Figure 7.

Summary of the molecular mechanisms by which sleep deprivation could alter clock gene expression in the forebrain. A negative feedback loop underlies circadian rhythm generation with, as the positive arm, NPAS2 (or CLOCK)::BMAL1 heterodimers activating the transcription of Per and Cry (only Per2 shown) through their E-box enhancers. PER and CRY proteins then increase (green arrow) and, upon nuclear entry, associate with the NPAS2::BMAL1 complex to inhibit their own transcriptional activation thus providing negative feedback (red arrow). PER and CRY proteins then decrease resulting in a removal of this inhibition allowing the cycle to restart. As a result NPAS2::BMAL1 target genes, such as Per2, cycle with a near 24-h period in many tissues. Expression of other genes, including Dbp and E4bp4, are similarly regulated. Besides this circadian regulation, Per2 expression is regulated by other factors through which sleep deprivation might act: e.g., the cAMP response element (CRE), glucocorticoid response element (GRE), and D-box enhancers through which phosphorylated CRE binding protein (pCREB), ligand-bound glucocorticoid receptors (GR), and DBP can induce Per2 expression, respectively, while E4BP4, also acting on the D-box, can repress Per2 expression. Sleep deprivation, besides extending waking, also activates the HPA axis and metabolism, evidenced by its induction of corticosterone (CORT), increased CREB phosphorylation and Npas2 and E4bp4 expression (green dashed arrows), and decreased Dbp expression (red dashed arrow). In addition, sleep-deprivation-induced changes in metabolic state as evidenced by changes in NAD⁺, can directly affect NPAS2 mediated transcriptional activation and the SIRT1-mediated deacetylation (Ac) of PER2. These “non-circadian” changes in Per2 could impinge on the ongoing circadian oscillation as conceptualized in the model presented in Figure 3. See text for references.