The hypothalamic integrator for circadian rhythms

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Although the suprachiasmatic nucleus (SCN) is well established as providing a genetically based clock for timing circadian rhythms, the mechanisms by which the timing signal is translated into circadian rhythms of behavior and underlying physiology have only recently come to light. The bulk of the SCN outflow terminates in a column of tissue that arches upward and backward from the SCN, and which includes the subparaventricular zone (SPZ) and the dorsomedial nucleus of the hypothalamus. Neurons within the dorsal SPZ are necessary for organizing circadian rhythms of body temperature, whereas neurons in the ventral SPZ are needed for circadian rhythms of sleep and waking. Ventral SPZ neurons in turn relay to the dorsomedial nucleus, which is crucial for producing circadian rhythms of sleep and waking, locomotor activity, feeding and corticosteroid production. This multistage processor provides the animal with flexibility so that environmental cues, such as food availability, ambient temperature and social interactions, can be integrated with the clock signal to sculpt an adaptive pattern of rhythmic daily activities that maximize the chances of survival and reproduction.

Introduction

It has been known for nearly half a century that large lesions of the mediobasal hypothalamus cause loss of circadian rhythms of locomotor activity, feeding and drinking [1] but the location of the biological clock was not pinned down until 1972. A key series of experiments in that year established that the suprachiasmatic nucleus (SCN) receives the bulk of the retinal input to the hypothalamus 2, 3, and that lesions of the SCN cause loss of circadian rhythms 4, 5. Subsequent work showed that the individual neurons of the SCN contain a genetically driven clock mechanism, with a transcriptional–translational feedback loop that ensures a nearly 24 h cycle [6]. This cycle is then synchronized to the external light–dark cycle by input to the SCN from retinal ganglion cells that act as irradiance detectors (their slow responses are proportional to the light level) [7].

Although the events that control the SCN clock cycle have been delineated in considerable detail over the past decade, the mechanisms that convert that clock signal into patterning of a wide variety of physiological and behavioral rhythms have remained obscure. However, recent work has begun to identify the key pathways and neurotransmitters that are involved in this process. This review will focus on those mechanisms.

Section snippets

Output from the SCN

The projections from the SCN in rats were first shown by Swanson and Cowan in 1975 using autoradiographic tracing [8], and in more detail by Watts and colleagues in 1987 [9]. These same projections can be identified conveniently in sections through the SCN region that have been stained immunohistochemically for either arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP), which are contained in many of the output neurons [10].

The SCN provides three major output pathways. One

Which SCN targets regulate circadian cycles of specific functions?

Early lesion studies of the circadian system primarily used methods that damage both neuronal cell bodies and axons passing through or near the lesion site (e.g. electrolytic lesions, mechanical lesions or colchicine injections). Unfortunately, the complex interweaving of cell groups and fiber pathways present in the hypothalamus made the results of such studies difficult to interpret. The roles played by SCN targets in circadian control of specific functions have been reassessed recently by

Why have such a complicated, three-stage integrator?

This model for a hypothalamic circadian integrator allows the brain much more flexibility in sculpting circadian rhythms than would a simpler mechanism. For example, melatonin secretion, which is under the simplest type of monosynaptic regulation from the SCN to central effector neurons in the paraventricular nucleus, is hard-wired to the circadian clock in the SCN [31]. The SCN is more active during the light cycle, and its GABAergic neurons presumably inhibit the paraventricular premotor

Experimental manipulation of circadian patterns by restricted feeding

It is possible to manipulate the circadian rhythms of a wide range of behaviors and physiological functions by restricting the timing of food availability during the day [41]. When rats, which are typically nocturnal, are allowed access to food only during the middle of the light cycle, they quickly adapt to eating during the day (Figure 3b). Interestingly, they become active about an hour before the food is actually presented and reduce locomotor activity during the dark cycle, thus shifting

Summary

Within the past few years, the outline of the hypothalamic circadian integrator has finally begun to emerge. We now recognize that different functions can be controlled directly by the SCN clock (e.g. release of melatonin), or can be regulated by systems that are one synaptic relay (e.g. body temperature) or two synaptic relays (e.g. and feeding, locomotor activity, wake–sleep cycles and corticosteroid secretion) from the clock. The role of this complex integrator is now understood as allowing

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