Regulation and function of RFRP-3 neurons in the inhibition of mammalian reproduction

University Of California-San Diego, La Jolla CA

Investigators

Abstract

Stress can drastically inhibit fertility and reproductive status, but how this happens in the body and brain is poorly understood. Indeed, although the negative effects of stress on reproduction are well appreciated, the specific signaling factors and neural mechanisms that converge in the brain to inhibit reproduction under stressful conditions remain poorly defined. This proposal will use novel mouse models and neural gene profiling to test how psychosocial stress alters inhibitory neural circuits in the brain in relation to controlling fertility. This proposal will substantially expand our knowledge of how stressors "communicate" with specific parts of the brain that control reproduction. This information will significantly advance the field of reproductive neuroendocrinology. Moreover, given the common theme of stress inhibition on reproduction in many animals, this research will ultimately have broad impact for better understanding brain and hormone functioning of multiple vertebrate species. The research component is complemented and integrated with a comprehensive broader impact plan which includes training and mentoring undergraduate students and post-doctoral scholars, including women and under-represented minorities. The proposal also includes a program aimed at engaging under-represented minority high school students in science research, as well as a new brain research outreach program and internship collaboration with a local high school with students from diverse ethnic and socioeconomic backgrounds. Stress can inhibit fertility and reproductive status, but exactly how this occurs mechanistically is poorly understood. Reproduction is simulated by gonadotropin-releasing hormone (GnRH) secretion from the brain. The highly-conserved neuropeptide RFamide-related peptide-3 (RFRP-3), encoded by the Rfrp gene, negatively regulates the reproductive axis by inhibiting GnRH secretion. However, very little is known about the phenotype, regulation, or functional necessity of RFRP-3 neurons. As an inhibitor of GnRH, RFRP-3 is poised to relay inhibitory stress signals to the reproductive axis, but this requires testing. This proposal will utilize new transgenic RFRP-3 mouse models (the first of their kind), coupled with cutting-edge molecular tools, to functionally test the involvement and necessity of RFRP-3 neurons in mediating the negative effects of stress on reproductive status, as well as identify novel brain genes that are activated under stressful and non-stressful conditions. This study will therefore provide fresh insight into the physiological regulation and functional roles of RFRP-3 neurons and other brain circuitry in the modulation of reproductive status during stress, and will empirically probe RFRP-3 regulation and function in new ways that have not been possible with former histological and pharmacological methods.