Sleep Medicine Reviews, Vol. 5, No. 5, pp 399–410, 2001 doi:10.1053/smrv.2001.0160, available online at http://www.idealibrary.com on SLEEP MEDICINE reviews PHYSIOLOGICAL REVIEW The search for the molecular correlates of sleep and wakefulness Chiara Cirelli and Giulio Tononi Department of Psychiatry, University of Wisconsin at Madison, Madison, Wisconsin 53719, USA KEYWORDS cerebral cortex, DNA microarray, immediate early genes, mitochondria, mRNA differential display, rat, sleep deprivation Summary Knowledge of the molecular correlates of sleep and wakefulness is essential if we are to understand the restorative processes occurring during sleep and the cellular mechanisms underlying sleep regulation. In order to determine what molecular changes occur during the sleep–waking cycle, we have recently performed a systematic screening of gene expression in the brain of sleeping, sleep deprived and spontaneously awake rats. Out of the >10 000 genes screened so far, a small minority (>0.5%) was differentially expressed in the cerebral cortex across behavioral states. Most genes were upregulated in wakefulness and sleep deprivation relative to sleep, while only a few had higher expression in sleep relative to wakefulness and sleep deprivation. Almost all the genes upregulated in sleep, and several genes upregulated in wakefulness and sleep deprivation, did not match any known sequence. Known genes that were upregulated in wakefulness and sleep deprivation could be grouped into functional categories: immediate early genes/transcription factors, genes related to energy metabolism, growth factors/adhesion molecules, chaperones/heat shock proteins, vesicle- and synapse-related genes, neurotransmitter/hormone re- ceptors, neurotransmitter transporters, enzymes, and others. Although the charac- terization of the molecular correlates of sleep, wakefulness and sleep deprivation is still in progress, it is already apparent that the transition from sleep to waking can affect basic cellular functions such as RNA and protein synthesis, neural plasticity, neurotransmission, and metabolism.  2001 Harcourt Publishers Ltd primarily not the whole cerebrum, nor even the INTRODUCTION entire neocortex, but only those neurons or syn- apses, and possibly glia cells, which during wake- Sleep and wakefulness differ considerably in terms fulness are responsible for the brain functions of behavior, neural activity, and brain metabolism. An concerned with conscious behavior” [1]. He sug- intriguing question is whether sleep and wakefulness gested that cells or synapses supporting conscious may also differ at the molecular level. This is not activity during wakefulness undergo plastic changes, necessarily a novel idea. More than thirty years ago, and it is because of such cellular or synaptic changes Giuseppe Moruzzi argued that “. . . sleep concerns that we need to sleep. Moruzzi, however, did not speculate about the nature of such molecular changes. Correspondence should be addressed to: Chiara Cirelli, The typical duration of the sleep–waking cycle Department of Psychiatry, University of Wisconsin at Madison, and the time constants of its regulation are in the 6001 Research Park Blvd, Madison, WI 53719, USA. Fax: (608) 263 9340; E-mail: ccirelli@med.wisc.edu order of minutes to hours, thus raising the possibility 1087–0792/01/050399+12 $35.00/0  2001 Harcourt Publishers Ltd