Physiological and biochemical processes in nearly every species (including humans) are regulated by the circadian clock. For example, the reproductive system (of females) requires tight temporal organization of estrogen-sensitive neural circuits that allows the hypothalamo-pituitry gonadal (HPG) axis to function properly. In mammals, the body’s master pacemaker—the suprachiasmatic nucleus (SCN)—allows for coordination of such neuroendocrine events to ensure that ovulation occurs at the time in which reproductive success can be maximized. Evidence supporting the importance of proper clock function on fertility comes from several lines of work demonstrating that misalignment of biological rhythms or disrupted function of the body’s master clock (resulting from shift work, jet, lag, etc.) negatively impact reproduction—interfering with both male and female fertility. Along these lines, knock-down of clock genes leads to impairments in fertility, and disruption of circadian clock timing resulting from a reduction of sleep duration and/or architecture negatively impacts male sex hormones and semen quality and leads to ovulatory deficiencies in females. Despite these well- established observations that proper clock functioning is important to reproductive success, it is still unknown whether a circadian rhythm exists in the propensity for sexual behavior and to what degree such a behavioral rhythm may influence reproductive outcomes. Additionally, the neural circuits that mediate these behaviors as a function of time-of-day have yet to be studied. Of note, it was recently shown that the propensity for behavioral aggression follows a daily rhythm that is regulated by a circuit spanning the master clock (SCN), its postsynaptic target the subparaventricular zone (SPZ), and the ventromedial hypothalamus (VMH). Interestingly, the VMH has been shown to modulate both aggression and mating behaviors. Such results suggest that this SCN—SPZ—VMH circuit may also mediate time-of-day dependent sexual behaviors. Hence, this pathway may serve as a promising therapeutic target for the treatment of circadian dysfunction in people experiencing idiopathic infertility. In this proposal, I will study how circadian clock time affects reproductive behavior. I will first determine whether temporal overlap of male and female peak sexual behavior influences reproductive success (Aim 1). I will also examine the hypothalamic circuitry that underlies the rhythm in sexual behavior in mice (Aim 2), testing whether the first node of the pathway that regulates rhythms in aggression (i.e. SCN—SPZ) also regulates rhythms in sexual behavior. Finally, using a chemogenetic approach, I will test whether this hypothalamic circuit can be acutely manipulated to change sexual behavior levels across the day (Aim 3). This work will test the hypothesis that the circadian rhythm in sexual behavior impacts conception and that this drive is regulated by a similar circuit to that modulating aggression rhythms. Results from this project will lay groundwork for our understanding of how hypothalamic circuits that modulate reproductive behavior can be harnessed to treat infertility.

Globally, it is estimated that infertility affects approximately 10-15% of all couples trying to become pregnant, and while the exact cause of infertility is not always known, dysfunction in circadian timekeeping capacity likely plays a role in the inability to conceive. This research will examine whether time-of-day changes in sexual behavior influence reproductive success in mice and whether sexual behavior can be manipulated throughout the day to optimize fertility. Overall, this project may lead to a better understanding of the daily changes in sexual drive propensity and may help in the design of therapeutics for individuals with misaligned daily rhythms (shift workers, etc.) who are trying to conceive.