Chapter 15: The Hypothalamus and Regulation of Bodily Functions

The hypothalamus is crucial for maintaining normal organ function and for producing many of the behaviors necessary to meet basic needs such as feeding, drinking, mating, and sleeping. The hypothalamus thus ensures survival of both the individual and its species. Virtually every body organ depends on the hypothalamus for some aspect of control, including the heart, lungs, gastrointestinal tract, and genitourinary organs. The hypothalamus helps organize the body's reactions to disease, such as fever production in response to infection. Skeletal muscle depends on the hypothalamus for regulating its blood supply; even bone mass seems to depend on hypothalamic regulation. In animals, the hypothalamus controls complex behaviors, like sexual responsiveness, maternal care (eg, nursing), and aggression. Whereas it can only be speculated how much of similar human behaviors depend on the hypothalamus, it is now becoming clear that the hypothalamus is important in regulating aspects of human social behavior. The list goes on and on! Compared with just about every other region of the nervous system, each of which serves a small set of functions, the hypothalamus accomplishes a bewilderingly wide range of tasks. We will see that it does this largely by using information about the body's internal state, about emotions, and about critical environmental stimuli, to control hormone production and the autonomic nervous system, and to regulate the moment-to-moment functions of neural circuits for arousal.

This chapter first considers hypothalamic gross anatomy. Next, the chapter surveys its functional organization, highlighting several key aspects. Additional important functions of the hypothalamus are examined when we learn about its regional anatomy, later in the chapter. Chapter 16 revisits the hypothalamus and its role in motivational and appetitive behavior, along with other brain structures that comprise the limbic system for emotions.

The hypothalamus is a tiny diencephalic structure, about 1-cm square, that is located ventral and anterior to the thalamus (Figure 15–2). The third ventricle separates the two halves of the hypothalamus. On its medial, or ventricular, surface the hypothalamus is distinguished from the thalamus by a shallow groove, the hypothalamic sulcus. Anteriorly, part of the hypothalamus extends a bit beyond the anterior wall of the third ventricle. (The anterior wall of the third ventricle is the location of the most anterior portion of the developing central nervous system, or the lamina terminalis; Figure 15–2.) The hypothalamus reaches caudally, just beyond the mammillary bodies, paired hypothalamic nuclei on its ventral surface (Figure 15–3).

We will learn that the functions of the hypothalamus are organized by projection neurons in discrete nuclei, or small groups of nuclei, that interface with different effector systems and circuits in other parts of the central nervous system. These hypothalamic nuclei are arranged into three mediolateral zones, each with distinctive functions (Figures 15–3 and 15–4; Table 15–1):

1. The periventricular zone is the most medial and comprises thin nuclei that border the third ventricle. This zone is important in regulating the release of endocrine hormones from the anterior pituitary gland.

2. The middle zone, which is interposed between the periventricular and lateral zones, serves diverse functions. It contains nuclei that regulate the release of vasopressin and oxytocin from the posterior pituitary gland. It is also a major site for neurons that regulate the autonomic nervous system. The body's biological clock is set by neurons in this zone, as are aspects of the control of wakefulness.

3. The lateral zone is separated from the medial zone by the fornix, a C-shaped tract that interconnects limbic system structures (see Figure 1–11A). This zone contains neurons that integrate information from other hypothalamic nuclei and telencephalic structures engaged in emotions. This is also a region important for regulating sleep and wakefulness and feeding.

The nuclei of the hypothalamus are located at discrete anterior-posterior positions (Table 15–1). This describes an orthogonal regional organization that will be the basis for examining sections through the hypothalamus later in the chapter. Historically, this organization was stressed because scientists recognized distinctive differences between the functions of the anterior and posterior hypothalamus. Now, we recognize these differences in the context of discrete hypothalamic nuclei rather than its gross anatomy. Whereas the boundaries between the anterior-posterior regions are not precise, a general knowledge of their locations is essential for an understanding of the three-dimensional organization of the hypothalamus.

• The anterior part of the hypothalamus, located dorsal and rostral to the optic chiasm (see Figure 15–3, inset), includes the preoptic area, with its numerous preoptic nuclei. The preoptic area is sometimes considered separate from the hypothalamus. But because its functions are intimately related to other, more caudal, hypothalamic functions, it is best to consider them together. The principal nucleus for circadian rhythms is also located in the anterior hypothalamus.

• The middle hypothalamus is between the optic chiasm and the mammillary bodies. This portion contains the infundibular stalk, from which the pituitary gland arises. The nuclei for anterior and posterior pituitary hormone release are mostly located here.

• The posterior portion includes the mammillary bodies and nuclei dorsal to them.

Separate Parvocellular and Magnocellular Neurosecretory Systems Regulate Hormone Release From the Anterior and Posterior Lobes of the Pituitary

The pituitary gland is connected to the ventral surface of the hypothalamus by the infundibular stalk (Figure 15–4A). In humans, two major anatomical divisions of the pituitary gland mediate the release of distinct sets of hormones (Figure 15–5): the anterior lobe (also called the adenohypophysis; see Table 15–2) and the posterior lobe (or neurohypophysis). A third lobe, the intermediate lobe, although prominent in many simpler mammals, is vestigial in humans.

The anterior and posterior lobes are parts of two distinct neurosecretory systems, and hormone release from these lobes is regulated by different populations of hypothalamic neurons. The anterior lobe is part of the parvocellular neurosecretory system (Figure 15–5A). This system contains small-diameter hypothalamic neurons (hence the term parvocellular) that are located in numerous nuclei. They regulate hormone release by epithelial secretory cells of the anterior pituitary. Parvocellular neurosecretory neurons are located predominantly in nuclei of the periventricular zone. By contrast, the posterior lobe is part of the magnocellular neurosecretory system (Figure 15–5B). Here, axons of large-diameter hypothalamic neurons in two nuclei project to and release peptide hormones into the posterior lobe. Rostrocaudally, parvocellular neurosecretory neurons are located in all the three hypothalamic regions, whereas the magnocellular neurosecretory neurons are mostly located in the middle zone.

Regulatory peptides released into the portal circulation by hypothalamic neurons control secretion of anterior lobe hormones

The process by which the hypothalamus stimulates anterior lobe secretory cells to release their hormones (or to inhibit release) is quite unlike mechanisms of neural action considered in earlier chapters. Rather than synapse on anterior lobe secretory cells, the hypothalamic parvocellular neurosecretory neurons terminate on capillaries of the pituitary portal circulation in the floor of the third ventricle (Figure 15–5A).

A portal circulatory system is distinguished by the presence of separate portal veins interposed between two sets of capillaries. The first set is located in a region termed the median eminence, which is part of the proximal infundibular stalk. The portal veins are located in the distal part of the infundibular stalk. The second set of capillaries is found in the anterior pituitary. (In the systemic circulation, such as the vascular supply of the rest of the brain, capillary beds are interposed between arterial and venous systems.)

Parvocellular neurons release chemicals, most of which are peptides, that either promote (releasing hormones) or inhibit (release-inhibiting hormones) the release of hormones from anterior lobe secretory cells (Table 15–2). Release or release-inhibiting hormones are carried to the anterior lobe in the portal veins (Figure 15–5A), where they act directly on epithelial secretory cells.

An analogy can be drawn between the capillaries in the median eminence and the integrative function of spinal motor neurons (see Chapter 10). Separate descending pathways and spinal interneuronal systems synapse on the motor neuron. Thus, the motor neuron is the final common pathway for the integration of neuronal information controlling skeletal muscle. The final common pathway for control of anterior lobe hormone release comprises the capillaries of the median eminence. This is because different hypothalamic neurons secrete releasing or release-inhibiting hormones into the capillaries of the median eminence (Figure 15–5A), and summation of neurohormones occurs at this vascular site.

The distribution of neurons that project to the median eminence has been examined extensively in rodents. Although these neurons are widespread, the major sources are located in nuclei within the periventricular zone (Figures 15–4 and 15–5A). Among the major sources, and some of the hormones they release, are the following:

• The arcuate nucleus contains neurons that release gonadotropin-releasing hormone, luteinizing hormone–releasing hormone, somatostatin, and adrenocorticotropic hormone.

• Neurons in the periventricular portion of the parvocellular nucleus (the part that lies along the third ventricle) contain corticotropin-releasing hormone (CRH).

• The periventricular nucleus provides gonadotropin-releasing hormone, luteinizing hormone–releasing hormone, and dopamine (which inhibits prolactin release).

• The medial preoptic area contains parvocellular neurons that secrete luteinizing hormone–releasing hormone.

In addition, there are extrahypothalamic sources of releasing and release-inhibiting neurohormones. For example, the septal nuclei (see Chapter 16) are a source of gonadotropin-releasing hormone. Interestingly, many of these neurohormones are also found in hypothalamic neurons that do not project to the median eminence and in neurons in other regions of the central nervous system. This widespread distribution of neurohormones indicates that they are neuroactive compounds at these other sites and not just chemicals that regulate anterior pituitary hormone release. Individual neurons of the parvocellular system, as in the magnocellular system (see below), may synthesize and release more than one peptide. This peptide synthesis and release may be regulated by circulating hormones in the blood. This is one way in which environmental factors, such as prolonged exposure to stressful situations, may alter the neurohormonal composition in the portal circulation and thereby influence anterior pituitary hormone release. Note that the blood-brain barrier is less of an obstacle in the hypothalamus than in most other brain regions (see Figure 3–16B).

Hypothalamic neurons project to the posterior lobe and release vasopressin and oxytocin

Posterior pituitary hormones, vasopressin and oxytocin, are the neurosecretory products of hypothalamic neurons; they have diverse functions on body organs. The peptide vasopressin elevates blood pressure, for example, through its action on vascular smooth muscle. Vasopressin also promotes water reabsorption from the distal tubules of the kidney to reduce urine volume. Another name for vasopressin is antidiuretic hormone (sometimes called ADH). Oxytocin is a peptide with a chemical structure nearly identical to that of vasopressin, differing by amino acids at only two sites. Oxytocin is best known for its actions on female organs, where it functions to stimulate uterine contractions and to promote ejection of milk from the mammary glands. There are other important behavioral actions of vasopressin and oxytocin. Both are important for pair bonding in monogamous animals of both sexes, although most studies focus on oxytocin in females and vasopressin in males. Both peptides also are important in other aspects of social behavior, such as vasopressin in social recognition and oxytocin in formation of interpersonal trust.

In the hypothalamus, both vasopressin and oxytocin are synthesized primarily in two nuclei, the paraventricular nucleus and the supraoptic nucleus (Figure 15–5B). Experiments in animals have shown that the paraventricular nucleus comprises at least three distinct cell groups. As described earlier, there are parvocellular neurosecretory neurons in the portion of the nucleus that apposes the third ventricle. Lateral to these neurons are the magnocellular neurosecretory neurons that synthesize and release the two posterior lobe neurohormones. A third neuron group, typically considered magnocellular because of their morphology not hormonal function, gives rise to a descending brain stem and spinal projection for regulating autonomic nervous system functions (see next section). The supraoptic nucleus consists only of magnocellular neurosecretory neurons. However, a small number of oxytocin-containing neurons of both the paraventricular and supraoptic nuclei project to several other brain regions, where they are thought to regulate aspects of social behavior.

Both vasopressin and oxytocin are synthesized from larger prohormone molecules. The prohormone molecules from which vasopressin and oxytocin derive contain additional proteins, called neurophysins. It was once thought that vasopressin was synthesized in one nucleus and oxytocin in the other. With the use of immunocytochemical techniques, however, it has been established that different cells in each nucleus produce one or the other hormone.

The axons of the paraventricular and the supraoptic magnocellular neurons in the infundibular stalk (Figures 15–4A and 15–5B) do not make synaptic contacts with other neurons. Rather, they terminate on fenestrated capillaries in the posterior lobe of the pituitary. (Fenestrations, or pores, make capillaries leaky. Recall that the posterior lobe of the pituitary [see also Figure 3–16] is one of the brain regions lacking a blood-brain barrier. Thus, neurohormones can pass freely into the capillaries through the fenestrations.)

Immunocytochemical studies also have shown that magnocellular neurons, like their parvocellular counterparts, contain other peptides that act on neurons in the central nervous system and on peripheral organs. These other peptides also may be released into the circulation along with oxytocin or vasopressin and have coordinated actions on diverse structures. Vasopressin itself is an example of a brain peptide that has a diversity of coordinated functions at different sites. For example, it is a blood-borne hormone that influences the function of specific peripheral target organs, such as the kidney, and it is a neuroactive peptide involved in control of the autonomic nervous system (see below).

An understanding of the projections from other brain regions to magnocellular hypothalamic neurons provides insight into how the brain controls neurohormone release. For example, magnocellular neurons that contain vasopressin are important for regulating blood volume. These neurons receive inputs from three key sources that each serve a related function.

• First, magnocellular neurons receive an indirect projection from the solitary nucleus. This pathway conveys baroreceptor input from the glossopharyngeal and vagus nerves (see Chapter 6) to the hypothalamus, providing important afferent signals for controlling blood pressure and blood volume.

• The second major input source is from two circumventricular organs, the subfornical organ and the organum vasculosum of the lamina terminalis (see Figure 3–16). The circumventricular organs do not have a blood-brain barrier. As discussed in Chapter 3, the blood-brain barrier is a specific permeability barrier between capillaries in the central nervous system and the extracellular space. This barrier protects the brain from the influence of many neuroactive chemicals circulating in the blood. Without a blood-brain barrier, neurons in subfornical organ and the organum vasculosum of the lamina terminalis are capable of sensing plasma osmolality and circulating chemicals and thereby can regulate blood pressure and blood volume through their hypothalamic projections.

• The preoptic area provides the third input to the magnocellular neurons. This region is implicated in the central neural mechanisms for regulating the composition and volume of body fluids and thus indirectly affects the control of blood pressure.

The Parasympathetic and Sympathetic Divisions of the Autonomic Nervous System Originate From Different Central Nervous System Locations

The hypothalamus regulates the autonomic nervous system. The autonomic nervous system controls several organ systems of the body: cardiovascular and respiratory, gastrointestinal, exocrine, and urogenital. Two divisions of the autonomic nervous system—the parasympathetic and sympathetic nervous systems—originate from different parts of the central nervous system. Similar to the control of skeletal muscle, visceral control by the sympathetic and parasympathetic systems relies on both relatively simple reflexes, involving the spinal cord and brain stem, and more complex control by higher levels of the central nervous system, especially the hypothalamus.

The enteric nervous system is sometimes considered a third division of the autonomic nervous system. It is located entirely in the periphery. This system provides the intrinsic innervation of the gastrointestinal tract and mediates the complex coordinated reflexes for peristalsis. It is thought that the enteric nervous system functions independent of the hypothalamus and the rest of the central nervous system.

The next section reviews the anatomical organization of the sympathetic and parasympathetic divisions. An understanding of how these autonomic divisions connect to their target organs is essential before considering their higher-order regulation by the hypothalamus.

Sympathetic and parasympathetic system innervation of body organs differs from the way the somatic nervous system innervates skeletal muscle

The innervation of skeletal muscle is mediated directly by motor neurons located in spinal and cranial nerve motor nuclei (Figure 15–6, left side of spinal cord). Further, skeletal muscle is controlled primarily by the contralateral cerebral cortex (Figure 15–6, red line) and various brain stem motor control nuclei (see Chapter 10). For the autonomic innervation of the viscera, two neurons link the central nervous system with organs in the periphery: the preganglionic neuron and the postganglionic neuron. Visceral control is mediated by the ipsilateral hypothalamus (Figure 15–6, black line) and brain stem nuclei. This is shown for the sympathetic nervous system in Figure 15–6 (right side of spinal cord; see Figure 11–4); more is known about the central control of the sympathetic than parasympathetic nervous system. The cell body of the sympathetic preganglionic neuron is located in the central nervous system, and its axon follows a tortuous course to the periphery. From the ventral root and through various peripheral neural conduits, the axon of the preganglionic neuron finally synapses on postganglionic neurons in peripheral ganglia (Figure 15–6). A notable exception is the adrenal medulla, which receives direct innervation by preganglionic sympathetic neurons. This exception is related to the fact that adrenal medullary cells, like postganglionic neurons, develop from the neural crest (see Chapter 6).

Two major differences exist in the neuroanatomical organization of the sympathetic and parasympathetic divisions (Figure 15–7). First is the location of the preganglionic neurons in the central nervous system; second is the location of the peripheral ganglia. Sympathetic preganglionic neurons are found in the intermediate zone of the spinal cord, between the first thoracic and third lumbar spinal cord segments. Most of the neurons are located in the intermediolateral nucleus (Figure 15–6) (also called the intermediolateral cell column because, like Clarke's column, this nucleus has an extensive rostrocaudal organization; Figure 15–7, left).

In contrast, parasympathetic preganglionic neurons are found in the brain stem and the second through fourth sacral spinal cord segments (Figure 15–7, right). The general organization of the parasympathetic brain stem nuclei was described in Chapter 11 in the discussion of cranial nerve nuclei. Most brain stem preganglionic neurons are located in four nuclei: (1) Edinger-Westphal nucleus, (2) superior salivatory nucleus, (3) inferior salivatory nucleus, and (4) dorsal motor nucleus of the vagus. Others are scattered in the reticular formation. The parasympathetic preganglionic neurons in the sacral spinal cord are found in the intermediate zone, at sites analogous to those of sympathetic preganglionic neurons.

The second major difference in the neuroanatomy of the sympathetic and parasympathetic divisions is the location of the peripheral ganglia in which the postganglionic neurons are located. Parasympathetic ganglia, often called terminal ganglia, are located on or near their target organs. In contrast, sympathetic ganglia are found closer to the spinal cord. Postganglionic sympathetic neurons are located in paravertebral ganglia, which are part of the sympathetic trunk, and in prevertebral ganglia (Figure 15–7).

Hypothalamic nuclei regulate the functions of the autonomic nervous system through descending visceromotor pathways

The autonomic nervous system implements important aspects of hypothalamic control of body functions. How does the hypothalamus regulate the functions of the autonomic nervous system? The answer, perhaps surprising, is related to how the brain controls voluntary movement. As discussed in Chapter 10, distinct areas of the cerebral cortex and brain stem nuclei give rise to the descending motor pathways that regulate the excitability of motor neurons and interneurons (Figure 15–6). These spinal projections transmit control signals to steer voluntary movements and regulate spinal reflexes. Visceral motor functions—mediated by the autonomic nervous system—are subjected to a similar control by the brain (Figure 15–6). The descending autonomic pathways originate from the hypothalamus and various brain stem nuclei. The major hypothalamic nucleus for controlling sympathetic and parasympathetic functions is the paraventricular nucleus (Figure 15–8). The neurotransmitters used by this pathway include glutamate and the peptides vasopressin and oxytocin, the same peptides released by the magnocellular neurosecretory system. The neurons giving rise to the descending pathway, however, are distinct from those projecting to the posterior pituitary. Other hypothalamic sites contribute axons to the descending visceromotor pathways. These areas include neurons in the lateral hypothalamic zone, the dorsomedial hypothalamic nucleus, and the posterior hypothalamus. The visceromotor pathway descends laterally—and primarily ipsilaterally—through the hypothalamus in the medial forebrain bundle, which is located in the lateral zone. The descending axons leave the bundle and then run in the dorsolateral tegmentum in the midbrain, pons, and medulla (Figure 15–8). As is discussed below, lesions of the dorsolateral brain stem tegmentum can produce characteristic autonomic changes because of damage to these descending hypothalamic axons. The descending autonomic pathway synapses on brain stem parasympathetic nuclei, such as the dorsal motor nucleus of the vagus, spinal sympathetic neurons in the intermediolateral nucleus of the thoracic and lumbar segments, and spinal parasympathetic neurons in the sacral cord (Figure 15–8).

The visceral and somatic motor systems communicate with one another to mediate coordinated responses. When we are preparing to increase muscular exertion, there are anticipatory increases in blood pressure and heart rate. There is evidence that some somatic motor control centers, in addition to projecting to spinal somatic muscle control regions, also project to the intermediolateral nucleus to help coordinate visceral and vascular responses with skeletal muscle contraction. Many of the brain stem nuclei described earlier, including the solitary and parabrachial, receive convergent connections from centers controlling somatic muscle and visceral structures, such as the kidney. This is a way to make sure that metabolic byproducts of muscular action are properly excreted.

Hypothalamic Nuclei Coordinate Integrated Visceral Responses to Body and Environmental Stimuli

Most bodily functions necessary for survival have important hypothalamic control. So far, this chapter has considered the substrates for basic hypothalamic control of endocrine hormone release (both anterior and posterior pituitary) and visceromotor control by the autonomic nervous system. The hypothalamus also plays a key role in coordinating endocrine and autonomic control, together with somatic motor functions, to produce highly integrated and purposeful responses. The hypothalamus engages in five major integrative functions, each with clear neuroanatomical substrates: (1) regulation of blood pressure and body fluid electrolyte composition, (2) temperature regulation, (3) regulation of energy metabolism, (4) reproductive functions, and (5) organization of a rapid response to emergency situations. For each of these regulatory functions, the hypothalamus senses environmental or body signals and uses this information, first, to organize an appropriate response and, then, to command other brain regions to implement the response. Complex environmental stimuli, such as recognizing a threatening situation or assessing the social context, require extensive processing by telencephalic structures, including the amygdala and the cerebral cortex. This information, which is transmitted to the hypothalamus, can trigger organized and stereotypic behavioral and visceral responses.

Five major brain stem structures work together with the hypothalamus to help regulate the autonomic nervous system and coordinate responses. They do so by projecting to other brain stem viscerosensory and visceromotor nuclei, as well as by projecting directly to brain stem and spinal cord sympathetic and parasympathetic nuclei.

• The solitary nucleus (see Figure 15–13C) relays viscerosensory information from the glossopharyngeal and vagus nerves to the hypothalamus, as well as to the parabrachial nucleus (see Figure 15–13B), the thalamus, and other forebrain structures (see Chapter 6). It also has a component that projects directly to the intermediolateral nucleus.

• The parabrachial nucleus receives viscerosensory information from the solitary nucleus and, in turn, projects to diverse forebrain centers involved in various homeostatic functions, such as food and water intake. The parabrachial nucleus connects with the paraventricular and other hypothalamic nuclei.

• Neurons in the ventrolateral medulla (see Figure 15–13C) give rise to an adrenergic projection to brain stem and spinal autonomic nuclei. These neurons play an important role in regulating blood pressure.

• Neurons of the pontomedullary reticular formation have dense projections to autonomic preganglionic neurons in the brain stem and spinal cord. Because many of these neurons also project to spinal motor and premotor neurons, they may coordinate complex behavioral responses such as defense reactions that involve both visceral and somatic changes. For example, when you are startled by an unexpected, loud noise, many of your skeletal muscles respond and your blood pressure rises.

• The serotonergic dorsal raphe nucleus receives strong inputs from the hypothalamus and provides serotonin throughout the forebrain. Other, more caudally located raphe nuclei project to spinal and brain stem autonomic nuclei. One function of the raphespinal system is to suppress dorsal horn pain transmission (see Chapter 5) in relation to the individual's emotional state.

The Hypothalamus Coordinates Circadian Responses, Sleep, and Wakefulness

Sleep is a recurring change in the functional state of the brain, a state in which responsiveness is reduced. A decreased ability to react to stimuli distinguishes sleep from quiet wakefulness. Sleep impacts many bodily functions, such as respiration and metabolism; also, we are usually immobile during sleep, indicating an important influence over somatic muscle control. Sleep is essential. No species is known not to sleep. Without sleep, people and animals suffer dearly; ultimately sleep deprivation is fatal. Given the importance of sleep to the individual, it is not surprising that the hypothalamus plays a central role in its regulation. As sleep impacts so many bodily functions, the integrated capacity for the hypothalamus to regulate neuroendocrine, autonomic, and somatic functions makes it well suited for regulating wakefulness.

Circadian signals from the suprachiasmatic nucleus regulate sleep and wakefulness through connections with other hypothalamic nuclei

The hypothalamus is the brain region essential for establishing the circadian functions of the body, including sleep and wakefulness. It does so through connections within the hypothalamus as well as descending projections to brain stem structures that regulate arousal and motor control, on the one hand, and ascending projections to telencephalic structures for cognition and emotion, on the other. The brain's clock is in the suprachiasmatic nucleus of the hypothalamus (Figure 15–9A), located directly above the optic chiasm. The actions of neurons in this nucleus are governed by a genetically-controlled molecular circadian clock. All neurons in this nucleus keep the same time, a time that is set by daylight signals arising directly by connections from a unique class of retinal ganglion neuron that contain the photopigment melanopsin. Recall, light sensitivity of most retinal ganglion neurons is conferred by the input from photoreceptors, relayed by bipolar neurons (see Figure 7–7). The suprachiasmatic nucleus, in turn, connects with other hypothalamic neurons, so that their functions are entrained to the circadian rhythm. For example, diurnal regulation of melatonin from the pineal gland occurs through a projection to the paraventricular nucleus to regulate the sympathetic nervous system, which projects to the pineal gland (Figure 15–9A).

The preoptic area helps switch from wakefulness to sleep

The key hypothalamic region for switching from wakefulness to sleep is the preoptic area sleep center (Figure 15–9B), in particular the ventral lateral preoptic nucleus. Many preoptic neurons that regulate sleep are GABAergic. Through their connections, they are thought to inhibit brain stem neurons that maintain arousal. The preoptic sleep center also has dense connections with the tuberomammillary nucleus of the hypothalamus, which uses histamine as its neurotransmitter to activate neurons in wide areas of the forebrain. Recall that a common side effect of antihistamines for allergic reactions is drowsiness. The preoptic sleep center also connects with brain stem nuclei important for arousal, including the locus ceruleus and the dorsal raphe nucleus (see Chapter 2, Figure 2–3), which use noradrenaline and 5-HT, respectively. Another component of the brain stem arousal center is the pedunculopontine nucleus, which uses acetylcholine as its neurotransmitter. Through projections especially to the thalamus, cholinergic neurons of the pedunculopontine nucleus help to activate thalamocortical circuits. Recall that the pedunculopontine nucleus is a target for deep brain stimulation in Parkinson disease, where it is used predominantly in ameliorating bradykinesia. When these various brain stem arousal nuclei are inhibited by the preoptic sleep center (brain stem-directed arrow, Figure 15–9), the arousal level of the brain decreases, and this helps to bring on sleep. Many of its brain stem targets, in turn, inhibit the preoptic sleep center (hypothalamus-directed arrow, Figure 15–9); this inhibition is thought to enable the brain to switch back into wakefulness.

Orexin neurons in the lateral hypothalamus help switch from non-REM to REM sleep

While we sleep, we cycle through different stages, or depths. One sleep stage is called rapid eye movement or REM sleep. Most of our dreams are during REM sleep. In addition to the occurrence of rapid eye movements during dreaming, REM sleep is also characterized by muscle atonia and a paradoxically high level of forebrain arousal (ie, the electroencephalogram, or EEG, is desynchronized). Muscle atonia prevents us from acting out our dreams. REM sleep is orchestrated by antagonistic sets of REM-on and REM-off neurons in the REM sleep center in the rostral pontine tegmentum (Figure 15–9C). REM-on neurons drive forebrain activity up—likely contributing to dreaming—and trigger muscle atonia, through direct and indirect reticulospinal projections that inhibit motor neurons. Importantly, motor neurons for respiratory muscles are not inhibited. REM-off neurons have the opposite functions.

The switch from non-REM to REM sleep is under important hypothalamic and brain stem regulation. Cholinergic neurons in the brain stem arousal center promote entry into REM sleep, while serotonergic and noradrenergic brain stem arousal neurons inhibit entry (Figure 15–9C). The hypothalamus also has antagonistic control. The preoptic sleep center helps turn on REM sleep (Figure 15–9C). Another set of hypothalamic neurons in the lateral hypothalamus that contain the peptide orexin inhibits entry into REM sleep. Not surprisingly, orexin neurons also have diverse forebrain projections that are important in maintaining arousal, just like their hypothalamic and brain stem counterparts that use histamine, acetylcholine, 5-HT, and noradrenaline.

Orexin may be central to the sleep disorder narcolepsy. Narcolepsy is a condition in which the person suddenly experiences excessive daytime sleepiness. One of the signs of narcolepsy is sudden switch from waking to sleep atonia, termed cataplexy. Often, the switch is triggered by a strong emotion, such as laughing. Mutation in an orexin receptor produces narcolepsy in animals. Some people with narcolepsy have reduced numbers of orexin-containing neurons in the brain, suggesting that orexin is associated with this sleep disorder. It has been suggested that narcolepsy could be an autoimmune disease in which the immune system mistakes orexin receptors for a foreign protein.

We now consider the regional anatomy of the hypothalamus from rostral to caudal. Three levels are considered, through the anterior, middle, and posterior parts of the hypothalamus. Then we will follow the descending visceromotor projection into the brain stem and spinal cord.

The Preoptic Area Influences Release of Reproductive Hormones From the Anterior Pituitary

The preoptic area is the most anterior part of the hypothalamus (Figures 15–4 and 15–10). It contains many small nuclei that serve five key functions. First, neurons in the medial preoptic area contain gonadotropin-releasing hormone. These neurons are believed to regulate pituitary reproductive hormone release because they project to the median eminence. Second, nuclei in the medial preoptic area and anterior hypothalamus of animals show sexual dimorphism (ie, morphological differences in males and females). In rats, gender affects the size of a sexually dimorphic nucleus as well as the architecture of neurons within the nucleus. Moreover, the size of this nucleus is dependent on perinatal exposure to gonadal steroids. This is an interesting example of how sexual differentiation alters brain morphology. In humans, identification of sexual dimorphism in the hypothalamus and other forebrain regions is controversial, with evidence existing for and against sex differences in the preoptic area and anterior hypothalamus. Part of the problem in identifying sex differences is that the human preoptic area has a complex organization, with numerous small and sometimes poorly differentiated nuclei. One of the nuclei reported to show sexual dimorphism in the human is part of the interstitial nuclei of the anterior hypothalamus, a small nucleus located at the level of the section shown in Figure 15–10. A third function of the preoptic area, discussed earlier, is in regulating sleep and wakefulness (Figure 15–9). Fourth, the preoptic area is important for regulating urination (discussed in a later section). Finally, the preoptic area, along with the posterior hypothalamus, is involved in thermoregulation. Neural circuits in the preoptic area dissipate heat, through coordinated actions on the autonomic nervous system, to produce vasodilation and increased sweating, and, in animals, on the somatic motor system, to promote panting. By contrast, the posterior hypothalamus is involved in heat conservation (see section on posterior hypothalamus).

The suprachiasmatic nucleus is located dorsal to the optic chiasm. As discussed earlier, neurons in the suprachiasmatic nucleus act as circadian clocks. They receive a direct projection from the retina— the retinohypothalamic tract—thereby allowing visual stimuli to synchronize (or reset) the internal clock (or circadian rhythm) of the body. The clinical significance of normal circadian rhythms and the function of the suprachiasmatic nucleus are just beginning to be appreciated. For example, defects in circadian rhythms are believed to underlie some sleep disorders and certain forms of depression, notably seasonal affective disorder.

Section Through the Median Eminence Reveals Parvocellular and Magnocellular Nuclei

The three mediolateral zones are shown schematically in Figure 15–11B, which is a coronal section through the proximal portion of the infundibular stalk. The infundibular stalk connects the basal hypothalamic surface with the pituitary gland. The median eminence, which contains the primary capillaries of the hypophyseal portal system, is located in the proximal portion of the infundibular stalk (Figure 15–4). Recall that the blood-brain barrier is absent in the median eminence (see Figure 3–16). As discussed, parvocellular neurosecretory neurons project to the median eminence. Releasing and release-inhibiting hormones secreted by the parvocellular neurosecretory neurons pass directly into the portal circulation through fenestrations, or pores, in the capillaries of the median eminence. Portal veins carry releasing and release-inhibiting hormones to the anterior lobe of the pituitary. Note that the lobes of the pituitary gland have different developmental histories. The anterior lobe is of nonneural ectodermal origin, developing from a diverticulum in the roof of the developing oral cavity, called Rathke's pouch. In contrast, the posterior lobe develops from the neuroectoderm. Early in development, the ectodermal and neuroectodermal portions fuse to form a single structure.

The arcuate nucleus is located in the periventricular hypothalamic region (Figure 15–4). Parvocellular neurons in the arcuate nucleus contain various releasing and release-inhibiting hormones. In addition, many neurons in the arcuate nucleus contain β-endorphin, an endogenous opiate cleaved from the large peptide proopiomelanocortin. Some of these neurons may play a role in opiate analgesia because they project to the periaqueductal gray matter, where electrical stimulation produces analgesia (see Chapter 5). Neurons in the arcuate nucleus are sensitive to three circulating hormones that play important roles in the control of feeding: insulin, leptin, and ghrelin. Because the blood-brain barrier in the arcuate nucleus is weak compared to most other brain regions, circulating peptides have access to arcuate neurons. Insulin, produced by the pancreas, circulates in relation to body energy balance (ie, the difference between energy consumed and energy expended). Leptin is produced by adipocytes in proportion to the amount of body fat. Both leptin and insulin are signals that act to inhibit food intake and increase energy expenditure. Both are normally available during times of plenty. Reductions in leptin and insulin, usually signaling anorexia, are stimuli to increase food intake and inhibit energy expenditure. Ghrelin, which is produced by enteroendocrine cells of the stomach, promotes feeding. Fasting stimulates its release; therefore, it has the opposite effects of insulin and leptin. In addition, neurons in the arcuate nucleus contain peptide neurotransmitters that have strong effects on feeding. For example, neuropeptide Y is contained in arcuate neurons and promotes feeding when injected intracerebrally into laboratory animals. Another major nucleus important in feeding is located in the rostrocaudal middle of the hypothalamus, the ventromedial hypothalamic nucleus (Figure 15–4). This nucleus receives input from a major limbic system structure, the amygdala (see Chapter 16). The ventral medial hypothalamus is also involved in regulating other appetite and consummatory behaviors.

Magnocellular neurosecretory cells of the paraventricular and supraoptic nuclei (Figure 15–11) project to the posterior lobe of the pituitary gland to release vasopressin and oxytocin onto systemic capillaries in the posterior lobe of the pituitary (Figure 15–5B). The axons travel down the infundibular stalk to contact capillaries that are part of the systemic circulation in the posterior lobe. Damage to the infundibular stalk, such as after traumatic head injury, may cut the axons of magnocellular neurosecretory cells as they pass to the posterior pituitary. This damage results in diabetes insipidus, in which excessive amounts of urine are produced. Fortunately the condition can be temporary because the cells are capable of forming a new, functional posterior lobe with nearby capillaries.

In addition to projecting to the posterior pituitary lobe, the paraventricular and supraoptic nuclei project to other brain regions. Importantly, both of these nuclei also use vasopressin and oxytocin at these other synapses. Recall that the paraventricular nucleus has a complex organization. In addition to the magnocellular division, it contains a parvocellular division that projects to the median eminence and an autonomic division that projects to brain stem and spinal cord nuclei containing autonomic preganglionic neurons (Figure 15–11B). Many neurons in each subdivision contain vasopressin or oxytocin. Release of vasopressin or oxytocin at the various target sites of neurons in the paraventricular nucleus may serve similar sets of functions. For example, vasopressin can be used by the projections of the paraventricular nucleus to the medulla, for regulating blood pressure, and the projections to the intermediolateral nucleus, for regulating blood volume by the kidney. The supraoptic nucleus also comprises vasopressin- and oxytocin-containing neurons and, like the paraventricular nucleus, also has projections to sites other than the posterior lobe. For example, some oxytocin-containing neurons of the supraoptic nucleus project to the nucleus accumbens; this projection is part of a reward circuit. Oxytocin-containing neurons are not just located in the paraventricular and supraoptic nuclei; they are also located in the lateral hypothalamus and the bed nucleus of the stria terminalis, a component of the limbic system (see Chapter 16). Note that while there are magnocellular neurons with diverse projections, only neurons that project to the posterior pituitary lobe are considered magnocellular neurosecretory cells.

Many hypothalamic neurons in the lateral zone (see Figure 15–12B) also have widespread projections to the cerebral cortex. One population of lateral hypothalamic neurons is particularly intriguing because the neurons contain peptides, termed orexins (or termed hypocretins), that, as discussed earlier, are essential for regulating sleep and arousal. The lateral hypothalamus is also important in feeding and food-seeking behavior. Lesions of the lateral hypothalamus in laboratory animals can cause reduced food intake and weight loss. This role in food intake also involves the orexin neurons. In addition to being the only brain area that contains orexin, the lateral hypothalamus is the only site containing neurons with melanin-concentrating hormone, another factor important in feeding behavior.

The Posterior Hypothalamus Contains the Mammillary Bodies

A section through the posterior hypothalamus reveals the mammillary nuclei (or bodies) (Figure 15–12). Each mammillary body contains two nuclei: the prominent medial mammillary nucleus and the smaller lateral mammillary nucleus. Remarkably, the mammillary bodies establish virtually no intrahypothalamic connections. By contrast, most other hypothalamic nuclei have extensive intrahypothalamic connections. This shows that the function of the mammillary bodies is unlike that of the other hypothalamic nuclei. They receive their major input from a portion of the hippocampal formation, via the fornix (Figures 15–4 and 15–12A; see Chapter 16). The efferent projections of the mammillary bodies are carried primarily in the mammillothalamic tract, which projects to the anterior nuclei of the thalamus (see Figure AII–19). The mammillary bodies also have a descending projection to the midbrain and pons, the mammillotegmental tract. Whereas the mammillothalamic tract originates from the medial and lateral mammillary nuclei, the mammillotegmental tract originates only from the lateral nucleus. The outputs of the mammillary bodies are considered part of the limbic system and are discussed further in Chapter 16.

Another nucleus in the posterior hypothalamus, the tuberomammillary nucleus (Figure 15–12B), contains histamine. Like the brain stem monoamine systems, noradrenalin, dopamine, and serotonin, histaminergic neurons in the tuberomammillary nucleus have widespread projections. This system is important in maintaining arousal. Blockade of histamine reduces cortical neuronal responsiveness, and antihistamine therapy in humans can produce drowsiness if the drug crosses the blood-brain barrier. The tuberomammillary nucleus is important in regulating sleep and wakefulness (Figure 15–9).

Other nuclei within the posterior hypothalamus do not contribute in a major way to neuroendocrine function. Rather, this region plays a role in regulating autonomic functions and mediating integrated behavioral responses to environmental stimuli. For example, the posterior hypothalamus is important in conserving body heat, which includes promoting vasoconstriction and shivering in response to low temperatures. This is also the only region to contain dopaminergic neurons that project directly to the spinal cord. Whereas the normal functions of these neurons are not yet known, loss of this dopaminergic projection has been implicated in restless legs syndrome, a disorder in which patients experience abnormal sensations in their legs that prompt the urge to move their legs to quell the sensation. The abnormal sensations and movements are more common during rest and sleep.

Descending Autonomic Fibers Course in the Periaqueductal Gray Matter and in the Lateral Tegmentum

Hypothalamic regulation of the autonomic nervous system is mediated, in large part, by descending projections to four sets of neurons: (1) brain stem parasympathetic nuclei, (2) brain stem visceral integrative nuclei (solitary nuclei, ventrolateral medulla, and parabrachial nucleus; Figure 15–13C), (3) sympathetic neurons in the intermediolateral nucleus in thoracic and lumbar spinal segments (see Figure 15–15A), and (4) parasympathetic neurons in the intermediate zone of the sacral spinal cord (see Figure 15–15B). The major path from the hypothalamus taken by the descending autonomic pathway is through the medial forebrain bundle (MFB), which is in the lateral zone (Figure 15–12B). This path is a conduit for axons from diverse sources, including ascending and descending connections between the brain stem, the hypothalamus, and the cerebral hemisphere. Neurons in the lateral zone tend not to be organized into distinct nuclei but rather are interspersed along the MFB. The MFB becomes dispersed in the brain stem, where the descending autonomic pathway courses in the lateral tegmentum (Figure 15–13A). (The term medial forebrain bundle is reserved for the portion in the hypothalamus only.) The Edinger-Westphal nucleus, which contains parasympathetic preganglionic neurons innervating the ciliary ganglion, is located at this level.

Another hypothalamic pathway, the dorsal longitudinal fasciculus, contains ascending viscerosensory and descending fibers. This pathway courses within the gray matter along the wall of the third ventricle, in the midbrain periaqueductal gray matter and the gray matter in the floor of the fourth ventricle. Although diffuse in the diencephalon and midbrain, fibers constituting this pathway can be identified in the pons and in the medulla (in the dorsal portion of the hypoglossal nucleus; Figure 15–13C).

Nuclei in the Pons Are Important for Bladder Control

The pons is an important site for bladder control, receiving control signals from the preoptic area: Neurons in the medial preoptic area project to a cluster of neurons in the dorsolateral pons that trigger urination. These neurons project to the parasympathetic bladder motor neurons and interneurons that inhibit urethral sphincter motor neurons. Separate pontine neurons, located laterally and ventrally, that excite urethral sphincter motor neurons are implicated in circuitry to prevent urination (ie, sphincter contraction). A positron emission tomography (PET) scan obtained while a human subject urinated is shown in Figure 15–14A, whereas a scan from a subject who was unable to voluntarily urinate during the scan—presumably because sphincter tone was too high—is shown in Figure 15–14B. These two scans reveal two distinct regions of the pons that control urination. Surprisingly, only the right pons became activated, suggesting cerebral lateralization of this function.

Dorsolateral Brain Stem Lesions Interrupt Descending Sympathetic Fibers

Several key structures for controlling the autonomic nervous system are located in the medulla (Figure 15–13C). The dorsal motor nucleus of the vagus contains parasympathetic preganglionic neurons that innervate the various terminal ganglia. This nucleus was considered in Chapter 11. The solitary nucleus, considered in Chapter 6, is the major brain stem relay for visceral afferent fibers. Different populations of projection neurons in the solitary nucleus ascend to the parabrachial nucleus (Figure 15–13B) and the hypothalamus and descend to the spinal cord. Adrenergic neurons in the ventrolateral medulla project to the intermediolateral cell column for blood pressure control.

Damage to the dorsolateral pons or medulla can produce Horner syndrome, a disturbance in which the functions of the sympathetic nervous system become impaired (see clinical case in this chapter; see also Box 15–1). Surprisingly, parasympathetic functions are spared (see below). Such damage typically occurs as a consequence of occlusion of the posterior inferior cerebellar artery (PICA) (see Figure 3–3B3). The most common signs of Horner syndrome and their causes are as follows:

• Ipsilateral pupillary constriction (miosis), resulting from the unopposed action of the pupillary constrictor innervation by the parasympathetic Edinger-Westphal nucleus (see Chapter 12).

• Partial dropping of the eyelid, or pseudoptosis, produced by removal of the sympathetic control of the smooth muscle (tarsal muscle) assisting the action of the levator palpebrae muscle.

• Decreased sweating and increased warmth and redness of the ipsilateral face, related to reduced sympathetic control of facial blood flow.

It is not understood why damage to the dorsal motor nucleus of the vagus following PICA occlusion does not produce parasympathetic signs. Perhaps the parasympathetic functions of the nucleus are not well lateralized and the intact side can take over the functions of the damaged side.

Preganglionic Neurons Are Located in the Lateral Intermediate Zone of the Spinal Cord

The descending autonomic fibers from the hypothalamus course in the lateral column of the spinal cord, within the region of the lateral corticospinal tract (Figure 15–15), and terminate in the intermediolateral nucleus (or cell column) of the thoracic and lumbar cord (Figure 15–15A) to regulate sympathetic functions. This is where sympathetic preganglionic motor neurons are located. Projections to the intermediate zone of the second through fourth sacral segments regulate parasympathetic functions (Figure 15–15B). This is where parasympathetic preganglionic motor neurons are located. Additional sympathetic and parasympathetic preganglionic neurons are scattered medially in the intermediate zone. At certain thoracic levels, the intermediolateral nucleus extends into the lateral column (Figure 15–15A), which explains why this region is sometimes called the intermediate horn of the spinal cord gray matter. The inset in Figure 15–15 shows the columnar shape of the intermediolateral nucleus. This organization is similar to that of Clarke's nucleus (see Figure 13–6) and the cranial nerve nuclei (see Figure 6–6). Because important control of the sympathetic nervous system is present in divisions of the central nervous system, it is not surprising that damage at different levels can produce Horner syndrome (Box 15–1). Somatic motor neurons that innervate the urinary sphincter are located in Onuf's nucleus, in the ventral horn of the sacral spinal cord.

General Hypothalamic Anatomy

The hypothalamus is a part of the diencephalon. On the midline it is bounded by the rostral wall of the third ventricle rostrally and the hypothalamic sulcus dorsally. The preoptic area extends farther anteriorly (Figure 15–4). The lateral boundary is the internal capsule. The hypothalamus has a mediolateral anatomical and functional organization, with separate periventricular, medial, and lateral zones (Figure 15–4).

Neuroendocrine Control

Neuroendocrine control by the hypothalamus is mediated by separate parvocellular and magnocellular neurosecretory systems, which control hormone release from the anterior and posterior pituitary, respectively (Figure 15–5).

Parvocellular neurosecretory neurons (Figure 15–5A) regulate anterior lobe hormone release by secreting releasing or release-inhibiting hormones (Table 15–2) into the portal circulation in the median eminence (Figure 15–5). The major parvocellular nuclei, which are largely located in the periventricular zone, are the periventricular nuclei, the arcuate nucleus, the paraventricular nucleus (medial, or periventricular, part, only), and the medial preoptic area. Additional hypothalamic and extrahypothalamic sites project to the median eminence and release gonadotropin-releasing hormones.

Two nuclei form the magnocellular system: the magnocellular division of the paraventricular nucleus and the supraoptic nucleus (Figures 15–4, 15–5B, and 15–11). Axons from the magnocellular neurons in these nuclei project into the infundibular stalk, which connects the pituitary gland with the brain (Figure 15–5). Their termination site is the posterior lobe, where they release vasopressin and oxytocin directly into the systemic circulation. Separate neurons in the paraventricular and supraoptic nuclei synthesize either vasopressin or oxytocin (Figure 15–11). Both parvocellular and magnocellular neurons colocalize additional neuroactive peptides.

Autonomic Nervous System and Visceromotor Functions

The autonomic nervous system has two anatomical components: the sympathetic division and the parasympathetic division. The enteric nervous system is the intrinsic innervation of the gut. For the sympathetic and parasympathetic divisions, two neurons link the central nervous system with their target organs (Figures 15–6, 15–7, and 15–8): a preganglionic neuron, located in the central nervous system, and a postganglionic neuron, located in peripheral ganglia. The sympathetic division originates from the spinal cord, between the first thoracic and third lumbar segments (Figure 15–7). Preganglionic neurons of this division are located in the intermediolateral nucleus (Figure 15–15A). The parasympathetic division originates from the brain stem and the sacral spinal cord. Four parasympathetic nuclei in the brain stem contain preganglionic neurons (see Chapters 11 and 12): the Edinger-Westphal nucleus, the superior salivatory nucleus, the inferior salivatory nucleus, and the dorsal motor nucleus of the vagus. The lateral intermediate zone of the second through fourth sacral segments contains parasympathetic preganglionic neurons (Figure 15–15B).

Hypothalamic control of the autonomic nervous system is through descending pathways whose axons synapse on preganglionic neurons (Figures 15–6 and 15–8). The major source of this projection is the autonomic division of the paraventricular nucleus. This hypothalamic pathway courses in the medial forebrain bundle (Figure 15–12B), located laterally in the hypothalamus, and its caudal extension in the lateral tegmentum of the brain stem (Figure 15–13) and the lateral column of the spinal cord (Figure 15–15A). Disruption of axons of this pathway at any level can produce Horner syndrome (Figure 15–16). The hypothalamus also projects to other sites important in visceral sensory and motor function: the parabrachial nucleus, the solitary nucleus, raphe nuclei, ventrolateral medulla, and the reticular formation (Figure 15–13).

Circadian Rhythms and Sleep and Wakefulness

The suprachiasmatic nucleus (Figures 15–2 and 15–9) is the brain's master clock, receiving retinal input to entrain brain functions to the circadian cycle. Other hypothalamic nuclei receive input from the suprachiasmatic nucleus to organize circadian control of neuroendocrine and autonomic functions (Figure 15–9). The preoptic sleep center (Figures 15–9 and 15–10) and tuberomammillary nucleus (Figure 15–12B) regulate brain stem arousal centers, which include the pedunculopontine nucleus, locus ceruleus, and dorsal raphe nucleus, and, in turn, are regulated by these centers. The lateral pontine tegmentum is key to atonia during REM sleep.