47: The Autonomic Motor System and the Hypothalamus

• The Autonomic Motor System Mediates Homeostasis

• The Autonomic System Contains Visceral Motor Neurons That Are Organized into Ganglia

  • Preganglionic Neurons Are Localized in Three Regions Along the Brain Stem and Spinal Cord

  • Sympathetic Ganglia Project to Many Targets Throughout the Body

  • Parasympathetic Ganglia Innervate Single Organs

  • The Enteric Ganglia Regulate the Gastrointestinal Tract

• Both the Pre- and Postsynaptic Neurons of the Autonomic Motor System Use Co-Transmission at Their Synaptic Connections

• Autonomic Behavior Is the Product of Cooperation Between All Three Autonomic Divisions

• Autonomic and Endocrine Functions Are Coordinated by a Central Autonomic Network Centered in the Hypothalamus

• The Hypothalamus Integrates Autonomic, Endocrine, and Behavioral Responses

  • Magnocellular Neuroendocrine Neurons Control the Pituitary Gland Directly

  • Parvicellular Neuroendocrine Neurons Control the Pituitary Gland Indirectly

• An Overall View

When we are frightened our heart 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 accompanying fear are mediated by the autonomic motor system, which controls heart muscle, smooth muscle, and exocrine glands. The autonomic motor system is controlled by a central neuronal network that includes the hypothalamus.

As we shall learn in this and the next two chapters, the hypothalamus regulates the autonomic circuits so as to recruit appropriate physiological responses for specific emotions and to coordinate these physiological and emotional responses with other aspects of behavior to insure constancy of the internal environment (homeostasis). The hypothalamus contributes to the maintenance of homeostasis by acting on three major systems: the autonomic motor system, the endocrine system, and an ill-defined neural system concerned with motivation.

The autonomic motor system is distinct from the somatic motor system, which controls skeletal muscle. Nevertheless, to produce behaviors the somatic and autonomic motor systems must work together. Whereas neurons in the somatic motor system regulate contractions of striated muscles (see Chapter 34), the autonomic motor system regulates gland cells as well as smooth and cardiac muscle, maintains constant body temperature, and controls eating, drinking, and sexual behavior.

Although the autonomic motor system is largely involuntary, the behaviors controlled by it are tightly integrated with voluntary movements controlled by the somatic motor system. Running, climbing, and lifting are voluntary actions with metabolic requirements and thermoregulatory consequences that are automatically met by the autonomic system through changes in cardiorespiratory drive, cardiac output, regional blood flow, and ventilation. Autonomic behaviors similarly are linked to emotional arousal, stress, motivation, and defensive reactions. Feelings of fear, anger, happiness, and sadness have characteristic autonomic manifestations.

In this chapter we first examine the peripheral components of the autonomic system and then their role in mediating behaviors. We then explore how these "autonomic behaviors" are orchestrated through a central autonomic network in the brain stem and hypothalamus. We conclude by considering the role of the amygdala and specialized areas of cerebral cortex in coordinating autonomic function with motivation, volition, and emotion. The autonomic and hypothalamic mechanisms involved in emotion and motivation are examined in more detail in the next two chapters.

In the middle of the 19th century Claude Bernard in Paris drew attention to the stability of the body's internal environment, which includes the "fluid that surrounds and bathes all tissues," during a broad range of behavioral states and external conditions. Bernard wrote: "The internal environment (le milieu interior) is a necessary condition for a free life." Building on this idea, in the 1930s Walter B. Cannon introduced the concept of homeostasis to describe the mechanisms that maintain within a narrow physiological range the constancy of composition of the bodily fluids, body temperature, blood pressure, and other physiological variables.

As envisioned by Cannon, homeostatic mechanisms are adaptive because they extend the range of human behavior. For example, during exercise healthy people can increase their cardiac output four- to five-fold while maintaining blood pressure within a much narrower range. In the absence of these normal compensatory changes, blood pressure would increase in direct proportion to cardiac output, and the resulting increase in pressure would rupture blood vessels, perturb fluid composition, and alter the balance among the vascular, interstitial, and intracellular compartments. Increases in pressure of that proportion do not normally happen because the increase during exercise is curbed by an increase in diameter of the arteries that supply the working muscles and a resulting reduction of total vascular resistance to blood flow.

All homeostatic behavior, including control of the circulation, arises from neural modulation of the physiological properties of organ systems, mediated by hypothalamic control of the autonomic motor system and the endocrine system. We begin the discussion of these mechanisms by considering the peripheral components: the autonomic ganglia. The circuits of the ganglia connect with the spinal cord and brain stem and mediate simple reflexes that are the components of more complex behaviors.

Unlike the somatic motor system, in which the motor neurons are located in the ventral spinal cord and brain stem, the cell bodies of autonomic motor neurons are found in enlargements of peripheral nerves called ganglia.¹ The autonomic ganglia contain motor neurons that innervate the secretory epithelial cells in glands or smooth and cardiac muscle.

Overall, the nervous system has many more autonomic than somatic motor neurons. In humans the entire spinal cord contains only approximately 120,000 somatic motor nerve cells, whereas the superior cervical ganglion alone contains approximately 900,000 autonomic motor neurons. Although the significance of this difference in numbers is uncertain, it may reflect the great diversity and complexity of autonomically controlled target tissues—the stomach, intestine, bladder, heart, lungs, and vasculature—as compared to the relative uniformity of skeletal muscle controlled by the somatic motor system. Most autonomic ganglia contain far fewer cells. For example, in the lungs and gastrointestinal tract of humans there are many microscopic ganglia, each with only tens to hundreds of neurons. These differences in number of cells are thought to reflect differences in the degree of control and the size of peripheral target fields.

Efforts to understand the principles of organization of autonomic ganglia began in 1880 in England with the work of Walter Gaskell and were later continued by John N. Langley. Their pioneering studies determined how individual autonomic ganglia are functionally regulated by central nerves, and in turn how the different ganglia regulate different peripheral targets. Gaskell and Langley stimulated autonomic nerves and observed the responses of end-organs (eg, vasoconstriction, piloerection, sweating, pupillary constriction). They used nicotine to block signals from individual ganglia to test interactions between ganglia. In the course of these studies Langley proposed that specific chemical substances must be released by neurons of the autonomic ganglia and that these substances act by binding to receptors on the target cells. These ideas set the stage for the later investigations of chemical synaptic transmission. Langley also distinguished the autonomic and somatic motor systems and in so doing created much of our current nomenclature.

Langley divided the autonomic system into three divisions: sympathetic, parasympathetic, and enteric. All neurons in sympathetic and parasympathetic ganglia are controlled by preganglionic neurons whose cell bodies lie in the spinal cord and brain stem. The pre-ganglionic neurons synthesize and release the neurotransmitter acetylcholine (ACh), which acts on nicotinic ACh receptors in postganglionic neurons, producing fast excitatory postsynaptic potentials and initiating action potentials that propagate to synapses with effector cells in end-organs (Figure 47–1). The sympathetic and parasympathetic systems are distinguished by five criteria:

1. The segmental organization of their preganglionic neurons in the spinal cord and brain stem

2. The peripheral locations of their ganglia

3. The types and locations of end-organs they innervate

4. The effects they produce on end-organs

5. The neurotransmitters employed by their postganglionic neurons

Preganglionic Neurons Are Localized in Three Regions Along the Brain Stem and Spinal Cord

The parasympathetic pathways arise from a cranial nerve zone in the brain stem and a second zone in sacral segments of the spinal cord (Figure 47–2). These parasympathetic zones surround a sympathetic zone that extends continuously in thoracic and lumbar segments of the cord.

The cranial parasympathetic pathways arise from preganglionic neurons in the general visceral motor nuclei of four cranial nerves: the oculomotor nerve (N. III) in the midbrain and the facial (N. VII), glossopharyngeal (N. IX), and vagus (N. X) nerves in the medulla. The cranial parasympathetic nuclei are described in Chapter 45 together with the mixed cranial nerves (such as the facial, glossopharyngeal, and vagus). The spinal parasympathetic pathway originates in preganglionic neurons in sacral segments two to four (S2–S4). The cell bodies of most of these neurons are located in intermediate regions of the gray matter, and their axons project in peripheral nerves through the ventral roots.

The sympathetic preganglionic cell column extends between the cervical and lumbosacral enlargements of the spinal cord, corresponding to the first thoracic segment (T1) and third lumbar segment (L3) in humans (Figure 47–2). Most of the cell bodies of sympathetic preganglionic neurons are located in the intermediolateral cell column, near the lateral margin of the spinal gray matter at the level of the central canal (Figure 47–3). Others are found in the central autonomic area surrounding the central canal and in a band connecting the central area with the intermediolateral cell column. The axons of preganglionic sympathetic neurons project from the spinal cord through the nearest ventral root and then run with small connecting nerves known as rami communicantes before terminating on postganglionic cells in the paravertebral sympathetic chain (Figure 47–3).

Sympathetic Ganglia Project to Many Targets Throughout the Body

The sympathetic motor system regulates systemic physiological parameters such as blood pressure and body temperature by influencing target cells within virtually every tissue throughout the body (Figure 47–2). This regulation depends on afferent pathways from the spinal cord and from supraspinal structures that control the activity of the preganglionic neurons. Preganglionic neurons form synapses with neurons in paravertebral and prevertebral sympathetic ganglia (Figure 47–3) that in turn form synapses with a variety of end-organs, including blood vessels, heart, bronchial airways, piloerector muscles, and salivary and sweat glands. The preganglionic neurons also synapse on chromaffin cells in the medulla of the adrenal gland (Figure 47–3), which secrete epinephrine (adrenaline) and norepinephrine (noradrenaline) into the circulation as hormones to act on distant targets.

The paravertebral and prevertebral sympathetic ganglia differ both in location and organization. Paravertebral ganglia are distributed segmentally, extending bilaterally as two chains from the first cervical segment to the last sacral segment. The chains lie lateral to the vertebral column at its ventral margin and generally contain one ganglion per segment (Figures 47–2 and 47–3). Two important exceptions are the superior cervical and stellate ganglia. The superior cervical ganglion is a coalescence of several cervical ganglia and supplies sympathetic innervation to the entire head, including the cerebral vasculature. The stellate ganglion, which innervates the heart and lungs, is a coalescence of ganglia from lower cervical segments and the first thoracic segment. These sympathetic pathways have an orderly somatotopic relation to one another, from their segmental origin in preganglionic neurons to their terminus in peripheral targets.

The prevertebral ganglia are midline structures that lie close to the arteries for which they are named (Figures 47–2 and 47–3). In addition to sending sympathetic signals to visceral organs in the abdomen and pelvis, these ganglia also receive sensory feedback from their end-organs.

Parasympathetic Ganglia Innervate Single Organs

In contrast to sympathetic ganglia, which regulate many targets and lie some distance from their targets close to the spinal cord, parasympathetic ganglia generally innervate single end-organs and lie near to or within the end-organs they regulate (Figure 47–2). In addition, the parasympathetic system does not influence skin or skeletal muscle except in the head, where it regulates vascular beds in the jaw, lip, and tongue.

The cranial and sacral parasympathetic ganglia innervate different targets. The cranial outflow includes four ganglia in the head. The oculomotor (III) nerve projects to the ciliary ganglion, which controls pupillary size and focus by innervating the iris and ciliary muscles. The facial (VII) nerve and a small component of the glossopharyngeal (IX) nerve project to the pterygopalatine (or sphenopalatine) ganglion, which promotes production of tears by the lacrimal glands and mucus by the nasal and palatine glands. Cranial nerve IX and a small component of nerve VII project to the otic ganglion, which innervates the parotid, the largest salivary gland. Nerve VII also projects to the submandibular ganglion, which controls secretion of saliva by the submaxillary and sublingual glands.

The vagus (X) nerve projects broadly to parasympathetic ganglia in the heart, lungs, liver, gall bladder, and pancreas. It also projects to the stomach, small intestine, and more rostral segments of the gastrointestinal tract. The caudal parasympathetic outflow supplies the large intestine, rectum, bladder, and reproductive organs.

The Enteric Ganglia Regulate the Gastrointestinal Tract

The entire gastrointestinal tract, from the esophagus to the rectum—and including the pancreas and gall bladder—is controlled by the system of enteric ganglia. This system, by far the largest and most complex division of the autonomic nervous system, contains as many as 100 million neurons in humans.

The enteric system has been studied most extensively in the small intestine of the guinea pig, where the diversity of enteric neurons and their organization has been analyzed in two interconnected plexuses, small islands of interconnected neurons. The myenteric plexus controls smooth muscle movements of the gastrointestinal tract; the submucous plexus controls mucosal function (Figure 47–4). Working together, this distributed network of ganglia coordinates the orderly peristaltic propulsion of gastrointestinal contents and controls the secretions of the stomach and intestines and other components of digestion. In addition, the enteric system regulates local blood flow and is modulated by external inputs from sympathetic prevertebral ganglia and from parasympathetic components of the vagus nerve.

Unlike the sympathetic and parasympathetic divisions of the autonomic nervous system, the enteric ganglia contain interneurons and sensory neurons in addition to motor neurons. This intrinsic neural circuitry can maintain the basic functions of the gut even after the splanchnic sympathetic and vagal parasympathetic pathways are cut. Through splanchnic nerves and the vagus nerve the gastrointestinal tract also sends sensory information about the physiological states of the tract to the spinal cord and brain stem.

Synaptic transmission in the peripheral autonomic nervous system was originally thought to be a simple tale of two neurotransmitters, ACh and norepinephrine. According to this idea, all preganglionic neurons in the sympathetic and parasympathetic systems use ACh as their neurotransmitter, binding and exciting ionotropic nicotinic ACh receptors on ganglionic neurons and thus opening nonselective cation channels similar to the nicotinic ACh receptors at the neuromuscular junction. The resulting action potentials propagate to postganglionic synapses with end-organs in the periphery. At these synapses parasympathetic neurons release ACh that activates muscarinic receptors whereas sympathetic neurons release norepinephrine that activates α- and β-adrenergic G protein-coupled receptors. The consequences can be either excitatory or inhibitory, depending on the type of target cell and its receptors (Table 47–1).

In addition to acting on different receptors in different postsynaptic cells, one transmitter can activate two or more receptor types in the same postsynaptic cell. This principle was first discovered in sympathetic ganglia where ACh activates both nicotinic and muscarinic postsynaptic receptors to produce both a fast and slow excitatory postsynaptic potential (EPSP) (Figure 47–5A, and see Chapter 13). In some cases one transmitter can activate both a postsynaptic receptor as well as a receptor on the presynaptic terminals from which the transmitter was released. Such presyn-aptic responses can either reduce transmitter release (presynaptic inhibition) or enhance it (presynaptic facilitation). This mechanism, also widespread, was discovered at autonomic junctions with blood vessels where different types of α-adrenergic receptors are expressed by some pre- and postsynaptic cells (Figure 47–5B). This specialization of synaptic transmission in sympathetic and parasympathetic neurons leads to functional diversity in the regulation of end-organ function.

Today we know that many transmitters are co-released at a single synapse, activating multiple receptor types and contributing to functional diversity. Many autonomic neurons release co-transmitters, often together with ACh or norepinephrine.

The cellular principles of co-transmission have been elucidated in part in a series of studies of paravertebral sympathetic ganglia in the bullfrog. These ganglia contain two major groups of neurons. Secretomotor B neurons selectively innervate mucous glands in the skin, whereas vasomotor C neurons selectively innervate arteries that supply striated muscle and skin. In addition, each cell group receives input from a distinct group of preganglionic neurons in the spinal cord. These cell types differ from one another in part by expressing different neuropeptides. Preganglionic B cells selectively express calcitonin gene-related peptide (CGRP). Preganglionic C neurons express luteinizing hormone-releasing hormone (LHRH), also known as gonadotropin-releasing hormone (GnRH), and their postganglionic target cells express neuropeptide Y (Figure 47–6A).

The co-release of LHRH and ACh by the pregang-lionic C neurons was discovered in 1979 by Stephen Kuffler with Lily Jan and Yuh Nung Jan. This discovery illustrated three general principles, establishing LHRH-mediated synaptic transmission as a model for other neuropeptide actions. First, peptides can mediate very slow synaptic events, even slower than those caused by muscarinic ACh receptor stimulation. Although mammalian preganglionic neurons do not express LHRH, they release other neuropeptides that produce slow synaptic actions similar to those seen in bullfrog sympathetic ganglia. Second, peptides act diffusely at a distance and thereby provide cross talk between different sympathetic cell types. Although LHRH is released by preganglionic inputs to C cells that do not form synapses with B cells (Figure 47–6A), it can diffuse many micrometers to activate LHRH receptors on adjacent B neurons. Finally, different transmitters can share intracellular signaling pathways. For example, the actions of LHRH both resemble and block the excitatory, muscarinic response to ACh in B cells (a process called cross-desensitization).

Studies of bullfrog sympathetic ganglia also illustrate how preganglionic release of ACh can co-activate different forms of muscarinic (slow) responses together with the nicotinic (fast) EPSP. The muscarinic responses include a slow EPSP in B neurons, a slow inhibitory postsynaptic potential (IPSP) in C neurons, and inhibition of ACh release from preganglionic nerve terminals in the B cell system (Figure 47–6B). Each of these events arises through regulation of different ion channels. In both mammalian and amphibian sympathetic neurons the slow EPSP is mediated by suppression of the voltage-gated M-type K⁺ channel belonging to the KCNQ (K_v 9) family. The slow IPSP is produced by activation of G protein-coupled, inward-rectifying K⁺ channels (GIRKs) (K_ir 3), and presynaptic inhibition by inhibition of N-type voltage-gated Ca²⁺ channels (Ca_v 2.2).

The time courses of the fast and slow synaptic events reflect fundamental differences in synaptic signaling mechanisms. The EPSPs initiated by the nicotinic ACh receptors are brief, lasting 10 to 50 ms because ionotropic receptor-channels are directly gated by ligand binding (see Figure 8–9). In contrast, synaptic events initiated at metabotropic receptors—the muscarinic ACh, peptide, and epinephrine receptors as well as a type of adenosine triphosphate (ATP) receptor (P_2Y)—are slow, with time courses lasting hundreds of milliseconds to minutes, because the receptor and ion channel are coupled by a multistep signaling cascade (see Chapter 11).

The final motor responses elicited by all three divisions of the autonomic system also depend on the properties of synaptic transmission at neuro-effector junctions. In particular they depend on the identity of postganglionic neurotransmitters and the pre- and postsynaptic receptors (Table 47–1). Understanding the pharmacology of these receptors and the second-messenger signaling pathways they control is important in the treatment of numerous medical conditions, including hypertension, heart failure, asthma, emphysema, allergies, sexual dysfunction, and incontinence.

Here again co-transmission is operative. Acetylcholine and vasoactive intestinal peptide (VIP) are frequently co-released from neurons that control glandular secretion (Figure 47–5C). In salivary glands, for example, the two transmitters act directly to evoke secretion. In addition, VIP causes dilation of the blood vessels supplying the gland. Because co-transmitters can be released in varying proportions that depend on the frequency of presynaptic firing, different patterns of activity can regulate the volume of secretions, their protein and water content, and their viscosity. This regulation operates both through a direct effect on the gland cells and through indirect effects on the glandular blood flow that provides the water contained in secretions.

To survive, animals and humans must have a "fight-or-flight" response that prepares an animal to stand and fight a predator or run away and live to see another day. Walter Cannon, in addition to introducing the concept of homeostasis, also appreciated that this "fight-or-flight" response is a critical sympathetic function.

Two important ideas underlie this insight. First, the sympathetic and parasympathetic systems play complementary, even antagonistic, roles; the sympathetic system promotes arousal, defense, and escape, whereas the parasympathetic system promotes eating and procreation. Second, actions of the sympathetic system are diffuse; they influence all parts of the body and once turned on can persist for some time. These ideas are behind the popular notion of the "adrenaline rush" produced by excitement, as by a roller coaster ride.

We now know that extreme sympathetic responses such as the "fight-or-flight" response can have long-term pathological consequences resulting in the syndrome known as post-traumatic stress disorder (see Chapter 63). This disorder was first recognized in soldiers during World War I when it was referred to as "shell shock." A variety of life-threatening experiences, ranging from sexual abuse and domestic violence to aircraft disasters, can also induce post-traumatic stress disorder, a disorder that affects millions of people in the United States alone.

Because the fight-or-flight model assumes antagonistic roles for the sympathetic and parasympathetic systems, Cannon's model led to an overemphasis on the extremes of autonomic behavior. Actually during everyday life the different divisions of the autonomic system are tightly integrated. In addition, we now know that the sympathetic system is less diffusely organized than first envisioned by Cannon. Subsets of neurons even within the sympathetic division control specific targets, and these pathways can be activated independently.

As in the somatic motor system, reflexes in the autonomic motor system are elicited through sensory pathways and are hierarchically organized. The simplest feedback loops are confined to the periphery and spinal cord, whereas more complex loops extend to higher centers. An important feature of this organization is that it allows for coordination between the different divisions of the autonomic system. The interplay between different systems in simple autonomic behaviors is analogous to the role of antagonist muscles in locomotion. To walk, one must alternately contract antagonist muscles that flex and extend a joint. Similarly, the sympathetic and parasympathetic systems are often partners in the regulation of end-organs. In most cases, ranging from the simplest reflexes to more complex behaviors, all three peripheral divisions of the autonomic system work together.

We illustrate this organization with three examples: contractions of the gut (peristalsis), control of the bladder (micturition reflex), and regulation of blood pressure.

Peristalsis

Peristalsis of circular smooth muscle normally propels the contents of the gastrointestinal tract in the oral–anal direction. This coordinated motor program is generated locally by the enteric neural network (Figure 47–4C) and can be elicited as a simple reflex by passive distension of the gut wall. The reflex activates excitatory motor neurons located rostral (oral) to the stimulus and inhibitory motor neurons located caudal (anal) to the stimulus. The synaptic connections between antagonistic motor neurons and sensory neurons are so arranged that the enteric network can build a cycle of contraction and relaxation that propagates in unidirectional waves of contractions.

The sensory information required to initiate the basic reflex originates in and is integrated locally within the enteric network. Two groups of sensory neurons in the system provide additional feedback to higher centers. One group lies in the dorsal root ganglia and projects from the gut to the prevertebral sympathetic ganglia and into the spinal cord and ascending pathways. The other group projects through the vagus nerve to sensory neurons in the brain stem. These pathways signal hunger and satiety. In response, the central nervous system can enhance or inhibit digestion through excitatory parasympathetic efferents in the vagus nerve and inhibitory sympathetic efferents in prevertebral splanchnic nerves.

Micturition Reflex

The micturition reflex is another example of a physiological cycle resulting from coordination between sympathetic and parasympathetic systems. In this cycle the bladder is emptied by the parasympathetic pathway, which contracts the bladder and relaxes the urethra. The sympathetic system allows the bladder to fill by stimulating the urethra and inhibiting the parasympathetic pathway, thus inhibiting the reflex for bladder emptying. The sensory feedback required for this behavior is integrated with the motor outflow at both spinal and supraspinal levels.

Spinal components of the reflex are most influential during the storage phase of the micturition cycle, when sympathetic and somatic motor effects predominate. When the bladder is full, its distension triggers a sensory signal sufficient to activate the pontine micturition center. Parasympathetic mechanisms then predominate to empty the bladder. Somatic control of the external urinary sphincter, which consists of striated muscle, contributes to both phases of the micturition cycle and is a voluntary behavior that originates through forebrain mechanisms (Figure 47–7). Patients with spinal cord injuries at the cervical or thoracic levels retain the reflex but not voluntary control of urination because the connections between the bladder and the pons are severed.

Baroreceptor Reflex

The baroreceptor reflex is one of the simplest mechanisms for regulating blood pressure and an example of homeostatic control by antagonist sympathetic and parasympathetic pathways. It prevents orthostatic hypotension and fainting by compensating for rapid hydrostatic effects produced by changes in posture.

When a recumbent person stands up, the sudden elevation of the head above the heart causes a transient decrease of cerebral blood pressure that is rapidly sensed by baroreceptors in the carotid sinus in the neck. Other important pressure sensors are located in the aortic arch and in the pulmonary circulation. When neurons in the ventrolateral medulla detect the decrease in afferent baroreceptor activity produced by low blood pressure, they produce a reflexive suppression of parasympathetic activity and stimulation of sympathetic activity. These changes in autonomic tone restore blood pressure by increasing heart rate, the strength of cardiac contractions, and the overall vascular resistance to blood flow through arterial vasoconstriction.

Under the converse condition of elevated arterial pressure, the increase in baroreceptor activity enhances parasympathetic inhibition of the heart and decreases sympathetic stimulation of cardiac function and vascular resistance. In general, the parasympathetic component of the baroreceptor reflex has a more rapid onset and is briefer than the sympathetic component. Consequently, parasympathetic activity is critical for the rapid response of baroreceptor reflexes but less important than sympathetic activity for long-term blood pressure regulation.

Homeostatic control of physiological functions such as blood pressure and body temperature often involves negative feedback loops. In the baroreceptor reflex, for example, the firing of sensory neurons conveys information about arterial pressure that medullary circuits use as feedback to control descending commands and thereby regulate preganglionic sympathetic neurons. This feedback is said to be negative because of the inverse relation between sensory input and functional motor output: An increase in blood pressure increases sensory activity that decreases sympathetic motor tone, which then reduces pressure.

Set point and gain are critical components of this type of control, as they are in regulating motivational state. The set point is the target for regulation and is analogous to thermostat settings on home heating systems. Gain, as we will see in Chapter 49, is the amplification generated by the feedback loop. The mathematics of control theory shows that the accuracy and speed of regulation through negative feedback are established by the gain of the loop. At a higher gain the reflex loop will control pressure more effectively and more quickly (Figure 47–8B). The overall gain of the baroreceptor reflex is regulated by cellular mechanisms in the sensory transduction process, in the medulla, in paravertebral sympathetic ganglia where integration of nicotinic EPSPs can produce activity-dependent gain, and at the neurovascular junctions where co-release of neuropeptide Y can potentiate the actions of norepinephrine on arteries.

Sympathetic and parasympathetic response are coordinated by a central autonomic network, a network of brain regions that interacts with two other brain systems to support homeostasis, the "fight-or-flight" response, and reproduction. These other two systems control endocrine responses, especially from the pituitary gland, and the expression of eating and drinking behavior and defensive and reproductive (sexual and parental) behaviors common to all animals. Like the central autonomic network, these two systems are widely distributed in the brain, and their critical control elements are centered in the hypothalamus.

General visceral sensory information reaches the central autonomic network mainly through two cranial nerves (IX and X), which end in the nucleus of the solitary tract, and through the abdominal splanchnic nerves, which end in the spinal cord (see Chapter 45). Splanchnic information is transmitted to the brain through the spinothalamic tract (see Chapter 22), which branches out along the way to several parts of the central autonomic network, including the nucleus of the solitary tract (Figure 47–9A).

The nucleus of the solitary tract has two basic functions. First, it projects to networks in the brain stem and spinal cord that control and coordinate autonomic reflexes. For example, visceral sensory signals relayed through the nucleus regulate vagal motor control of the heart and gastrointestinal tract directly. Some neurons in the nucleus project to neurons in the ventrolateral medullary reticular formation that control blood pressure by regulating blood flow in particular vascular beds differentially (Figure 47–9B). Second, the nucleus has ascending projections that integrate autonomic with neuroendocrine and behavioral responses. As we will see, the forebrain plays an important role in this higher-order coordination.

The nucleus of the solitary tract has direct and indirect projections to the forebrain. A major indirect target is the pontine parabrachial nucleus, which is important for behavioral responses to visceral information as well as taste. Lesions of the nucleus prevent behavioral conditioning with gustatory stimuli. The general pattern of ascending projections from the nucleus is remarkably similar to that from the nucleus of the solitary tract. Furthermore, both nuclei receive inputs from many central autonomic centers in the forebrain.

The periaqueductal gray, surrounds the cerebral aqueduct in the midbrain, which also receives inputs from most parts of the central autonomic network and projects to the medullary reticular formation to initiate integrated behavioral and autonomic responses. For example, in the defensive "fight-or-flight" response the periaqueductal gray helps redirect blood flow from the digestive system to the hind limbs, thus enhancing running.

Viscerosensory and gustatory information is relayed from the nucleus of the solitary tract and parabrachial nucleus in axons that end topographically in a specialized part of the thalamus, the parvicellular (small-cell) part of the ventral posterior nucleus. The parvicellular projections to viscerosensory and gustatory areas in the rostral half of the insular cortex relay information related to hunger, abdominal fullness, dry throat, and holding your breath. Information from the splanchnic nerves is transmitted to the main part of the ventral posterior nucleus, which receives somatosensory information (see Chapter 22).

The medial prefrontal region of the cerebral cortex is a visceral sensory-motor region. It includes two functional areas that interact with each other: the rostral insular cortex and the rostromedial tip of the cingulate gyrus (also referred to as the infralimbic and prelimbic areas). Stimulation here can produce a variety of autonomic effects including contractions of the stomach and changes in blood pressure. These visceral sensory and motor areas of cortex send descending projections to the parts of the central autonomic network in the brain stem already discussed. Lesions here may produce loss of visceral sensations and taste, as well as a condition known as abulia, where patients show blunted emotional responses to external stimuli.

Finally, visceral regions of cortex, along with many subcortical parts of the central autonomic network, interact with the amygdala. Complex pathways between certain amygdalar cell groups underlie conditioned emotional responses—learned associations between specific stimuli and behaviors with accompanying autonomic responses. When a rat learns that a mild electric shock follows an auditory cue, the auditory cue alone produces an elevated heart rate and the freezing reaction originally elicited by the shock alone (see Chapter 48). Such learned responses are prevented by selective lesions of the amygdalar region, which projects to the hypothalamus and lower brain stem parts of the central autonomic network (including the motor nucleus of the vagus nerve).

Transection of the brain axis roughly between the midbrain and diencephalon (hypothalamus), without lesioning the hypothalamus, eliminates all spontaneous behavior. In contrast, removal of the entire cerebral hemisphere (cortex and basal nuclei) and thalamus, sparing the hypothalamus, leaves animals able to eat and drink enough to maintain body weight and blood pressure, bear offspring (females only), defend against environmental threats with coordinated behavioral responses, and maintain a constant body temperature. The only difference in the two procedures is whether or not the hypothalamus is left intact (Figure 47–10). The functions of the hypothalamus (Table 47–2) can be enhanced or eliminated when particular sites are experimentally manipulated.

Magnocellular Neuroendocrine Neurons Control the Pituitary Gland Directly

Large neurons in the paraventricular and supraoptic nuclei (and a few neurons scattered in between) form the magnocellular component of the neuroendocrine motor system of the hypothalamus (Figure 47–11). The magnocellular neurons send their axons through the hypothalamo-hypophysial tract to the posterior pituitary or neurohypophysis (Figure 47–12). Under normal conditions approximately one-half of the magnocellular neuroendocrine neurons synthesize and secrete vasopressin (the antidiuretic hormone) into the general circulation, whereas the other half synthesize and secrete the structurally similar hormone oxytocin (Figure 47–11). These hormones circulate to organs that control blood pressure, water balance, uterine smooth muscle, and milk release.

In the 1950s Vincent DuVigneaud discovered that vasopressin and oxytocin are peptide hormones, each containing nine amino acid residues (Table 47–3). We later learned that, like other peptide hormones, they are synthesized in the cell body as larger prohormones (see Chapter 13) and then cleaved within Golgi transport vesicles before traveling down the axon to release sites in the posterior pituitary. The genes for these peptides are similar and probably arose by duplication.

Parvicellular Neuroendocrine Neurons Control the Pituitary Gland Indirectly

In the 1950s Geoffrey Harris proposed that the anterior pituitary or adenohypophysis is regulated indirectly by the hypothalamus. He showed that the hypophysial portal veins, which carry blood from the hypothalamic median eminence to the anterior pituitary, transport signals released from hypothalamic neurons that control anterior pituitary hormone secretion (Figure 47–12).

In the 1970s Andrew Schally, Roger Guillemin, and Wylie Vale determined the structure of a group of hypothalamic peptide hormones that control pituitary hormone secretion from five classic endocrine cell types in the anterior pituitary. These hormones fall into two classes: releasing hormones and release-inhibiting hormones (Table 47–4). Only one anterior pituitary hormone, prolactin, is under predominantly inhibitory control. Thus transection of the pituitary stalk increases prolactin secretion but causes insufficiency of adrenal cortical, thyroid, gonadal, and growth hormones.

The parvicellular neuroendocrine motor zone is centered along the wall of the third ventricle (Figure 47–10A). One population of parvicellular neurons releases GnRH. During embryogenesis these neurons arise in a specialized region of the olfactory placode or epithelium and then migrate along the terminal nerves to enter the base of the brain and eventually surround the rostral end of the third ventricle. Remarkably, only about a thousand GnRH neurons control all aspects of reproductive physiology and behavior.

Most of the remaining parvicellular neuroendocrine neurons are exceptionally important for the regulation of metabolism. This population lies within the paraventricular and arcuate nuclei and the short periventricular region between them (Figures 47–10 and 47–12). Distinct pools of neurons release corticotropin-releasing hormone (CRH), thyrotropin- releasing hormone (TRH), or somatostatin (or growth hormone release-inhibiting hormone). The pool of CRH neurons in the paraventricular nucleus controls the release of anterior pituitary adrenocorticotropic hormone (ACTH), which in turn controls the release of cortisol (glucocorticoids) from the adrenal cortex. Thus this pool of CRH neurons is the "final common pathway" for all centrally mediated stress responses.

The arcuate nucleus contains two critical pools of parvicellular neuroendocrine neurons. One group releases growth hormone-releasing hormone (GRH) and the other dopamine, which inhibits prolactin secretion. Some of the dopaminergic neurons are distributed dorsally as far as the paraventricular nucleus.

The axons of all these parvicellular neuroendocrine neurons travel in the hypothalamo-hypophysial tract and end in the specialized proximal end of the pituitary stalk, the median eminence (Figure 47–12). There, in a region of fenestrated capillary loops in the external zone of the median eminence, the axon terminals release the various hypophysiotrophic factors. The capillary loops are the proximal end of the hypophysial portal system of veins that carry the factors to the anterior pituitary, where they act on cognate receptors on the five types of endocrine cells (Figure 47–11).

The three divisions of the autonomic nervous system form an integrated motor system that acts in parallel with the somatic and neuroendocrine motor systems to maintain homeostasis. Although once viewed as a system that exerts a diffuse control over its targets, recent work has made clear that autonomic neurons are exquisitely specialized to control different targets and that during different behaviors functional subsets of autonomic neurons can be selectively activated.

Synaptic convergence and co-transmission allow autonomic ganglia to operate in different modes: as relays, filters, or amplifiers of preganglionic activity. Even the simplest reflexes in the gut, bladder, or cardiovascular system involve the integration of sensory information and coordination of antagonistic functions.

Visceral sensory afferents are important regulators of motor outflow, and the nucleus of the solitary tract in the medulla is the most important relay station for this sensory information to reach the rest of the central autonomic control network. The hypothalamus integrates autonomic, neuroendocrine, and somatic behavioral responses, which are modulated by inputs from virtually all parts of the nervous system.

Looking back over the past 100 years, autonomic neuroscience has been very influential in shaping general concepts of synaptic transmission—from the first discoveries of neurotransmitters to the first discoveries of co-transmitters—while also having broad impact in the field of medicine. Many of the most commonly prescribed drugs act on the autonomic system and its target tissues.

In this present time of aging populations it is also important to note that many of the physical signs and symptoms associated with old age are autonomic in origin. Think how many people are affected by cardiovascular disease, metabolic and digestive disease, and problems with urogenital function.

One very exciting challenge for the future will therefore be to understand in greater detail how the central autonomic network can be manipulated therapeutically to counteract the loss of peripheral autonomic function. This will require closer interaction between the communities of scientists who study peripheral and central autonomic mechanisms. A second exciting challenge will be to unravel the still mysterious links between motivation, emotion, autonomic function, stress, and neuropsychiatric disorders. By combining current advances in molecular biology, genetics, and computational modeling, meeting all of these challenges now seems possible.