Investigating relationships between sexual behavior rhythms, core body temperature, and sleep in female mice: implications for (in)fertility - PROJECT SUMMARY/ABSTRACT Physiological and biochemical processes in nearly every species are regulated by the circadian (24 hr) clock. For example, in mammals, the female reproductive system requires tight temporal organization by the body’s master pacemaker—the suprachiasmatic nucleus (SCN)—which ensures that ovulation occurs at a time when reproductive success can be maximized. Evidence supporting the importance of proper clock function on female fertility comes from several lines of work demonstrating that misalignment of biological rhythms, as occurs with shift work or jet lag, negatively impacts reproduction. Despite these clear observations, lack of knowledge regarding how the (circadian) timing of sex might impact fertility and whether the circadian clock modulates other factors that may also lead to successful conception and maintenance of pregnancy, are major barriers. Helping to overcome these barriers, my data in female mice indicate that core body temperature (Tb)—which is increased during the active phase of the estrus (sexually receptive) period—is an overlooked circadian-controlled factor that regulates female fertility. Indeed, I have shown that mild reductions in Tb immediately after copulation reduce pregnancy success, suggesting a critical causal role for Tb in early conception. Building on these findings, I propose to: 1) identify brain circuit(s) that regulate female sexual behavior rhythms (K99), 2) determine whether mild cooling in vivo immediately after copulation affects embryo development ex vivo (K99), 3) define critical (temporal) windows as to when manipulations in Tb affect female fertility and early embryos (R00), and 4) test whether periconceptional warming rescues fertility deficits in female mice exposed to chronic shift work (R00). Importantly, the 2021 NIH Sleep Research Plan highlights research on sleep and circadian mechanisms underlying health/disease as a priority, and the NICHD has put particular emphasis on studies that examine female fertility, circadian cues regulating fertility, and biomarkers of reproductive transitions. This proposal, which logically builds upon my past/current training in cellular and circuit-level neuroscience, sleep, circadian timing, and thermoregulation, helps address these research needs and fundamental ideas. With guidance provided by my mentor, Dr. Clifford Saper, and by my advisory members and collaborators, Drs. Charles Czeisler, Victor Navarro, Emily Seidler, Natalia Machado, Mark Andermann, and Joel Lawitts, I will receive training in professional development, mouse preimplantation embryonic culture, optogenetic manipulations, and in vivo calcium imaging, helping me to achieve full scientific independence. The multi-disciplinary approaches fill critical knowledge gaps in our understanding of circadian regulation of female sexual and reproductive behaviors and the thermoregulatory mechanisms underlying fertility. Results obtained during the R00 phase will provide strong preliminary data for future R01 applications and could inform the development of novel therapeutics for female (in)fertility management. Overall, this application will establish the foundation for my independent research program and allow me to achieve my long-term research goals.
