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):

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   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.

   
   
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   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.

   
   
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   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.

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  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.

  
  
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  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.

  
  
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  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:

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

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

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

  
  
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  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.

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  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.

  
  
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  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.

  
  
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  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).