A non-circadian role for clock-genes in sleep homeostasis:a strain comparison

In all three strains per expression was increased when animals were kept awake but the rate of increase during the SD as well as the relative increase in per after 6 h SD were highest in the strain for which the sleep rebound was smallest; i.e., DBA/2J (D2). Moreover, whereas in the other two strains per1 and per2 reverted to control levels with recovery sleep, per2 expression specifically, remained elevated in D2 mice. dbp expression increased during the light period both during baseline and during SD although levels were reduced during the latter condition compared to baseline. In contrast to per2, dbp expression reverted to control levels with recovery sleep in D2 only, whereas in the two other strains expression remained decreased.These findings support and extend our previous findings that clock genes in the forebrain are implicated in the homeostatic regulation of sleep and suggest that sustained, high levels of per2 expression may negatively impact recovery sleep.At the cellular level, circadian rhythms are thought to be generated by transcriptional-translational feedback loops made up of positively and negatively acting transcriptional regulators [1]. In mammals, the core positive elements are CLOCK and NPAS2 and their obligate dimerization partner BMAL1. These transcription factors drive per and cry transcription. PER and CRY proteins, in turn, interact with CLOCK/NPAS2:BMAL1 heterodimers to inhibit their own transcription, thus constituting the negative feedback elements. The circuitry is clearly more complex as additional feedback loops and post-translational modifications are involved [1]. Clock genes underlie circadian rhythm generation in many tissues, but the circadian rhythm in the suprachiasmatic nucleus (SCN) is required for the manifestation of overt physiological and behavioral rhythms, and is therefore considered the master circadian pacemaker [1,2].Although the role of clock genes in generating circadian rhythms is firmly established, we and ot