Sydney Aten, PhD
Beth Israel Deaconess Medical Center
Oscar Ramirez, Emma Fishbein, Natalia Machado, Nicole Lynch, Yaniv Sela, Clifford Saper
Physiological and biochemical processes in nearly every species (including humans) are regulated by the circadian clock. For example, the female reproductive system requires tight temporal organization of estradiol-sensitive neural circuits that ultimately converge to drive hypothalamo-pituitry gonadal (HPG) axis functioning. 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, in mice, it is still unknown whether a circadian rhythm exists in the propensity for sexual behavior and to what degree such a 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 observations suggest that this SCN—SPZ—VMH circuit may also mediate time-of-day dependent sexual behaviors. Here, I show that male mouse sexual drive behaviors are circadian—with peak sexual drive occurring around CT13-CT16 and nadir at CT7. I also show that a circadian rhythm in sexual drive propensity exists in female mice. Currently, I am determining whether temporal overlap of male and female peak sexual behavior influences reproductive success. I am also examining the hypothalamic circuitry that underlies the rhythm in sexual behavior in mice, testing whether the novel pathway that regulates rhythms in aggression also regulates rhythms in sexual arousal. Finally, using viral-based approaches, I am assessing whether this hypothalamic circuit can be acutely manipulated to change arousal levels across the day. Taken together, results from this project will lay groundwork for our understanding of how hypothalamic circuits that modulate reproductive behavior can be harnessed to treat infertility.