Neural circuit mechanisms underlying pubertal timing

PROJECT SUMMARY The pubertal transition marks a significant physiological, hormonal, and social change in animals and occurs at a very stereotyped timepoint within each species. However, the neural circuit mechanisms underlying the timing of puberty onset remain unknown. More generally, we know little about how the brain orchestrates long- timescale postnatal developmental timing, which is crucial for normal behavioral and social development. Puberty is initiated by the pulsatile release of gonadotropin releasing hormone (GnRH) from hypothalamic GnRH neurons. However, the causal neural mechanisms and stimuli underlying the developmental activation of GnRH neurons are poorly understood. Three neuronal populations have been speculated to control GnRH neuron activation, including RFamide-related peptide (RFRP) neurons, which I hypothesize control the timing of puberty initiation. Administration of the RFRP peptide is sufficient to delay puberty, and the population of neurons expressing RFRP decreases in cell number over development. However, RFRP neurons are poorly characterized, and their role in pubertal timing has not been systematically tested. The overarching goal of this proposal is to functionally and architecturally characterize this neuronal population and its developmental plasticity to delineate their role in pubertal timing and, more broadly, how coordinated changes in the brain mediate development. I propose to use state-of-the-art molecular genetic tools to establish the role of RFRP neurons in pubertal timing and delineate their molecular and connectomic changes through development. Fulfillment of my aims will provide the most comprehensive characterization of RFRP neurons to date, focusing on their role in puberty and using them as a model to understand how neural plasticity underlies postnatal development. This will lay the groundwork for a better understanding of the regulation of pubertal timing, providing potential therapeutic targets for pathologies such as precocious puberty and a better understanding of the most drastic transformation in postnatal development. The goal of my research career is to perform cutting-edge research to answer fundamental biological questions as a faculty in academia. The proposed goals will be accomplished in the UCSD laboratories of Dr. Dhananjay Bambah-Mukku – an expert on social behavior and genetic tools for neural circuit research, Dr. Alexander Kauffman – an expert on the neurobiology of puberty, and Dr. Edward Callaway – a pioneer of viral tract tracing methods. Together, we have outlined a comprehensive plan for the acquisition of technical and professional skills that will enable me to accomplish my scientific and career goals at UCSD, which provides an extraordinary environment with all the resources needed for my training and career development.