It has long been clear that mammals and other organisms exhibit daily cycles in physiology and behavior that persist in the absence of sensory input from the environment. These cycles are approximately 1 day in length (hence the term circadian) and in normal circumstances are synchronized with the environment. In essence, they are rhythms of behavior and physiology that are tightly coupled to the most pervasive signal in our environment, the daily rhythm of light and dark. The adaptive significance of such an endogenous timekeeping mechanism is obvious when one considers the practical benefits of synchronizing behavior to the light-dark cycle. Certainly, the restriction of the activity of nocturnal animals to nighttime has the practical advantage of reducing the possibility of predation, and the ability to precisely measure day length permits seasonal breeders to deliver their progeny during the portion of the year when nutrients are most prevalent. Thus, it is not surprising that this endogenous timekeeping system is among the oldest and most highly conserved systems of regulatory control in the animal kingdom.
Although circadian rhythms in both plants and animals have been long been recognized, determination that a ''biological clock'' resides in the hypothalamus of mammals is a relatively recent event that can be traced to anatomical studies conducted in the early 1970s. Recognizing that the entraining influences of light are essential to any timekeeping system, two research groups independently utilized new methods of defining neuronal connectivity to demonstrate that a circumscribed group of neurons overlying the optic chiasm receives dense retinal inputs. These neurons, comprising the suprachiasmatic nuclei (SCN), became the experimental focus of circadian biologists and there is now considerable evidence supporting the conclusion that a biological clock resides in the SCN of mammals. Specifically, animal studies have shown that the cells of the SCN exhibit a circadian rhythm of activity that is entrained by light, and that rhythmic aspects of physiology and behavior are abolished in animals in which the SCN have been destroyed. Importantly, it is also known that the rhythmicity of SCN neurons is genetically determined rather than the emergent property of a network, and "clock" genes that impart rhythmicity to SCN neurons have been identified. Thus, the hypothalamus contains a clock, the SCN, whose activity is synchronized to the external environment by virtue of sensory input transduced by the retina.
Elucidating the connections of the SCN has been an important component of understanding how this group of hypothalamic neurons imposes its temporal message on the physiology and behavior of the parent organism. One of the most well-characterized systems in this regard is the circuitry through which the SCN exerts regulatory control over the secretion of the hormone melatonin. Melatonin is secreted by the pineal gland in a circadian manner but is also responsive to light such that light stimulation during the dark phase of the photoperiod inhibits the normally high levels of melatonin secretion. This dynamic regulatory capacity renders the temporal profile of melatonin secretion a precise measure of day length. A large literature has established that the SCN controls both the circadian and photoperiodic aspects of melatonin secretion through multisynaptic pathways that sequentially involve the paraventricular hypothalamic nucleus, the intermediolateral cell column of the spinal cord, and neurons of the superior cervical ganglion that project to the pineal. Additionally, binding studies and localization of melatonin receptors have revealed that melatonin exerts feedback influence on the brain by binding to neurons in the SCN, paraventricular thalamic nucleus, and pars tuberalis of the infundibular stalk. Thus, the SCN not only regulates the secretion of melatonin but also is subject to feedback regulation by the hormone that it modulates. This is a common feature of the neurohumoral regulation exerted by the hypothalamus.
The SCN also imparts temporal organization to other systems and appears to do so through efferent projections that are largely confined to the hypothalamus. SCN neurons project to a relatively restricted group of nuclei in the hypothalamus that includes, but is not limited to, the region subjacent to the paraven-tricular nucleus (the subparaventricular zone), the preoptic area, and medial hypothalamic nuclei (e.g., arcuate and dorsomedial) involved in neuroendocrine regulation of pituitary function. These projections provide a substrate through which the SCN imparts temporal influences on a variety of systems.
Evidence that the hypothalamus is involved in the control of sleep emerged from a large literature dating to the early 1900s. Lesion studies correlating anterior hypothalamic damage with insomnia and caudal hypothalamic damage with somnolence were particularly informative. These and subsequent studies resulted in the concept of hypothalamic "sleep centers." A fascinating recent literature has demonstrated a cellular basis for hypothalamic influences on sleep and also provided insights into the means through which temporal organization is imparted on this behavior. It is now apparent that at least two distinct populations of neurons in the rostral and caudal hypothalamus are responsible for the hypothalamic effects on sleep. Using a creative experimental approach, it was demonstrated that neurons in a circumscribed region of the preoptic area [the ventrolateral preoptic nucleus (VLPO)] in rats express Fos, the protein product of the protooncogene c-fos, shortly following the onset of sleep. Since Fos expression reflects neuronal activation, this observation raised the possibility that VLPO neurons are involved in the initiation of sleep. A number of subsequent observations have validated this hypothesis and also revealed the larger network of hypothalamic neurons that participate in this function. Specifically, evidence now supports the conclusion that VLPO neurons inhibit arousal through projections to histaminergic neurons in the tuberomammil-lary (TM) nuclei of the caudal hypothalamus. In support of this conclusion, it was shown that GA-BAergic neurons in VLPO synapse on TM neurons and that pharmacological inhibition of TM neurons or blockade of histaminergic receptors promotes sleep. Those who recall the drowsiness that typically follows the use of early antihistamines (which act on central as well as peripheral histamine receptors) prescribed for the treatment of colds and allergies can appreciate the major influence of the diffusely projecting neurons of the TM nuclei upon arousal.
Importantly, neurochemical lesions of VLPO and surrounding neurons have revealed greater functional parcellation of the anterior hypothalamic circuitry involved in sleep regulation. Cell-selective lesions that do not interrupt fibers of passage were shown to compromise different aspects of sleep based on the localization of the lesion. Lesions confined to the compact portion of VLPO dramatically reduce non-REM sleep and, in circumstances in which lesions are incomplete, the amount of non-REM sleep is linearly correlated with the number of Fos-expressing neurons in the portion of the VLPO that survived the lesion. Interestingly, lesions dorsal to VLPO that eliminate galanin-containing neurons that project to TM produce sleep deficits more closely associated with REM than with non-REM sleep. Collectively, these observations provide compelling evidence in support of a prominent role for the hypothalamus in sleep regulation and further indicate that there is functional parcellation in the neurons of the VLPO that participate in this control.
It is also clear that the hypothalamus plays an important role in the temporal organization of the sleep-wake cycle. Sleep is a circadian function, and although the SCN is not essential for the generation of sleep, it is responsible for consolidation of sleep within cycles that occur within a circadian framework. Thus, if the SCN are destroyed, rats will sleep approximately the same amount of time but this sleeping time will be distributed in many short bouts throughout the light-dark cycle rather than in a consolidated period. The circuitry through which the SCN imposes this circa-dian influence on sleep remains to be established, but it is likely that it occurs via polysynaptic connections that link the clock to nuclei involved in sleep regulation.
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