Functional neuroanatomy of sleep and circadian rhythms

Abstract

The daily sleep–wake cycle is perhaps the most dramatic overt manifestation of the circadian timing system, and this is especially true for the monophasic sleep–wake cycle of humans. Considerable recent progress has been made in elucidating the neurobiological mechanisms underlying sleep and arousal, and more generally, of circadian rhythmicity in behavioral and physiological systems. This paper broadly reviews these mechanisms from a functional neuroanatomical and neurochemical perspective, highlighting both historical and recent advances. In particular, I focus on the neural pathways underlying reciprocal interactions between the sleep-regulatory and circadian timing systems, and the functional implications of these interactions. While these two regulatory systems have often been considered in isolation, sleep–wake and circadian regulation are closely intertwined processes controlled by extensively integrated neurobiological mechanisms.

Introduction

Considerable progress has been made in elucidation of the functional neurocircuitries regulating mammalian sleep and circadian rhythms. Early research on the neural control of sleep suggested that both forebrain and brainstem regions contribute to the control of sleep and wake states, and more recent analyses have identified a number of specific anatomically and chemically-defined structures within these regions that appear to be involved in triggering and/or maintaining episodes of sleep and wakefulness. These findings indicate that sleep–wake cycles and related phenomena are controlled by a highly complex, widely distributed neural system, with several functionally distinct components. In contrast, identification of a preeminent role for the suprachiasmatic nucleus (SCN) in circadian rhythm generation in the early 1970's led to a period of extreme research focus in which circadian timekeeping was viewed as a highly localized anterior hypothalamic function. More recently, however, it has become clear that circadian timekeeping is in fact a broadly distributed cellular process occurring in a semi-autonomous manner in many structures of the central nervous system, as well as in peripheral, non-neural tissues. Indeed, the circadian timing system is, if anything, more broadly distributed than the sleep-regulatory system: while sleep is still viewed fundamentally as a state of the brain, a multitude of local circadian clocks coordinate tissue-specific timing processes and thus contribute to the overall temporal coordination of the organism.

Neurobiological research on the sleep-regulatory and circadian timing systems has developed largely independently. Circadian biologists have often viewed sleep as simply one of many physiological processes – along with body temperature, hormone secretion, metabolism, and behavioral activation – that are temporally modulated by signals emerging from the circadian timing system. In turn, sleep researchers focused much of their early neurobiological work on the cat, in large part because these animals exhibit only weak circadian modulation of behavior, and are prone to sleep at all phases of the day–night cycle. More recently, however, sleep and circadian neurobiology have become progressively more integrated as a consequence of several conceptual and empirical advances. Thus, the emergence of the “two-process model” of human sleep regulation in the mid-1980's (Borbely, 1982, Daan et al., 1984) resulted in widespread appreciation of the importance of interactions between homeostatic and circadian mechanisms in sleep regulation, including in non-human animals. In addition, the realization that sleep and arousal states provide important modulatory inputs to the circadian clock (Antle and Mistlberger, 2000, Mrosovsky et al., 1989, Reebs and Mrosovsky, 1989) also served to promote integration of sleep and circadian research. More recently, claims that episodes of behavioral quiescence (“rest”) in invertebrates (e.g., flies (Hendricks et al., 2000, Shaw et al., 2000), worms (Raizen et al., 2008)) and non-mammalian vertebrates (e.g., zebrafish (Prober et al., 2006, Yokogawa et al., 2007, Zhdanova, 2006)) represent functional analogues and perhaps even evolutionary homologues to mammalian sleep have helped further blur the traditional distinction between “sleep–wake” and “rest–activity” cycles. Together, these advances highlight the importance of identifying not only the neural mechanisms regulating sleep and circadian rhythms, but also the critical pathways underlying reciprocal functional interactions between sleep and circadian regulation.