Neuroscience: Exploring the Brain - Chapter 15 - PDF

 CHAPTER FIFTEEN Chemical Control of the Brain and Behavior INTRODUCTION THE SECRETORY HYPOTHALAMUS An Overview of the Hypothalamus Homeostasis Structure and Connections of the Hypothalam...

 CHAPTER FIFTEEN Chemical Control of the Brain and Behavior INTRODUCTION THE SECRETORY HYPOTHALAMUS An Overview of the Hypothalamus Homeostasis Structure and Connections of the Hypothalamus Pathways to the Pituitary Hypothalamic Control of the Posterior Pituitary Hypothalamic Control of the Anterior Pituitary BOX 15.1 OF SPECIAL INTEREST: Stress and the Brain THE AUTONOMIC NERVOUS SYSTEM ANS Circuits Sympathetic and Parasympathetic Divisions The Enteric Division Central Control of the ANS Neurotransmitters and the Pharmacology of Autonomic Function Preganglionic Neurotransmitters Postganglionic Neurotransmitters THE DIFFUSE MODULATORY SYSTEMS OF THE BRAIN Anatomy and Functions of the Diffuse Modulatory Systems BOX 15.2 OF SPECIAL INTEREST: You Eat What You Are The Noradrenergic Locus Coeruleus BOX 15.3 PATH OF DISCOVERY: Exploring the Central Noradrenergic Neurons, by Floyd Bloom The Serotonergic Raphe Nuclei The Dopaminergic Substantia Nigra and Ventral Tegmental Area The Cholinergic Basal Forebrain and Brain Stem Complexes Drugs and the Diffuse Modulatory Systems Hallucinogens Stimulants CONCLUDING REMARKS 521 519–550_Bear_15_revised_final.indd 521 12/20/14 5:26 AM  522 PART THREE THE BRAIN AND BEHAVIOR INTRODUCTION INTRODUC CTION It should be obvious by now that knowing the organization of synaptic connections is essential to understanding how the brain works. It’s not from a love of Greek and Latin that we belabor neuroanatomy! Most of the connections we have described are precise and specific. For example, for you to be able to read these words, there must be a very fine-grained neural mapping of the light falling on your retina—how else could you see the dot in this question mark? The information must be carried centrally and dispersed precisely to many parts of the brain for processing, coor- dinated with control of the motor neurons that closely regulate the six muscles of each eye as it scans the page. In addition to anatomical precision, point-to-point communication in the sensory and motor systems requires mechanisms that restrict synap- tic communication to the cleft between the axon terminal and its target. It just wouldn’t do for glutamate released in the somatosensory cortex to activate neurons in the motor cortex! Furthermore, transmission must be brief enough to allow rapid responses to new sensory inputs. Thus, at these synapses, only minute quantities of neurotransmitter are released with each impulse, and these molecules are then quickly destroyed enzy- matically or taken up by neighboring cells. The postsynaptic actions at transmitter-gated ion channels last only as long as the transmitter is in the cleft, a few milliseconds at most. Many axon terminals also possess presynaptic “autoreceptors” that detect the transmitter concentrations in the cleft and inhibit release if they get too high. These mechanisms ensure that this type of synaptic transmission is tightly constrained, in both space and time. The elaborate mechanisms that constrain point-to-point synaptic transmission are somewhat like those in telecommunications. Telephone systems make possible very specific connections between one place and another so that your mother in Tacoma can talk just to you in Providence, reminding you that her birthday was last week. The telephone lines or cellular transmissions act like precise synaptic connections. The influ- ence of one neuron (your mother) is targeted to a small number of other neurons (in this case, only you). The embarrassing message is limited to your ears only. The influence of a neuron in one of the sensory or motor systems discussed so far usually extends to the few dozen or few hun- dred cells it synapses on—a conference call, to be sure, but still relatively specific. Now imagine your mother being interviewed on a television talk show broadcast on a satellite network. The widespread satellite transmission may allow her to tell millions of people that you forgot her birthday, and the loudspeaker in each television set will announce the message to anyone within earshot. Likewise, certain neurons communicate with hundreds of thousands of other cells. These widespread systems tend to act rela- tively slowly, over seconds to minutes. Because of their broad, protracted actions, such systems in the brain can orchestrate entire behaviors, rang- ing from falling asleep to falling in love. Indeed, many of the behavioral dysfunctions collectively known as mental disorders are believed to result specifically from imbalances of certain of these chemicals. In this chapter, we look at three components of the nervous system that operate in expanded space and time (Figure 15.1). One component is the secretory hypothalamus. By secreting chemicals directly into the blood- stream, the secretory hypothalamus can influence functions throughout both the brain and the body. A second component, controlled neurally by the hypothalamus, is the autonomic nervous system (ANS), introduced 519–550_Bear_15_revised_final.indd 522 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 523 (a) (b) (c) (d) ▲ FIGURE 15.1 Patterns of communication in the nervous system. (a) Most of the systems we have discussed in this book may be described as point-to-point. The proper functioning of these systems requires restricted synaptic activation of target cells and signals of brief duration. In contrast, three other components of the nervous system act over great distances and for long periods of time. (b) Neurons of the secretory hypothalamus affect their many targets by releasing hormones directly into the bloodstream. (c) Networks of interconnected neurons of the ANS can work together to activate tissues all over the body. (d) Diffuse modulatory systems extend their reach with widely divergent axonal projections. in Chapter 7. Through extensive interconnections within the body, the ANS simultaneously controls the responses of many internal organs, blood vessels, and glands. The third component exists entirely within the central nervous system (CNS) and consists of several related cell groups that differ with respect to the neurotransmitter they use. All of these cell groups extend their spatial reach with highly divergent axonal projec- tions and prolong their actions by using metabotropic postsynaptic recep- tors. Members of this component of the nervous system are called the diffuse modulatory systems of the brain. The diffuse systems are believed to regulate, among other things, the level of arousal and mood. This chapter serves as a general introduction to these systems. Later chapters will explore how they contribute to specific behaviors and brain states: motivation (Chapter 16), sexual behavior (Chapter 17), emotion (Chapter 18), sleep (Chapter 19), and psychiatric disorders (Chapter 22). 519–550_Bear_15_revised_final.indd 523 12/20/14 5:26 AM  524 PART THREE THE BRAIN AND BEHAVIOR THE SECRETORY SECRE ETORY HYPOTHAL HYPOTHALAMUS LAMUS Recall from Chapter 7 that the hypothalamus sits below the thalamus, along the walls of the third ventricle. It is connected by a stalk to the pituitary gland, which dangles below the base of the brain, just above the roof of your mouth (Figure 15.2). Although this tiny cluster of nuclei makes up less than 1% of the brain’s mass, the influence of the hypo- thalamus on body physiology is enormous. Let’s take a brief tour of the hypothalamus and then focus on some of the ways in which it exerts its Dorsal thalamus Third powerful influence. (cut edge) ventricle An Overview of the Hypothalamus The hypothalamus and dorsal thalamus are adjacent to one another, but their functions are very different. As we saw in the previous seven chap- ters, the dorsal thalamus lies in the path of all the point-to-point path- ways whose destination is the neocortex. Accordingly, the destruction of a small part of the dorsal thalamus can produce a discrete sensory or motor deficit, such as a little blind spot or a lack of feeling on a portion of skin. In contrast, the hypothalamus integrates somatic and visceral responses in accordance with the needs of the brain. A tiny lesion in the hypothala- Optic chiasm Pituitary Hypothalamus mus can produce dramatic and often fatal disruptions of widely dispersed ▲ FIGURE 15.2 bodily functions. Locations of the hypothalamus and pituitary. This is a midsagittal section. Homeostasis. In mammals, the requirements for life include a narrow Notice that the hypothalamus, whose borders are indicated with a dashed line, range of body temperatures and blood compositions. The hypothalamus forms the wall of the third ventricle and regulates these levels in response to a changing external environment. sits below the dorsal thalamus. This regulatory process is called homeostasis, the maintenance of the body’s internal environment within a narrow physiological range. Consider temperature regulation. Biochemical reactions in many cells of the body are fine-tuned to occur at about 37°C. A deviation of more than a few degrees in either direction can be catastrophic. Temperature- sensitive cells in the hypothalamus detect changes in brain temperature and orchestrate the appropriate responses. For example, if you stroll naked through the snow, the hypothalamus issues commands that cause you to shiver (generating heat in the muscles), develop goose bumps (a futile attempt to fluff up your nonexistent fur for better insulation—a reflexive remnant from our hairier ancestors), and turn blue (shunting blood away from cold surface tissues to keep the sensitive core of the body warmer). In contrast, when you go for a jog in the tropics, the hypothala- mus activates heat-loss mechanisms that make you turn red (shunting blood to surface tissues where heat can radiate away) and sweat (cooling the skin by evaporation). Other examples of homeostasis are the tight regulation of blood vol- ume, pressure, salinity, acidity, and blood oxygen and glucose concentra- tions. The means by which the hypothalamus achieves these different types of regulation are remarkably diverse. Structure and Connections of the Hypothalamus. Each side of the hypo- thalamus has three functional zones: lateral, medial, and periventricular (Figure 15.3). The lateral and medial zones have extensive connections with the brain stem and the telencephalon and regulate certain types of behavior, as we will see in Chapter 16. Here we are concerned only with the third zone, which actually receives much of its input from the other two. The periventricular zone is so named because, with the exception of a thin finger of neurons that are displaced laterally by the optic tract 519–550_Bear_15_revised_final.indd 524 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 525 Lateral Medial Hypo- thalamus Periven- tricular Third ventricle ▲ FIGURE 15.3 Zones of the hypothalamus. The hypothalamus has three functional zones: lat- eral, medial, and periventricular. The periventricular zone receives inputs from the other zones, the brain stem, and the telencephalon. Neurosecretory cells in the periventricular zone secrete hormones into the bloodstream. Other periventricular cells control the autonomic nervous system. (called the supraoptic nucleus), the cells of this region lie right next to the wall of the third ventricle. Within this zone exists a complex mix of neurons with different functions. One group of cells constitutes the supra- chiasmatic nucleus (SCN), which lies just above the optic chiasm. These cells receive direct retinal innervation and function to synchronize circa- dian rhythms with the daily light–dark cycle (see Chapter 19). Other cells in the periventricular zone control the ANS and regulate the outflow of the sympathetic and parasympathetic innervation of the visceral organs. The cells in a third group, called neurosecretory neurons, extend axons down toward the stalk of the pituitary gland. These are the cells that now command our attention. Pathways to the Pituitary We have said that the pituitary dangles below the base of the brain, which is true when the brain is lifted out of the head. In a living brain, however, the pituitary is gently held in a cradle of bone at the base of the skull. It requires this special protection because it is the “mouthpiece” from which much of the hypothalamus “speaks” to the body. The pituitary has two lobes, posterior and anterior. The hypothalamus controls the two lobes in different ways. Hypothalamic Control of the Posterior Pituitary. The largest of the hy- pothalamic neurosecretory cells, magnocellular neurosecretory cells, extend axons down the stalk of the pituitary and into the posterior lobe (Figure 15.4). In the late 1930s, Ernst and Berta Scharrer, working at the University of Frankfurt in Germany, proposed that these neurons release chemical substances directly into the capillaries of the posterior lobe. At the time, this was quite a radical idea. It was well established that chemical messengers called hormones were released by glands into the bloodstream, but no one had thought that a neuron could act like a gland or that a neurotransmitter could act like a hormone. The Scharrers were correct, however. The substances released into the blood by neurons are now called neurohormones. 519–550_Bear_15_revised_final.indd 525 12/20/14 5:26 AM  526 PART THREE THE BRAIN AND BEHAVIOR Magnocellular neurosecretory cells Hypothalamus Optic chiasm Posterior lobe of pituitary Anterior lobe of pituitary Capillary bed ▲ FIGURE 15.4 Magnocellular neurosecretory cells of the hypothalamus. This is a midsagittal view of the hypothalamus and pituitary. Magnocellular neurosecretory cells secrete oxytocin and vasopressin directly into capillaries in the posterior lobe of the pituitary. The magnocellular neurosecretory cells release two neurohormones into the bloodstream, oxytocin and vasopressin. Both of these chemicals are peptides, each consisting of a chain of nine amino acids. Oxytocin has sometimes been called the “love hormone” because levels rise dur- ing sexual or intimate behaviors and promote social bonding (discussed further in Chapter 17). In women, it also plays a critical role during the final stages of childbirth by causing the uterus to contract and facilitat- ing the delivery of the newborn. It also stimulates the ejection of milk from the mammary glands. All lactating mothers know about the complex “letdown” reflex that involves the oxytocin neurons of the hypothalamus. Oxytocin release may be stimulated by the somatic sensations generated by a suckling baby. But the sight or sound of a baby (even someone else’s) can also trigger the release of milk beyond the mother’s conscious control. In each case, information about a sensory stimulus—somatic, visual, or auditory—reaches the cerebral cortex via the usual route, the thalamus, and the cortex ultimately stimulates the hypothalamus to trigger oxyto- cin release. The cortex can also suppress hypothalamic functions, such as when anxiety inhibits the letdown of milk. Vasopressin, also called antidiuretic hormone (ADH), regulates blood volume and salt concentration. When the body is deprived of water, the blood volume decreases and blood salt concentration increases. These changes are detected by pressure receptors in the cardiovascular system and salt concentration-sensitive cells in the hypothalamus, respectively. 519–550_Bear_15_revised_final.indd 526 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 527 Vasopressin-containing neurons receive information about these changes and respond by releasing vasopressin, which acts directly on the kidneys and leads to water retention and reduced urine production. Under conditions of lowered blood volume and pressure, communi- cation between the brain and the kidneys actually occurs in both direc- tions (Figure 15.5). The kidneys secrete an enzyme into the blood called renin. Elevated renin sets off a sequence of biochemical reactions in the blood. Angiotensinogen, a large protein released from the liver, is con- verted by renin to angiotensin I, which breaks down further to form an- other small peptide hormone, angiotensin II. Angiotensin II has direct effects on the kidney and blood vessels, which help increase blood pres- sure. But angiotensin II in the blood is also detected by the subfornical organ, a part of the telencephalon that lacks a blood-brain barrier. Cells in the subfornical organ project axons into the hypothalamus where they activate, among other things, the vasopressin-containing neurosecretory cells. In addition, the subfornical organ activates cells in the lateral area of the hypothalamus, somehow producing an overwhelming thirst that Subfornical organ Hypothalamus Pituitary Angiotensin II Blood vessels, kidney ADH Angiotensin I Renin Angiotensinogen Liver Lowered blood pressure Kidney ▲ FIGURE 15.5 Communication between the kidneys and the brain. Under conditions of low- ered blood volume or pressure, the kidney secretes renin into the bloodstream. Renin in the blood promotes the synthesis of the peptide angiotensin II, which excites the neurons in the subfornical organ. The subfornical neurons stimulate the hypothalamus, causing an increase in vasopressin (ADH) production and a feeling of thirst. 519–550_Bear_15_revised_final.indd 527 12/20/14 5:26 AM  528 PART THREE THE BRAIN AND BEHAVIOR motivates drinking behavior. It may be difficult to accept, but it’s true: To a limited extent, our brain is controlled by our kidneys! This example also illustrates that the means by which the hypothalamus maintains homeostasis go beyond control of the visceral organs and can include be- havioral responses. In Chapter 16, we will explore in more detail how the hypothalamus incites behavior. Hypothalamic Control of the Anterior Pituitary. Unlike the posterior lobe, which really is a part of the brain, the anterior lobe of the pituitary is an actual gland. The cells of the anterior lobe synthesize and secrete a wide range of hormones that regulate secretions from other glands throughout the body (together constituting the endocrine system). The pituitary hor- mones act on the gonads, the thyroid glands, the adrenal glands, and the mammary glands (Table 15.1). For this reason, the anterior pituitary was traditionally described as the body’s “master gland.” But what controls the anterior pituitary? The secretory hypothalamus. The hypothalamus itself is the true master gland of the endocrine system. The anterior lobe is under the control of neurons in the periventricular area called parvocellular neurosecretory cells. These hypothalamic neurons do not extend axons all the way into the anterior lobe; instead, they communicate with their targets via the bloodstream (Figure 15.6). These neurons secrete what are called hypophysiotropic hormones into a uniquely specialized capillary bed at the floor of the third ventricle. These tiny blood vessels run down the stalk of the pituitary and branch in the anterior lobe. This network of blood vessels is called the hypo- thalamo-pituitary portal circulation. Hypophysiotropic hormones se- creted by hypothalamic neurons into the portal circulation travel down- stream until they bind to specific receptors on the surface of pituitary cells. Activation of these receptors causes the pituitary cells to either se- crete or stop secreting hormones into the general circulation. Regulation of the adrenal glands illustrates how this system works. Located just above the kidneys, the adrenal glands consist of two parts, a shell called the adrenal cortex and a center called the adrenal me- dulla. The adrenal cortex produces the steroid hormone cortisol; when it is released into the bloodstream, cortisol acts throughout the body to mobilize energy reserves and suppress the immune system, preparing us to carry on in the face of life’s various stresses. In fact, a good stimulus for cortisol release is stress, ranging from physiological stress, such as a loss of blood; to positive emotional stimulation, such as falling in love; to psychological stress, such as anxiety over an upcoming exam. TABLE 15.1 Hormones of the Anterior Pituitary Hormone Horm Ho rmon onee Targ Ta Target rget et Acti Ac Action tion on Follicle-stimulating hormone Gonads Ovulation, spermatogenesis (FSH) Luteinizing hormone (LH) Gonads Ovarian and sperm maturation Thyroid-stimulating hormone Thyroid Thyroxin secretion (increases (TSH); also called thyrotropin metabolic rate) Adrenocorticotropic hormone Adrenal Cortisol secretion (mobilizes (ACTH); also called cortex energy stores, inhibits immune corticotropin system, other actions) Growth hormone (GH) All cells Stimulation of protein synthesis Prolactin Mammary Growth and milk secretion glands 519–550_Bear_15_revised_final.indd 528 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 529 Parvocellular neurosecretory cells Hormone transport Hypothalamus in axons Hypophysiotropic Capillary beds hormones Anterior lobe released of pituitary Hormone transport in blood Stimulation or inhibition of anterior pituitary hormone release Hormone- secreting cells Hormone transport in blood Action on organs of the body ▲ FIGURE 15.6 Parvocellular neurosecretory cells of the hypothalamus. Parvocellular neurosecretory cells secrete hypophysiotropic hormones into specialized capillary beds of the hypothalamo-pituitary portal circulation. These hormones travel to the anterior lobe of the pituitary, where they trigger or inhibit the release of pituitary hormones from secretory cells. Parvocellular neurosecretory cells that control the adrenal cortex de- termine whether a stimulus is stressful or not (as defined by the release of cortisol). These neurons lie in the periventricular hypothalamus and release a peptide called corticotropin-releasing hormone (CRH) into the blood of the portal circulation. CRH travels the short distance to the ante- rior pituitary, where, within about 15 seconds, it stimulates the release of corticotropin, or adrenocorticotropic hormone (ACTH). ACTH enters the general circulation and travels to the adrenal cortex where, within a few minutes, it stimulates cortisol release (Figure 15.7). Blood levels of cortisol are, to some extent, self-regulated. Cortisol is a steroid, a class of biochemicals related to cholesterol. Thus, corti- sol is a lipophilic (“fat-loving”) molecule, which dissolves easily in lipid membranes and readily crosses the blood-brain barrier. In the brain, cortisol interacts with specific receptors that lead to inhibition of CRH release, thus ensuring that circulating cortisol levels do not get too high. Physicians need to be mindful of this feedback regulation when they pre- scribe prednisone, a synthetic form of cortisol. Prednisone is a powerful medicine, frequently used to suppress inflammation. When administered for several days, however, the prednisone circulating in the bloodstream 519–550_Bear_15_revised_final.indd 529 12/20/14 5:26 AM  530 PART THREE THE BRAIN AND BEHAVIOR Hypothalamus Other brain regions Pituitary Adrenal ACTH cortex Adrenal Cortisol medulla Kidney ▲ FIGURE 15.7 The stress response. Under conditions of physiological, emotional, or psycho- logical stimulation or stress, the periventricular hypothalamus secretes corticotropin-releasing hormone (CRH) into the hypothalamo-pituitary portal circu- lation. This triggers the release of adrenocorticotropic hormone (ACTH) into the general circulation. ACTH stimulates the release of cortisol from the adrenal cortex. Cortisol can act directly on hypothalamic neurons, as well as on other neurons elsewhere in the brain. fools the brain into thinking that naturally released levels of cortisol are too high and shutting down the release of CRH and the adrenal cortex. Abrupt discontinuation of prednisone treatment does not give the adrenal cortex enough time to ramp up cortisol production and can thus result in what is called adrenal insufficiency. Among the symptoms of adrenal in- sufficiency are severe abdominal pain and diarrhea, extremely low blood pressure, and changes in mood and personality. Adrenal insufficiency is also a feature of a rare disorder called Addison’s disease, named after Thomas Addison, the British physician who first described the condition in 1849. Addison recognized that one cause of this constellation of symp- toms is degeneration of the adrenal gland. Perhaps the most famous suf- ferer of Addison’s disease was U.S. President John F. Kennedy. Kennedy required a daily regimen of hormone replacement therapy to compensate for the loss of cortisol, a fact that was concealed during his presidency to protect his youthful and vigorous image. The flip side of adrenal insufficiency is a condition called Cushing’s disease, caused by pituitary gland dysfunction that results in elevated levels of ACTH and, consequently, cortisol. The symptoms include rapid weight gain, immune suppression, sleeplessness, memory impairment, and irritability. Not surprisingly, the symptoms of Cushing’s disease are a common side effect of prednisone treatment. The myriad behavioral changes caused by too much (or too little) cortisol may be explained by 519–550_Bear_15_revised_final.indd 530 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 531 BOX 15.1 OF SPECIAL INTEREST Stress and the Brain B iological stress is created by the brain in response to real or imagined stimuli. The many physiological responses several weeks caused dendrites to wither in many neurons with corticosterone receptors. A few weeks later, these cells associated with stress help protect the body and the brain started to die. A similar result was found when, instead of from the dangers that triggered the stress in the first place. daily hormone injections, the rats were stressed every day. But stress in chronic doses can have insidious harmful effects Sapolsky’s studies of baboons in Kenya further reveal as well. Neuroscientists have only begun to understand the the scourges of chronic stress. Baboons in the wild main- relationship between stress, the brain, and brain damage. tain a complex social hierarchy, and subordinate males steer Stress leads to the release of the steroid hormone cortisol clear of dominant males when they can. During one year from the adrenal cortex. Cortisol travels to the brain through when the baboon population boomed, local villagers caged the bloodstream and binds to receptors in the cytoplasm of many of the animals to prevent them from destroying their many neurons. The activated receptors travel to the cell nu- crops. Unable to escape the “top baboons” in the cages, cleus, where they stimulate gene transcription and ultimately many of the subordinate males subsequently died—not from protein synthesis. One consequence of cortisol’s action is wounds or malnutrition but apparently from severe and sus- that neurons admit more Ca2⫹ through voltage-gated ion tained stress-induced effects. They had gastric ulcers, colitis, channels. This may be due to a direct change in the chan- enlarged adrenal glands, and extensive degeneration of neu- nels, or it may be indirectly caused by changes in the cell’s rons in their hippocampus. Subsequent studies suggest that energy metabolism. Whatever the mechanism, presumably it is the direct effect of cortisol that damages the hippocam- in the short term cortisol makes the brain better able to cope pus. These effects of cortisol and stress resemble the effects with the stress—perhaps by helping it figure out a way to of aging on the brain. Indeed, research has clearly shown that avoid it! chronic stress causes premature aging of the brain. But what about the effects of chronic, unavoidable stress? In humans, exposure to the horrors of combat, sexual In Chapter 6, we learned that too much calcium can be a bad abuse, and other types of extreme violence can lead to post- thing. If neurons become overloaded with calcium, they die traumatic stress disorder, with symptoms of heightened anxi- (excitotoxicity). The question naturally arises: Can cortisol kill? ety, memory disturbances, and intrusive thoughts. Imaging Bruce McEwen and his colleagues at Rockefeller University, studies have consistently found degenerative changes in and Robert Sapolsky and his colleagues at Stanford the brains of victims, particularly in the hippocampus. In University, have studied this question in the rat brain. They Chapter 22, we will see that stress, and the brain’s response found that daily injections of corticosterone (rat cortisol) for to it, play a central role in several psychiatric disorders. the fact that neurons with cortisol receptors are found widely distributed in the brain, not just in the hypothalamus. In these other CNS locations, cortisol has been shown to have significant effects on neuronal activity. Thus, we see that the release of hypophysiotropic hormones by cells in the secretory hypothalamus can produce widespread alterations in the physiology of both the body and the brain (Box 15.1). THE A AUTONOMIC UTON NOMIC NERVOUS S SYSTEM YSTEM Besides controlling the ingredients of the hormonal soup that flows in our veins, the periventricular zone of the hypothalamus also controls the autonomic nervous system (ANS). The ANS is an extensive network of interconnected neurons that are widely distributed inside the body. From the Greek autonomia (roughly meaning “independence”), auto- nomic functions are usually carried out automatically, without conscious, voluntary control. They are also highly coordinated functions. Imagine a sudden crisis. In a morning class, as you are engrossed in a crossword puzzle, the instructor unexpectedly calls you to the blackboard to solve an 519–550_Bear_15_revised_final.indd 531 12/20/14 5:26 AM  532 PART THREE THE BRAIN AND BEHAVIOR impossible-looking equation. You are faced with a classic fight-or-flight situation, and your body reacts accordingly, even as your conscious mind frantically considers whether to blunder through it or beg off in humili- ation. Your ANS triggers a host of physiological responses, including increased heart rate and blood pressure, depressed digestive functions, and mobilized glucose reserves. These responses are all produced by the sympathetic division of the ANS. Now imagine your relief as the class- ending bell suddenly rings, saving you from acute embarrassment and the instructor’s anger. You settle back into your chair, breathe deeply, and read the clue for 24 down. Within a few minutes, your sympathetic responses decrease to low levels, and the functions of your parasym- pathetic division crank up again: Your heart rate slows and blood pressure drops, digestive functions work harder on breakfast, and you stop sweating. Notice that you may not have moved out of your chair throughout this unpleasant event. Maybe you didn’t even move your pencil. But your body’s internal workings reacted dramatically. Unlike the somatic motor system, whose alpha motor neurons can rapidly excite skeletal muscles with pinpoint accuracy, the actions of the ANS are typically multiple, widespread, and relatively slow. Therefore, the ANS operates in expanded space and time. In addition, unlike the somatic motor system, which can only excite its peripheral targets, the ANS balances synaptic excitation and inhibition to achieve widely coordinated and graded control. ANS Circuits Together, the somatic motor system and the ANS constitute the total neural output of the CNS. The somatic motor system has a single func- tion: It innervates and commands skeletal muscle fibers. The ANS has the complex task of commanding every other tissue and organ in the body that is innervated. Both systems have upper motor neurons in the brain that send commands to lower motor neurons, which actually innervate the target structures outside the nervous system. However, they have some interesting differences (Figure 15.8). The cell bodies ANS Somatic motor Sympathetic Parasympathetic CNS Preganglionic fibers Autonomic (sympathetic) ganglion ▲ FIGURE 15.8 PNS The organization of the three neural outputs of the CNS. The sole output of Somatic Autonomic the somatic motor system is the lower mo- motor (parasympathetic) tor neurons in the ventral horn of the spinal fiber ganglion cord and the brain stem, which control skeletal muscle. Visceral functions such as Postganglionic salivating, sweating, and genital stimulation fibers depend on the sympathetic and parasym- pathetic divisions of the ANS, whose lower Skeletal Smooth muscle, cardiac muscle, = ACh motor neurons (i.e., postganglionic neurons) muscle gland cells lie outside the CNS in autonomic ganglia. = NE 519–550_Bear_15_revised_final.indd 532 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 533 of all somatic lower motor neurons lie within the CNS in either the ventral horn of the spinal cord or the brain stem. The cell bodies of all autonomic lower motor neurons lie outside the central nervous system, within cell clusters called autonomic ganglia. The neurons in these ganglia are called postganglionic neurons. Postganglionic neurons are driven by preganglionic neurons, whose cell bodies are in the spinal cord and brain stem. Thus, the somatic motor system controls its targets (skeletal muscles) via a monosynaptic pathway, while the ANS influences its targets (smooth muscles, cardiac muscle, and glands) using a disynaptic pathway. Sympathetic and Parasympathetic Divisions. The sympathetic and parasympathetic divisions operate in parallel, but they use pathways that are quite distinct in structure and in their neurotransmitter sys- tems. Preganglionic axons of the sympathetic division emerge only from the middle third of the spinal cord (thoracic and lumbar segments). In contrast, preganglionic axons of the parasympathetic division emerge only from the brain stem and the lowest (sacral) segments of the spi- nal cord, so the two systems complement each other anatomically (Figure 15.9). The preganglionic neurons of the sympathetic division lie within the intermediolateral gray matter of the spinal cord. They send their axons through the ventral roots to synapse on neurons in the ganglia of the sympathetic chain, which lies next to the spinal column, or within collateral ganglia found within the abdominal cavity. The preganglionic parasympathetic neurons, on the other hand, sit within a variety of brain stem nuclei and the lower (sacral) spinal cord, and their axons travel within several cranial nerves as well as the nerves of the sacral spi- nal cord. The parasympathetic preganglionic axons travel much farther than the sympathetic axons because the parasympathetic ganglia are typically located next to, on, or in their target organs (see Figures 15.8 and 15.9). The ANS innervates three types of tissue: glands, smooth muscle, and cardiac muscle. Thus, almost every part of the body is a target of the ANS, as shown in Figure 15.9. The ANS: Innervates the secretory glands (salivary, sweat, tear, and various mucus-producing glands). Innervates the heart and blood vessels to control blood pressure and flow. Innervates the bronchi of the lungs to meet the oxygen demands of the body. Regulates the digestive and metabolic functions of the liver, gastroin- testinal tract, and pancreas. Regulates the functions of the kidney, urinary bladder, large intestine, and rectum. Is essential to the sexual responses of the genitals and reproductive organs. Interacts with the body’s immune system. The physiological influences of the sympathetic and parasympathetic divisions generally oppose each other. The sympathetic division tends to be most active during a crisis, real or perceived. The behaviors related to it are summarized in the puerile (but effective) mnemonic used by medi- cal students, called the four Fs: fight, flight, fright, and sex. The para- sympathetic division facilitates various non–four-F processes, such as digestion, growth, immune responses, and energy storage. In most cases, 519–550_Bear_15_revised_final.indd 533 12/20/14 5:26 AM  534 PART THREE THE BRAIN AND BEHAVIOR Sympathetic division Parasympathetic division Dilates Constricts pupil pupil Oculomotor nerve (III) Eye Stimulates Facial Inhibits salivation nerve (VII) salivation Salivary glands Glossopharyngeal nerve (IX) Cranial Lungs Cranial Constricts blood vessels Cervical Relaxes Constricts Cervical airways airways Accelerates Slows heartbeat heartbeat Heart Stimulates glucose production and Liver Thoracic release Thoracic Stomach Inhibits Vagus nerve (X) digestion Stimulates digestion Stimulates secretion of Pancreas epinephrine and norepinephrine Stimulates pancreas from adrenal to release insulin medulla and digestive Lumbar enzymes Lumbar Dilates blood vessels in gut Small intestine Large Sacral intestine Sacral Collateral Rectum ganglia Bladder Relaxes urinary Stimulates urinary Sympathetic bladder bladder to contract chain Reproductive organs NE neurons Stimulates orgasm Stimulates sexual ACh neurons arousal Preganglionic Postganglionic Preganglionic neurons neurons neurons 519–550_Bear_15_revised_final.indd 534 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 535 the activity levels of the two ANS divisions are reciprocal; when one is high, the other tends to be low, and vice versa. The sympathetic division frenetically mobilizes the body for a short-term emergency at the expense of processes that keep it healthy over the long term. The parasympa- thetic division works calmly for the long-term good. Both cannot be stim- ulated strongly at the same time; their general goals are incompatible. Fortunately, neural circuits in the CNS inhibit activity in one division when the other is active. Some examples illustrate how the balance of activity in the sympa- thetic and parasympathetic divisions controls organ functions. The pace- maker region of the heart triggers each heartbeat without the help of neurons, but both divisions of the ANS innervate it and modulate it; sympathetic activity results in an increase in the rate of beating, while parasympathetic activity slows it down. The smooth muscles of the gas- trointestinal tract are also dually innervated, but the effect of each di- vision is the opposite of its effect on the heart. Intestinal motility, and thus digestion, is stimulated by parasympathetic axons and inhibited by sympathetic axons. Not all tissues receive innervation from both divi- sions of the ANS, however. For example, blood vessels of the skin, and the sweat glands, are innervated (and excited) only by sympathetic axons. Lacrimal (tear-producing) glands are innervated (and excited) only by parasympathetic input. Another example of the balance of parasympathetic–sympathetic activity is the curious neural control of the male sexual response. Erection of the human penis is a hydraulic process. It occurs when the penis becomes engorged with blood, which is triggered and sustained by parasympathetic activity. The curious part is that orgasm and ejac- ulation are triggered by sympathetic activity. You can imagine how complicated it must be for the nervous system to orchestrate the entire sexual act; parasympathetic activity gets it going (and keeps it going), but a shift to sympathetic activity is necessary to bring it to a suc- cessful conclusion. Anxiety and worry, and their attendant sympathetic activity, tend to inhibit erection and promote ejaculation. Not surpris- ingly, impotence and premature ejaculation are common complaints of the overstressed male. (We will discuss sexual behavior further in Chapter 17.) The Enteric Division. The “little brain,” as the enteric division of the ANS is sometimes called, is a unique neural system embedded in an un- likely place: the lining of the esophagus, stomach, intestines, pancreas, and ▲ FIGURE 15.9 The chemical and anatomical organization of the sympathetic and parasympathetic divisions of the ANS. Notice that the preganglionic inputs of both divisions use ACh as a neurotransmitter. The postganglionic parasympa- thetic innervation of the visceral organs also uses ACh, but the postganglionic sympathetic innervation uses NE (with the exception of innervation of the sweat glands and vascular smooth muscle within skeletal muscle, which use ACh). The adrenal medulla receives preganglionic sympathetic innervation and secretes epi- nephrine into the bloodstream when activated. Note the pattern of innervation by the sympathetic division: Target organs in the chest cavity are innervated by post- ganglionic neurons originating in the sympathetic chain, and target organs in the abdominal cavity are innervated by postganglionic neurons originating in the collateral ganglia. 519–550_Bear_15_revised_final.indd 535 12/20/14 5:26 AM  536 PART THREE THE BRAIN AND BEHAVIOR Blood Axon vessel Small intestine Submucous (Meissner’s) plexus Myenteric (Auerbach’s) plexus ▲ FIGURE 15.10 The enteric division of the ANS. This cross-sectional view of the small intestine shows the two networks of the enteric division: the myenteric plexus and the submucous plexus. They both contain visceral sensory and motor neurons that control the functions of the digestive organs. gallbladder. It consists of two complicated networks, each with sensory nerves, interneurons, and autonomic motor neurons, called the myenteric (Auerbach’s) plexus and submucous (Meissner’s) plexus (Figure 15.10). These networks control many of the physiological processes involved in the transport and digestion of food, from oral to anal openings. The en- teric system is not small; it contains about 500 million neurons, the same number of neurons as the entire spinal cord! If the enteric division of the ANS qualifies as “brain” (which may be overstating the case), it is because it can operate with a great deal of independence. Enteric sensory neurons monitor tension and stretch of the gastrointestinal walls, the chemical status of stomach and intesti- nal contents, and hormone levels in the blood. This information is used by enteric interneuronal circuits and motor neurons, which also reside in the gut, to govern smooth muscle motility, the production of mucous and digestive secretions, and the diameter of the local blood vessels. For example, consider a partially digested pizza making its way through the small intestine. The enteric nervous system ensures that lubricating mucus and digestive enzymes are delivered, that rhythmic (peristaltic) muscle action works to mix the pizza and enzymes thoroughly, and that intestinal blood flow increases to provide a sufficient fluid source and transport newly acquired nutrients to the rest of the body. The enteric division is not entirely autonomous. It receives input indi- rectly from the “real” brain via axons of the sympathetic and parasympa- thetic divisions. These provide supplementary control and can supersede the functions of the enteric division in some circumstances. For example, 519–550_Bear_15_revised_final.indd 536 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 537 the enteric nervous system and digestive functions are inhibited by the strong activation of the sympathetic nervous system that occurs during acute stress. Central Control of the ANS. As we have said, the hypothalamus is the main regulator of the autonomic preganglionic neurons. Somehow this diminutive structure integrates the diverse information it receives about the body’s status, anticipates some of its needs, and provides a coordi- nated set of both neural and hormonal outputs. Essential to autonomic control are the connections of the periventricular zone to the brain stem and spinal cord nuclei that contain the preganglionic neurons of the sym- pathetic and parasympathetic divisions. The nucleus of the solitary tract, located in the medulla and connected with the hypothalamus, is another important center for autonomic control. In fact, some autonomic functions operate well even when the brain stem is disconnected from all structures above it, including the hypothalamus. The solitary nucleus integrates sensory information from the internal organs and coordinates output to the autonomic brain stem nuclei. Neurotransmitters and the Pharmacology of Autonomic Function Even people who have never heard the word neurotransmitter know what it means to “get your adrenaline flowing.” (In the United Kingdom, this compound is called adrenaline, while in the United States, it is called epinephrine.) Historically, the autonomic nervous system has probably taught us more than any other part of the body about how neu- rotransmitters work. Because the ANS is relatively simple compared to the CNS, we understand the ANS much better. In addition, neurons of the peripheral parts of the ANS are outside the blood-brain barrier, so all drugs that enter the bloodstream have direct access to them. The relative simplicity and accessibility of the ANS have led to a deeper understanding of the mechanisms of drugs that influence synaptic transmission. Preganglionic Neurotransmitters. The primary transmitter of the pe- ripheral autonomic neurons is acetylcholine (ACh), the same transmitter used at skeletal neuromuscular junctions. The preganglionic neurons of both sympathetic and parasympathetic divisions release ACh. The imme- diate effect is that the ACh binds to nicotinic ACh receptors (nAChR), which are ACh-gated channels, and evokes a fast excitatory postsynaptic potential (EPSP) that usually triggers an action potential in the post- ganglionic cell. This is very similar to the mechanisms of the skeletal neuromuscular junction, and drugs that block nAChRs in muscle, such as curare, also block autonomic output. Ganglionic ACh does more than neuromuscular ACh, however. It also activates muscarinic ACh receptors (mAChR), which are metabotropic (G-protein-coupled) receptors that can cause both the opening and the closing of ion channels that lead to very slow EPSPs and IPSPs. These slow mAChR events are usually not evident unless the preganglionic nerve is activated repetitively. In addition to ACh, some preganglionic terminals release a variety of small, neuroactive peptides such as neuro- peptide Y (NPY) and vasoactive intestinal polypeptide (VIP). These also interact with G-protein-coupled receptors and can trigger small EPSPs that last for several minutes. The effects of peptides are modulatory; they do not usually bring the postsynaptic neurons to firing threshold, 519–550_Bear_15_revised_final.indd 537 12/20/14 5:26 AM  538 PART THREE THE BRAIN AND BEHAVIOR but they make them more responsive to the fast nicotinic effects when they do come along. Since more than one action potential is required to stimulate the release of these modulatory neurotransmitters, the pattern of firing in preganglionic neurons is an important variable in determining the type of postganglionic activity that is evoked. Postganglionic Neurotransmitters. Postganglionic cells—the autonomic motor neurons that actually trigger glands to secrete, sphincters to con- tract or relax, and so on—use different neurotransmitters in the sym- pathetic and parasympathetic divisions of the ANS. Postganglionic parasympathetic neurons release ACh, but those of most parts of the sympathetic division use norepinephrine (NE). Parasympathetic ACh has a very local effect on its targets and acts entirely through mAChRs. In contrast, sympathetic NE often spreads far, even into the blood where it can circulate widely. The autonomic effects of a variety of drugs that interact with cho- linergic and noradrenergic systems can be confidently predicted once you understand some of the autonomic circuitry and chemistry (see Figure 15.9). In general, drugs that promote the actions of norepineph- rine or inhibit the muscarinic actions of acetylcholine are sympathomi- metic; they cause effects that mimic activation of the sympathetic di- vision of the ANS. For example, atropine, an antagonist of mAChRs, produces signs of sympathetic activation, such as dilation of the pupils. This response occurs because the balance of ANS activity is shifted toward the sympathetic division when parasympathetic actions are blocked. On the other hand, drugs that promote the muscarinic actions of ACh or inhibit the actions of NE are parasympathomimetic; they cause effects that mimic activation of the parasympathetic division of the ANS. For example, propranolol, an antagonist of the ␤ receptor for NE, slows the heart rate and lowers blood pressure. For this reason, pro- pranolol is sometimes used to prevent the physiological consequences of stage fright. But what about the familiar flow of adrenaline? Adrenaline (epineph- rine) is the compound released into the blood from the adrenal medulla when activated by preganglionic sympathetic innervation. Epinephrine is actually made from norepinephrine (called noradrenaline in the United Kingdom), and it has effects on target tissues almost identical to those caused by sympathetic activation. Thus, the adrenal medulla is really nothing more than a modified sympathetic ganglion. You can imagine that as the epinephrine (adrenaline) flows, a coordinated, body-wide set of sympathetic effects kicks in. THE DIFFUSE DIFFU USE MODULATORY SYSTEMS OF THE TH HE BRAIN BR RAIN Consider what happens when you fall asleep. The internal commands “You are becoming drowsy” and “You are falling asleep” are messages that must be received by broad regions of the brain. Dispensing this infor- mation requires neurons with a particularly widespread pattern of axons. The brain has several such collections of neurons, each using a particular neurotransmitter and making widely dispersed, diffuse, almost mean- dering connections. Rather than carrying detailed sensory information, these cells often perform regulatory functions, modulating vast assem- blies of postsynaptic neurons (in structures such as the cerebral cortex, the thalamus, and the spinal cord) so that they become more or less excitable, more or less synchronously active, and so on. Collectively, they 519–550_Bear_15_revised_final.indd 538 12/20/14 5:26 AM  CHAPTER 15 CHEMICAL CONTROL OF THE BRAIN AND BEHAVIOR 539 are a bit like the volume, treble, and bass controls on a radio, which do not change the lyrics or melody of a song but dramatically regulate the impact of both. In addition, different systems appear to be essential for aspects of motor control, memory, mood, motivation, and metabolic state. Many psychoactive drugs affect these modulatory systems, and the sys- tems figure prominently in current theories about the biological basis of certain psychiatric disorders. Anatomy and Functions of the Diffuse Modulatory Systems The diffuse modulatory systems differ in structure and function, yet they have certain principles in common: Typically, the core of each system has a small set of neurons (several thousand). Neurons of the diffuse systems arise from the central core of the brain, most of them from the brain stem. Each neuron can influence many others because each one has an axon that may contact more than 100,000 postsynaptic neurons spread widely across the brain. The synapses made by many of these systems release transmitter mol- ecules into the extracellular fluid, so they can diffuse to many neurons rather than be confined to the vicinity of the synaptic cleft. We’ll focus on the modulatory systems of the brain that use either norepinephrine (NE), serotonin (5-HT), dopamine (DA), or acetylcholine (ACh) as a neurotransmitter. Recall from Chapter 6 that all of these trans- mitters activate specific metabotropic (G-protein-coupled) receptors, and these receptors mediate most of their effects; for example, the brain has 10–100 times more metabotropic ACh receptors than ionotropic nicotinic ACh receptors. Because neuroscientists are still working hard to determine the exact functions of these systems in behavior, our explanations here will neces- sarily be general. It is clear, however, that the functions of the diffuse modulatory systems depend on how electrically active they are, individu- ally and in combination, and on how much neurotransmitter is available for release (Box 15.2). The Noradrenergic Locus Coeruleus. Besides being a neurotransmit- ter in the peripheral ANS, NE is also used by neurons of the tiny locus coeruleus in the pons (from the Latin for “blue spot” because of the pig- ment in its cells). Each human locus coeruleus has about 12,000 neurons. We have two of them, one on each side. A major breakthrough occurred in the mid-1960s, when Nils-Åke Hillarp and Bengt Falck at the Karolinska Institute in Sweden devel- oped a technique that enabled the catecholaminergic (noradrenergic and dopaminergic) neurons to be visualized selectively in histological sections prepared from the brain (Figure 15.11). This analysis revealed that axons leave the locus coeruleus in several tracts but then fan out to innervate just about every part of the brain: all of the cerebral cortex, the thalamus and the hypothalamus, the olfactory bulb, the cerebellum, the midbrain, and the spinal cord (Figure 15.12). The locus coeruleus makes some of the most diffuse connections in the brain, considering that just one of its neurons can make more than 250,000 synapses, and it can have one axon branch in the cerebral cortex and another in the cerebellar cortex! The organization of this circuitry is so different from what was then known about synaptic connections in the brain that it took many years 519–550_Bear_15_revised_final.indd 539 12/20/14 5:26 AM  540 PART THREE THE BRAIN AND BEHAVIOR BOX 15.2 OF SPECIAL INTEREST You Eat What You Are A mericans, it seems, are always trying to lose weight. The low-fat, high-carbohydrate diets (think bagels) that were all who observed that several other amino acids (tyrosine, phe- nylalanine, leucine, isoleucine, and valine) compete with tryp- the rage in the 1990s were replaced by a low-carb craze tophan for transport across the blood-brain barrier. These (think omelets). Changing your diet can alter caloric intake other amino acids are rich in a high-protein diet, and they and the body’s metabolism, and it can also alter how your suppress the entry of the tryptophan into the brain. The situ- brain functions. ation is reversed with a high-carbohydrate meal that also The influence of diet on the brain is most clear in the contains some protein. Insulin, released by the pancreas in case of the diffuse modulatory systems. Consider serotonin. response to carbohydrates, decreases the blood levels of the Serotonin is synthesized in two steps from the dietary amino competing amino acids relative to tryptophan. So the trypto- acid tryptophan (see Figure 6.14). In the first step, a hydroxyl phan in the blood is efficiently transported into the brain, and group (OH) is added to tryptophan by the enzyme tryptophan serotonin levels rise. hydroxylase. The low affinity of the enzyme for tryptophan Increased brain tryptophan correlates with elevated mood, makes this step rate-limiting for serotonin synthesis—that is, decreased anxiety, and increased sleepiness, likely due to serotonin can be produced only as fast as this enzyme can changes in serotonin levels. Inadequate tryptophan may ex- hydroxylate tryptophan. And a lot of tryptophan is required plain the phenomenon of carbohydrate craving that has been to push the synthetic reaction as fast as it can go. However, reported in humans with seasonal affective disorder—the brain tryptophan levels are well below the level required to depression of mood brought on by reduced daylight during saturate the enzyme. Thus, the rate of serotonin synthesis winter. It may also explain why clinical trials for treating obe- is determined, in part, by the availability of tryptophan in the sity with extreme carbohydrate deprivation had to be stopped brain—more tryptophan, more serotonin; less tryptophan, because of complaints of mood disturbances (depression, less serotonin. irritability) and insomnia. Brain tryptophan levels are controlled by how much tryp- Based on these and other observations, Wurtman and his tophan is in the blood and by how efficiently it is transported wife Judith made the intriguing suggestion that our dietary across the blood-brain barrier. Tryptophan in the blood is de- choices may reflect our brain’s need for serotonin. Consistent rived from the proteins we digest in our diet, so a high-protein with this notion, drugs that elevate extracellular serotonin can diet will lead to sharply increased blood levels of tryptophan. be effective for weight loss (as well as depression), possi- Surprisingly, however, there is a decline in brain tryptophan bly by reducing the body’s demand for carbohydrates. We (and serotonin) for several hours after a hearty, high-protein will discuss the involvement of serotonin in appetite regula- meal. The paradox was resolved by Richard Wurtman and tion further in Chapter 16, and in the regulation of mood in his colleagues at the Massachusetts Institute of Technology Chapter 22. ▲ FIGURE 15.11 Norepinephrine-containing neurons of the locus coeruleus. Reaction of noradrenergic neurons with formaldehyde gas causes them to fluoresce green,