and smooth muscle Atropine (nonselective antagonist) Mydriatic

Cholinergic-muscarinic M3 ACh-induced secretion from glandular tissues (eg, Atropine (nonselective antagonist) Reduced drooling in Parkinson disease ) Others

Purinergic P1 (Four subtypes) Modulatory effects of adenosine on autonomic effector Theophylline (antagonist) Bronchodilator tissues

Purinergic P2 (Two subtypes) Fast and slow responses to ATP in smooth muscle Few drugs; suramin is P2Y antagonist None Nitric oxide (NO) Relaxant effects on smooth muscle, especially blood Glyceryl trinitrate and nitroprusside (generate NO) Coronary vasodilators for vessels 1ACh = acetylcholine; ATP = ; NE = norepinephrine.

Figure 49-7 A variety of neuropeptides coexist with norepinephrine and acetylcholine in neurons of the sympathetic ganglia, as shown here for the cat and the guinea pig. The sympathetic preganglionic nuclei extend from T1 to L3.MCG = WW ; WSCG = superior cervical ganglion; SG = . (Adapted from Elfvin et al. 1993.)

In postganglionic parasympathetic neurons that express VIP together with ACh, the peptide may contribute to the response of the target tissue because of its powerful vasodilator effects. For example, ACh triggers salivary gland secretion while VIP is responsible for the local increase in blood flow, which is important to the secretory response. Some of the complex modulatory functions that neuropeptides perform are illustrated in Figure 49-8.

A Central Autonomic Network Coordinates Autonomic Function

Autonomic functions ultimately must be coordinated with one another and the ongoing behavioral needs of the individual. This coordination is carried out by a highly interconnected set of structures in the brain stem and forebrain that form a central autonomic network.

A key component of this network is the nucleus of the solitary tract. The nucleus receives visceral input from cranial nerves VII, IX, and X and then uses this information to modulate autonomic function in two ways (Figure 49-9).

First, the nucleus of the solitary tract projects to neurons forming brain stem and spinal circuits that control simple autonomic responses. For example, visceral P.973 afferents relayed through the nucleus of the solitary tract directly regulate vagal motor control of the stomach and heart rate. Other outputs from the nucleus of the solitary tract innervate neurons in the ventrolateral medullary reticular formation and control blood pressure by regulating the blood flow in different vascular beds (Figure 49-10).

Second, the nucleus of the solitary tract acts to integrate autonomic function with more complex endocrine and behavioral responses, a process in which the hypothalamus, which we will consider below, plays an important role.

The visceral sensory outflow from the nucleus of the solitary tract is relayed to the forebrain by the parabrachial nucleus, which is important for the behavioral responses to taste and other visceral sensations. Lesions of the parabrachial nucleus prevent conditioned behavioral responses resulting from gustatory cues. The parabrachial nucleus surrounds the superior cerebellar peduncle in the upper pons and provides inputs to the hypothalamus, the matter, the amygdaloid complex, the visceral sensory , and the cortex. In turn, the parabrachial nucleus receives descending connections from these regions.

The periaqueductal gray matter surrounds the cerebral aqueduct in the midbrain. It receives inputs from the nucleus of the solitary tract, the parabrachial nucleus, and the hypothalamus and projects to the medullary reticular formation, where it produces behaviorally coordinated patterns of autonomic response. For example, during a “fight-or-flight” response, the periaqueductal gray matter redirects blood flow from internal organs to the hind limbs to support running behavior.

The amygdaloid complex plays a key role in regulation of the autonomic components of conditioned behavioral responses. Inputs to the amygdala from areas of the cortex and the thalamus concerned with behavior enter the lateral and basal nuclei, whereas the central nucleus receives inputs from the central autonomic system. Complex internal circuits allow the amygdala to associate autonomic responses with specific behaviors. For example, as we shall learn in the chapter on emotion (Chapter 50), when a rat learns that an auditory cue is followed by an electric shock, the auditory cue itself eventually produces an elevation of heart rate and behavioral freezing previously associated with the shock. Lesions of the central nucleus of the amygdala, which projects to the hypothalamus and the medulla, prevent this response.

Visceral sensory areas of the thalamus and the visceral sensory cortex both receive visceral sensory afferents directly from the parabrachial nucleus. In primates, the taste component of the nucleus of the solitary tract also projects to the thalamus, thus providing an even more direct relay of taste information to consciousness. The visceral sensory thalamic areas are located in a small-celled nucleus adjacent to the ventroposterior (somatic sensory) complex, the ventroposterior parvocellular nucleus. This thalamic nucleus relays taste and other visceral P.974 sensations ( pangs, abdominal fullness, breath-holding sensations) to the anterior insular cortex, where there is a topographic map of the internal systems. Taste is located most anteriorly in the insular cortex, with gastrointestinal, then cardiorespiratory sensations, more posteriorly.

Figure 49-8 Complex modulatory functions of neuropeptides. Sensory neurons in the wall of the colon that excite sympathetic ganglion cells in the inferior mesenteric ganglion (IMG) use several neuropeptides along with acetylcholine (ACh) as transmitters. The neurons that contain cholecystokinin and the vasoactive intestinal polypeptide (VIP) are mechanosensory. Other mechanosensory fibers originate in spinal ganglion cells and contain substance P (SP). They provide excitatory synapses to the sympathetic ganglion cells. Cholinergic fibers originating in the preganglionic spinal cord nuclei contain either enkephalins (ENK) or neurotensin (NT). The cholinergic neurons form an excitatory input to the ganglion cells. The enkephalin pathway inhibits release of ACh and SP, whereas the NT pathway facilitates release of SP and gives rise to an excitatory potential in some IMG neurons. Excitatory neurotransmitters and peptides are indicated in orange; inhibitory in gray. NA = noradrenaline; NE = norepinephrine; NPY = neuropeptide Y; SOM = somatostatin. (Adapted from Elfvin et al. 1993.) Figure 49-9 Pathways that distribute visceral sensory information in the brain. Visceral afferent information (solid line) enters the brain through the nucleus of the solitary tract. It is distributed to preganglionic neurons, to an area in the ventrolateral medulla that coordinates autonomic and respiratory reflexes, and via an ascending pathway to the forebrain. Less direct inputs (dotted line) relayed from the parabrachial nucleus bring visceral sensory information to the hypothalamus, the amygdala, the septum (not shown), the cortex, and the periaqueductal gray matter.

The visceral sensory cortex interacts with a portion of the anterior tip of the cingulate cortex, called the infralimbic area, which is a visceral motor region. Electrical or chemical stimulation here can cause gastric contractions or changes in blood pressure. Both the anterior insular and infralimbic areas project to the amygdala, hypothalamus, periaqueductal gray matter, parabrachial nucleus, nucleus of the solitary tract, and medullary reticular formation. Lesions of the visceral sensory cortex cause loss of conscious appreciation of visceral sensation such as taste. The visceral motor cortex is part of a region of cingulate cortex in which injury causes abulia, a condition in which patients fail to show emotional reactions to external stimuli.

The Hypothalamus Integrates Autonomic and Endocrine Functions With Behavior

The hypothalamus plays a particularly important role in regulating the autonomic nervous system and was once referred to as the “head ganglion” of the autonomic nervous system. But recent studies of hypothalamic function have led to a somewhat different view. Whereas early studies found that electrical stimulation or lesions in the hypothalamus can profoundly affect autonomic function, more recent investigations have demonstrated that many of these effects are due to involvement of descending and ascending pathways of the cerebral cortex or the basal forebrain passing through the hypothalamus. Modern studies indicate that the hypothalamus functions to integrate autonomic response and endocrine function with behavior, especially behavior concerned with the basic homeostatic requirements of everyday life.

The hypothalamus serves this integrative function by regulation of five basic physiological needs:

● It controls blood pressure and electrolyte composition by a set of regulatory mechanisms that range from control of drinking and salt appetite to the maintenance of blood osmolality and vasomotor tone.

● It regulates body temperature by means of activities ranging from control of metabolic thermogenesis to behaviors such as seeking a warmer or cooler environment.

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● It controls energy metabolism by regulating feeding, , and metabolic rate.

● It regulates reproduction through hormonal control of mating, , and .

● It controls emergency responses to stress, including physical and immunological responses to stress by regulating blood flow to muscle and other tissues and the secretion of adrenal stress . Figure 49-10 Pathways that control autonomic responses. Direct outputs to autonomic preganglionic neurons (solid line) arise from the paraventricular and , the parabrachial nucleus, the nucleus of the solitary tract, certain monoamine groups such as the A5 noradrenergic neurons (not shown), serotonergic raphe neurons (not shown), and adrenergic neurons in the ventrolateral medulla. Less direct outputs from the cerebral cortex, amygdala, and periaquaductal gray matter (dotted lines) are relayed into the cell groups with direct input to the preganglionic inputs. Nearly all of the cell groups illustrated in these drawings are also connected with one another, forming a central autonomic network.

The hypothalamus regulates these basic life processes by recourse to three main mechanisms. First, the hypothalamus has access to sensory information from virtually the entire body. It receives direct inputs from the visceral sensory system and the , as well as the retina. The visual inputs are used by the to synchronize the internal clock mechanism to the day-night cycle in the external world (Chapter 3). Visceral somatosensory inputs carrying information about are relayed to the hypothalamus from the spinal and trigeminal dorsal horn (Chapters 23 and 24). In addition, the hypothalamus has internal sensory neurons that are responsive to changes in local temperature, osmolality, , and sodium, to name a few examples. Finally, circulating hormones such as angiotensin II and leptin enter the hypothalamus at specialized zones along the margins of the called circumventricular organs, where they interact directly with hypothalamic neurons.

Second, the hypothalamus compares sensory information with biological set points. It compares, for example, local temperature in the to the set point of 37°C and, if the hypothalamus is warm, activates mechanisms for heat dissipation. There are set points for a wide variety of physiological processes, including blood sugar, sodium, osmolality, and hormone levels.

Finally, when the hypothalamus detects a deviation from a set point, it adjusts an array of autonomic, endocrine, and behavioral responses to restore homeostasis. If the body is too warm, the hypothalamus shifts blood flow from deep to cutaneous vascular beds and increases sweating, to increase heat loss through the skin. It increases secretion, to conserve water for sweating. Meanwhile, the hypothalamus activates coordinated behaviors, such as seeking to change the local ambient temperature or seeking a cooler environment. Figure 49-11 The structure of the hypothalamus.

A. Frontal view of the hypothalamus (section along the plane shown in part B).

B. A medial view shows most of the main nuclei. The hypothalamus is often divided analytically into three areas in a rostocaudal direction: the preoptic area, the tuberal level, and the posterior level.

All of these processes must be precisely coordinated. For example, adjustments in blood flow in different vascular beds are important for such diverse activities as thermoregulation, digestion, response to emergency, and sexual intercourse. In order to do this, the hypothalamus contains an array of specialized cell groups with different functional roles.

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The Hypothalamus Contains Specialized Groups of Neurons Clustered in Nuclei

Although the hypothalamus is very small, occupying only about 4 grams of the total 1400 grams of adult weight, it is packed with a complex array of cell groups and fiber pathways (Figure 49-11). The hypothalamus can be divided into three regions: anterior, middle, and posterior. The most anterior part of the hypothalamus, overlying the optic chiasm, is the preoptic area. The preoptic nuclei, which include the circadian pacemaker (suprachiasmatic nucleus), are mainly concerned with integration of different kinds of sensory information needed to judge deviation from physiological set point. The preoptic area controls blood pressure and composition; cycles of activity, body temperature, and many hormones; and reproductive activity.

The middle third of the hypothalamus, overlying the , contains the dorsomedial, ventromedial, paraventricular, supraoptic, and arcuate nuclei. The paraventricular nucleus includes both magnocellular and parvocellular neuroendocrine components controlling the posterior and anterior . In addition, it contains neurons that innervate both the parasympathetic and sympathetic preganglionic neurons in the medulla and the spinal cord, thus playing a major role also in regulating autonomic responses. The arcuate and periventricular nuclei, along the wall of the third ventricle, like the paraventricular nucleus contain parvocellular neuroendocrine neurons, whereas the contains additional magnocellular neuroendocrine cells. The ventromedial and dorsomedial nuclei project mainly locally within the hypothalamus and to the periaqueductal gray matter, to regulate complex integrative functions such as control of growth, feeding, maturation, and reproduction.

Finally, the posterior third of the hypothalamus includes the and the overlying posterior hypothalamic area. In addition to the mammillary nuclei, whose function remains enigmatic, this region includes the tuberomammillary nucleus, a histaminergic cell group that is important in regulating wakefulness and .

The major nuclei of the hypothalamus are located for the most part in the medial part of the hypothalamus, sandwiched between two major fiber systems. A massive longitudinal fiber pathway, the , runs through the lateral hypothalamus. The medial forebrain bundle connects the hypothalamus with the brain stem below, and with the basal forebrain, amygdala, and cerebral cortex above. Large neurons scattered among the fibers of the medial forebrain bundle provide long-ranging hypothalamic outputs that reach from the cerebral cortex to the sacral spinal cord. They are involved in organizing behaviors as well as autonomic responses.

Figure 49-12 The hypothalamus controls the pituitary gland both directly and indirectly through hormone-releasing neurons. Peptidergic neurons (5) release or vasopressin into the general circulation through the . Two general types of neurons are involved in regulation of the . Peptidergic neurons (3, 4) synthesize and release hormones into the hypophyseal-portal circulation. The second type of neuron is the link between the peptidergic neurons and the rest of the brain. These neurons, some of which are monoaminergic, are believed to form synapses with peptidergic neurons either on the cell body (1) or on the (2).

A second, smaller fiber system is located medial to the major hypothalamic nuclei, in the wall of the third P.978 ventricle. This periventricular fiber system contains longitudinal fibers that link the hypothalamus to the periaqueductal gray matter in the midbrain. This pathway is thought to be important in activating simple, stereotyped behavioral patterns, such as posturing during sexual behavior. The periventricular system also conveys the axons of the parvocellular neuroendocrine neurons located in the periventricular region, and including the paraventricular and arcuate nuclei, to the , for control of the anterior pituitary gland. They are met in the median eminence by the axons from the magnocellular neurons, which continue down the pituitary stalk to the posterior pituitary gland. Figure 49-13 The paraventricular nucleus of the hypothalamus is a microcosm of the autonomic and endocrine control systems. Two distinct populations of magnocellular neuroendocrine neurons produce oxytocin or vasopressin, which are secreted into the bloodstream in the posterior pituitary gland. Parvocellular neuroendocrine neurons in the medial paraventricular nucleus (medial parvocellular neuroendocrine neurons) contain hypothalamic releasing hormones, such as corticotropin-releasing hormone and release-inhibiting hormones, such as and somatostatin. Their axons project to the median eminence, where they release their hormones into the hypophysial portal circulation to control the anterior pituitary gland. Dorsal, ventral, and lateral (not shown) parvocellular neurons project to the preganglionic cell groups in the medulla and the spinal cord, as well as to other autonomic control nuclei in the brain stem. They use mainly oxytocin and vasopressin as neuromodulators. However, this is a completely distinct population from the magnocellular oxytocin and vasopressin neurons, as few if any cells send axons to both the posterior pituitary and the brain stem.

The Hypothalamus Controls the Endocrine System

The hypothalamus controls the endocrine system directly, by secreting neuroendocrine products into the general P.979 circulation from the posterior pituitary gland, and indirectly, by secreting regulatory hormones into the local portal circulation, which drains into the blood vessels of the anterior pituitary (Figure 49-12). These regulatory hormones control the synthesis and release of anterior pituitary hormones into the general circulation. The highly fenestrated (perforated) of the posterior pituitary and median eminence of the hypothalamus facilitate the entry of hormones into the general circulation or the portal plexus. Direct and indirect control form the basis of our modern understanding of hypothalamic control of endocrine activity.

Table 49-2 Hormones of the Posterior Pituitary Gland Name Structure Function

Vasopressin H-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 S-S Vasoconstriction, water resorption by the

Oxytocin H-Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2 S-S and milk ejection

Magnocellular Neurons Secrete Oxytocin and Vasopressin Directly From the Posterior Pituitary

Large neurons in the paraventricular and supraoptic nuclei, constituting the magnocellular region of the hypothalamus, project to the posterior pituitary gland (neurohypophysis). Some of the magnocellular neuroendocrine neurons in the paraventricular and supraoptic nuclei release the neurohypophyseal hormone oxytocin, while others release vasopressin into the general circulation by way of the posterior pituitary (Figure 49-13). These peptides circulate to target organs of the body that control water balance and milk release.

Oxytocin and vasopressin are peptides that contain nine amino acid residues (Table 49-2). Like other peptide hormones, they are cleaved from larger prohormones (see Chapter 15). The prohormones are synthesized in the cell body and cleaved within transport vesicles as they travel down the axons. The peptide neurophysin is a cleavage product of the processing of vasopressin and oxytocin and is released along with the hormone in the posterior pituitary. The neurophysin formed in neurons that release vasopressin differs somewhat from that produced in neurons that release oxytocin.

Parvocellular Neurons Secrete Peptides That Regulate Release of Anterior Pituitary Hormones

Geoffrey Harris proposed in the 1950s that the anterior pituitary gland is regulated indirectly by the hypothalamus. He demonstrated that the hypophysial portal , which carry blood from the hypothalamus to the anterior pituitary gland, convey important signals that control anterior pituitary secretion. In the 1970s the structure of a series of peptide hormones that carry these signals was elucidated. These hormones fall into two classes: releasing hormones and release-inhibiting hormones (Table 49-3). Of all the anterior pituitary hormones, only is under predominantly inhibitory control. Hence transection of the pituitary stalk causes insufficiency of , , gonadal, and growth hormones, but increased prolactin secretion.

Systematic electrical recordings have not been made from neurons that secrete releasing hormones. However, they are believed to fire in bursts because of the pulsatile of secretion of the anterior pituitary hormones, which show periodic surges throughout the day. Episodic firing may be particularly effective for causing hormone release and may limit receptor inactivation.

The neurons that make releasing hormones are found mainly along the wall of the third ventricle. The -releasing hormone (GnRH) neurons tend to be located most anteriorly, along the basal part of the third ventricle. Neurons that make somatostatin, corticotropin-releasing hormone (CRH), and dopamine are located more dorsally and are found in the medial part of the paraventricular nucleus. Neurons that make -releasing hormone (GRH), thyrotropin- releasing hormone (TRH), GnRH, and dopamine are found in the , an expansion of the periventricular gray matter that overlies the median eminence, in the floor of the third ventricle (see Figure 49-10). The median eminence contains a plexus of fine loops. These are fenestrated capillaries, and the terminals of the neurons that contain releasing hormones end on these loops. The blood then flows from the median eminence into a secondary (portal) venous system, which carries it to the anterior pituitary gland (See Figure 49-11).

Table 49-3 Hypothalamic Substances That Release or Inhibit the Release of Anterior Pituitary Hormones Hypothalamic substance Anterior pituitary hormone Releasing Thyrotropin-releasing hormone (TRH) Thyrotropin, prolactin Corticotropin-releasing hormone (CRH) Adrenocorticotropin, β-lipotropin Gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH), follicle-stimulating hormone (FSH) Growth hormone-releasing hormone (GHRH or GRH) Growth hormone (GH) Prolactin-releasing factor (PRF) Prolactin Melanocyte-stimulating hormone-releasing factor (MRF) Melanocyte-stimulating hormone (MSH), β-endorphin Inhibiting Prolactin release-inhibiting hormone (PIH), dopamine Prolactin Growth hormone release-inhibiting hormone (GIH or GHRIH; somatostatin) Growth hormone, thyrotropin Melanocyte-stimulating hormone release-inhibiting factor (MIF) Melanocyte-stimulating hormone (MSH)

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An Overall View

The three divisions of the autonomic nervous system comprise an integrated motor system that acts in parallel with the somatic motor system and is responsible for homeostasis. Esential to the functioning of the motor outflow are the visceral sensory afferents that are relayed from the nucleus of the solitary tract through a network of central autonomic control nuclei. The hypothalamus integrates somatic, visceral, and behavioral information from all of these sources, thus coordinating autonomic and endocrine outflow with behavioral state.

Several features of the autonomic nervous system permit rapid integrated responses to changes in the environment. The activity of effector organs is finely controlled by coordinated and balanced excitatory and inhibitory inputs from tonically active postganglionic neurons. Moreover, the sympathetic system is greatly divergent, permitting the entire body to respond to extreme conditions

In addition to the small molecule neurotransmitters— ACh and norepinephrine—a wide variety of peptides are thought to be released by autonomic neurons either onto postganglionic cells or their targets. Many of these peptides act to alter the efficacy of cholinergic or adrenergic transmission. The autonomic nervous system uses a rich variety of chemical mediators, several of which may commonly coexist in single autonomic neurons. The release of different combinations of chemical mediators from autonomic neurons may represent a means of “chemical coding” of information transfer in the different branches of the autonomic nervous system, although we are still only beginning to learn how to read the code

As we shall also see in the following two chapters, the autonomic nervous system is a remarkably adaptable system of homeostatic control. It can function locally through branches of primary sensory fibers that terminate in autonomic ganglia, or intrinsically through the entire nervous system on the functions of the digestive tract. Control centers in the brain stem are involved in several autonomic reflexes. While the hypothalamus integrates behavioral and emotional responses arising from the forebrain with ongoing metabolic need to produce highly coordinated autonomic control and behavior.

Selected Readings

Bacq ZM. 1974. Chemical Transmission of Nerve Impulses: A Historical Sketch. New York: Pergamon.

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Burnstock G. l972. Purinergic nerves. Pharmacol Rev 24:509–581.

Burnstock G, Hoyle CHV (eds). 1995. The Autonomic Nervous System. Vol. 1, Autonomic Neuroeffector Mechanisms. London: Harwood Academic.

Cannon WB. 1932. The Wisdom of the Body. New York: Norton. Costa M, Brookes SJ. 1994. The enteric nervous system. Am J Gastroenterol 89 (Suppl):S129–137.

Furness JB, Bornstein JC, Murphy R, Pompolo S. 1992. Roles of peptides in transmission in the enteric nervous system. Trends Neurosci 15:66–71.

Langley JN. 1921. The Autonomic Nervous System. Cambridge: Heffer & Sons.

Milner P, Burnstock G. 1995. Neurotransmitters in the autonomic nervous system. In: AD Korczyn (ed). Handbook of Autonomic Nervous System Dysfunction, pp. 5-32. New York: Marcel Dekker.

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