A role for androgens in regulating circadian behavior and the suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock controlling behavioral and physiological rhythms, including rhythmic secretion of gonadal hormones. Gonadectomy results in marked alteration of circadian behaviors, including lengthened free-running period, decreased precision of daily onset of running, and elimination of early-evening but not late-night activity bouts. Androgen replacement restores these responses. These aspects of rhythmicity are thought to be regulated by the brain clock, although the site of androgen action remains unknown. Anatomically, the rodent SCN is composed of a ventrolateral core and a dorsomedial shell, and the present studies show that androgen receptors (AR) are localized to the ventrolateral core SCN. Using a transgenic mouse bearing dual reporter molecules driven by the AR targeted to both membrane and nucleus, we find that projections of AR-containing cells form a dense plexus in the core, with their fibers appearing to exit the SCN dorsally. In a second transgenic strain, in which the retinorecipient gastrin-releasing peptide cells express a green fluorescent protein reporter, we show that gastrin-releasing peptide cells contain AR. Through immunocytochemistry, we also show that SCN AR cells express FOS after a light pulse. Importantly, gonadectomy reduces the FOS response after a phase-shifting light pulse, whereas androgen replacement restores levels to those in intact animals. Taken together, the results support previous findings of a hypothalamic neuroendocrine feedback loop. As such, the SCN regulates circadian rhythms in gonadal hormone secretion, and in turn, androgens act on their receptors within the SCN to alter circadian function.