Tuesday, May 7, 2024
5/7/2024
PROJECT SUMMARY The long-term goal of the proposed research is to determine the neural pathways by which physiological signals regulate gonadotropin secretion, which ultimately determines reproductive function. Modulation of luteinizing hormone (LH) secretion determines fertility and controls gonadal steroid concentrations, which has profound effects on cardiovascular, musculoskeletal, and mental health. Pulses of luteinizing hormone secretion are organized by neurons in the arcuate nucleus of the hypothalamus that contain kisspeptin, neurokinin B and dynorphin (KNDy neurons) in males and females. In females, the preovulatory LH surge is induced by estradiol and is dependent upon kisspeptin cells in the anteroventral periventricular region (AVPVKiss1). However, the higher order neural circuitry that governs these populations of kisspeptin cells remains a significant outstanding question. The nucleus of the solitary tract (NTS) is located in the brainstem and consists of a heterogenous population of neurons that receive rich interoceptive and central inputs and projects widely thought the brain. Interestingly, these neurons are implicated in both the inhibition of pulsatile LH secretion during stress, and the facilitation of enhanced LH secretion during the preovulatory LH surge. To address this apparent paradox, this K99/R00 proposal will test the central hypothesis that distinct subpopulations of neurons in the NTS suppress pulsatile LH secretion via inhibition of KNDy neurons and enhance LH secretion via activation of AVPVKiss1 cells. During the mentored phase, we will employ viral-mediated cell activation labeling techniques and light sheet microscopy of optically cleared tissue to determine if the same neurons are activated during stress and the LH surge, as well as single-cell RNA sequencing to identify the subpopulations of NTS neurons that are activated during stress and the LH surge (Aim 1). The mentored phase will consist of critical training in advanced neuroanatomical and neuroimaging techniques, next generation sequencing technologies, bioinformatic analysis, as well as career development experiences that are necessary for transitioning to an independent academic research position. In the independent phase, I propose to use chemogenetic and cell- specific viral-mediated neural ablation techniques to determine whether subpopulations of neurons identified in Aim 1 are sufficient and necessary for stress-induced suppression of LH secretion and KNDy cell activation (Aim 2) or for the preovulatory LH surge and AVPVKiss1 cell activation (Aim 3) and determine the locations in the brain these subpopulations project (Aims 2 & 3). These studies will launch my independent research program and will provide a neural framework that may influence the development of therapies to treat disorders of altered LH secretion, including amenorrhea, infertility, and polycystic ovary syndrome. Collectively, the commitment of the sponsoring/co-sponsoring team to my scientific and professional development, coupled with the stimulating academic environment and impressive resources at UC San Diego available to me will ensure achievement of the aims of this Career Development proposal and the training mission of UC San Diego and the NIH.
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