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.
A. Parvocellular neurosecretory system. B. Magnocellular neurosecretory system. Inset shows an MRI that distinguishes the anterior and posterior pituitary lobes of the pituitary gland. (A, reproduced from Sartor K. MR Imaging of the Skull and Brain. New York, NY: Springer; 1992.)
Table 15–2Anterior pituitary hormones and substances that control their release ||Download (.pdf) Table 15–2 Anterior pituitary hormones and substances that control their release
|Anterior pituitary hormones ||Releasing hormones (RH) ||Release-inhibiting hormones (RIH) |
|Growth hormone ||Growth hormone RH ||Somatostatin (growth hormone RIH) |
|Lutenizing hormone ||Gonadotrophin RH || |
|Follicle-stimulating hormone ||Gonadotrophin RH || |
|Thryotropin ||Thryotropin RH (or TRH) ||Somatostatin (growth hormone RIH) |
|Prolactin ||Prolactin RH ||Prolactin RIH; dopamine |
|Adrenocorticotropic hormone (ACTH) ||Corticotropin RH (CRH) || |
|Melanocyte-stimulating hormone (MSH) ||Melanocyte-stimulating hormone RH ||Melanocyte-stimulating hormone RIH |
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).
The circuits for skeletal muscle control and visceral organ innervation by the sympathetic nervous system. For the viscera, control is exerted primarily from the hypothalamus. Preganglionic sympathetic autonomic neurons are located in the intermediate zone of the spinal cord. Their axons exit the spinal cord through the ventral roots and project to ganglia in the sympathetic trunk (paravertebral ganglia) through the spinal nerves and white rami. The axons of postganglionic neurons in the sympathetic ganglia course to the periphery through the rami and spinal nerves. The white and gray rami contain, respectively, the myelinated and unmyelinated axons of preganglionic and postganglionic autonomic neurons. A postganglionic neuron in a prevertebral ganglion is also shown with input from a preganglionic neuron. For somatic muscle control, control derives from the descending motor paths; the corticospinal tract is shown. Muscle is innervated directly by motor neurons in the ventral horn. Note that for skeletal muscle control, only the direct path from the cerebral cortex to motor neurons is shown. In addition, there are indirect paths that relay in the brain stem and via spinal cord interneurons.
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).
Organization of the autonomic nervous system. The sympathetic nervous system is shown at left, and the parasympathetic nervous system is shown at right. Note that the postganglionic neurons for the sympathetic nervous system are located in sympathetic trunk ganglia and prevertebral ganglia (eg, celiac ganglion). The postganglionic neurons for the parasympathetic nervous system are located in terminal ganglia close to the target organ. (Adapted from Schmidt RF, Thews G, eds. Human Physiology. 2nd ed. Berlin, Heidelberg: Springer-Verlag; 1989.)
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).
Regions of origin, course, and termination sites of descending hypothalamic pathways.
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).
Sleep circuits of the brain. A. Circadian rhythms and the suprachiasmatic nucleus. The suprachiasmatic nucleus receives visual information that sets the clock. This nucleus projects to other hypothalamic nuclei to implement circadian functions. This example is for circadian control of melatonin release from the pineal gland. B. Preoptic area (POA) sleep center and sleep and wakefulness. The principal component of the preoptic sleep center is the ventrolateral preoptic nucleus. This nucleus is key to the switch from wakefulness to sleep. The preoptic nucleus acts on the brain stem arousal center, which includes the cholinergic pedunculopontine nucleus, the serotonergic dorsal raphe nucleus, and the noradrenergic locus ceruleus. This is shown as the negative sign by the brain stem-directed arrow in the arousal center. C. Rapid eye movement (REM) sleep control is extraordinarily complex, regulated by orexin neurons in the lateral hypothalamus, the preoptic sleep center, and several brain stem nuclei comprising the brain stem arousal center. The plus signs indicate structures that promote entry into REM sleep, whereas the negative signs indicate structures that retard entry.
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.