ABSTRACT

The field of sleep research has gained profound insights from molecular genetic and classical genetic studies over the past decade (reviewed in Refs. [22, 67, 86]). Sleep loss triggers a large scale change in transcriptional regulatory networks [19, 50], including the circadian clock genes [28, 88]. However, a link between these transcriptional changes and the restorative function of sleep remains elusive. Published studies document that sleep/wake cycles are sensitive to, and paralleled by, changes in cellular metabolic status in the brain (reviewed in Refs. [10, 19, 71]). Others demonstrate that cellular metabolic sensors regulate circadian clock gene function (reviewed in Refs. [5, 9, 39]). Still others demonstrate that circadian clock genes regulate sleep/wake cycles and molecular responses

to sleep loss in a manner that extends beyond their role in the generation of 24-hour rhythms (reviewed in Ref. [27] and Landgraf et al., this issue). This article seeks to unite these three themes in a unitary conceptual framework. The three themes converge to provide a framework whereby the interrelations of cellular metabolism, transcriptional regulatory events and sleep/ wake-related changes in neuronal activity are united as a functional entity within the brain (Fig. 1). By this proposed mechanism, the detection of cellular metabolic status by the transcriptional network centered around circadian clock genes regulates sleep states to maintain metabolic homeostasis in the brain. Future efforts might exploit the interrelationship of circadian clock genes, sleep and cellular energetics for therapeutic benefit.