HT2CRMediated Effects on Sleep and Entrainable Rhythms

As the above discussion suggests, 5-HT2CRs participate in the dynamic regulation of energy balance. To this effect, these receptors exert direct control over the hypothalamic generation of feeding behavior and indirectly influence important metabolic regulators of energy expenditure, including responsiveness to insulin and leptin signaling, tissue energy reserves, and baseline sympathetic tone. Recent studies also demonstrate that deficits in 5-HT2CR function alter both light and food entrainable circadian rhythms and change the quality of many sleep parameters.

Light signaling from the retina initially converges onto the suprachiasmatic nucleus (SCN) core, a specialized neuronal structure characterized by strong light-evoked patterns of gene expression (for review, see (Aton and Herzog 2005; Reppert and Weaver 2002). The SCN core is densely innervated by both NPY-ergic and serotonergic fibers (Abrahamson and Moore 2001) and strongly expresses 5-HT2CRs (in a manner largely complementary to arginine vasopressin [AVP] expression) (Hsu and Tecott LH in preparation). By contrast, neurons of the SCN shell do not receive significant input from the retina, demonstrate significant periodic changes in circadian gene expression, and do not express 5-HT2CRs. Simply put, the SCN shell is the endogenous circadian oscillator whose intrinsic periodicity is modulated by light input initially processed in the SCN core. Consistent with this interpretation, mice constitutively lacking 5-HT2CR expression show no phenotypic changes in circadian day length. Furthermore, constitutive 5-HT2CR /Y mice do not retard their clock phase in response to a brief light pulse at the beginning of the dark cycle (Hsu and Tecott LH in preparation). Thus, 5-HT2CR function is required for normal entraining of circadian clocks to changing day lengths.

Light is not the only environmental condition capable of entraining circadian clocks. Recent studies have also demonstrated the presence of an independent, food-entrainable oscillator that can modulate organism activity in cycle with the availability of food resources (Abe et al. 1989; Storch and Weitz 2009). While the molecular networks required for light-entrainable circadian rhythms have been well studied in the past, much of the structure of the food-entrainable network remains unknown (Davidson 2006). In this context, it is interesting to note that mice constitutively lacking 5-HT2CR function demonstrate pronounced deficits in their ability to entrain their activity levels to new feeding schedules (Hsu 2009). Specifically, it was observed that while intact C57BL/6 mice increase their home cage locomotor activity in the 30 min preceding food availability, constitutive 5-HT2CR -/Y mice lack food anticipatory increases in locomotion.

At a global level of behavioral organization, the changes in regulation of ingestive behavior, metabolism, and circadian entrainment give rise to observable phenotypic differences in sleep architecture (Frank et al. 2002). Over the entire day, constitutive 5-HT2CR /Y mice show less non-REM sleep (particularly during the active phase) and increased waking bouts (again, most prominent during the active phase) compared with wild-type littermates. Constitutive 5-HT2CR mutant mice also showed a greater homeostatic drive to sleep after 6 h of sleep deprivation. By EEG studies, no phenotypic differences in spectral power density were observed during REM sleep, non-REM sleep, or wakefulness.

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