Androgen receptors and sex differences in the biological clock

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Abstract Time of day is a strong determinant of our experience: waking, sleeping, meals, and working occur in predictable patterns. Endogenous clocks in the brain and peripheral tissues control the appropriate timing of physiology and behavior. But people are not all synchronized in the same way—some have an early chronotype (larks) and some have a late chronotype (owls). As with more severe disruptions of the clock, delayed chronotype is a predictor of sleep disorders, metabolic disease, and neurological disorders. Importantly, chronotype also differs between sexes, so differences in biological clock function may explain some of the sex biases in these pathologies. We have previously shown that (1) circadian clock function is strongly influenced by steroid hormones in males but not in females, (2) this is due to a change in the sensitivity of the clock to light, and (3) this is traceable to the effects of androgens on light-responsive neurons that express androgen receptors (AR) in the suprachiasmatic nucleus—the location of the brain’s circadian clock. Though lacking AR, the same neuronal population exists in females. The circadian clock is therefore an excellent system to determine the structural and functional pathways by which biological sex and androgen signaling control a circadian clock function (free-running period of the clock) and an output behavior (chronotype) that have relevance for health. We hypothesize that androgens reduce the clock’s photosensitivity to compensate for underlying organizational differences and thereby ensure similar behavior patterns between males and females. We will first investigate how androgens affect the excitability of identified AR-expressing neurons (Aim 1) and how this alters the spatiotemporal network of the brain’s clock (Aim 2). Next, we test how the presence of the receptor affects rhythmic behavior and light sensitivity (Aim 3). Finally, we will pharmacogenetically manipulate AR neurons for the first time in any neuronal system to determine the role that these neurons play in organizing clock function and controlling its response to light (Aim 4). These Aims are enabled by two important mouse models: one in which the AR can be knocked out conditionally, and one in which AR neurons express CRE recombinase. Using the latter, SCN neurons expressing AR can be identified and manipulated by pharmacogenetics.