Hormone control of embryonic brain development

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Overview. The hypothalamus is a small but powerful region of the brain that is responsible for the production of hormones that govern physiological functions such as thirst, sleep, mood, sex drive, and hunger. Despite considerable knowledge about hormonal targets and surges, little is known about the ontogeny of the neurons that produce them. We recently uncovered that hypothalamic progenitors respond to endogenous hormones (e.g., β-estradiol, E2) and hormone-mimicking chemicals (e.g., bisphenol A, BPA), suggesting that hormones might play an unappreciated neurotrophic role during embryonic brain development.*** Using isolated murine hypothalamic neural stem cells (NSCs) in culture as our model system, here we will test our hypothesis that during embryonic brain development, hypothalamic NSCs respond to hormones to influence proliferation and/or differentiation or both across three Aims: *** Aim 1. To determine whether hormones influence hypothalamic NSC proliferation and/or self-renewal. We have shown that the weak estrogen agonist BPA can cause precocious hypothalamic neurogenesis in zebrafish. In this aim, we seek to understand how hormones might be altering hypothalamic progenitor behavior by asking if murine hypothalamic NSCs display changes in self-renewal capacity or cell cycle exit or both. *** Aim 2. To investigate whether hormone exposure affects differentiation. Our previous work in zebrafish showed that BPA can induce hypothalamic neurogenesis, but stopped short of studying their influence on gliogenic decisions. Here, we will use in vivo and in vitro approaches to test if hormones can affect the ability of hypothalamic progenitors to differentiate into neuronal, oligodendrocyte, and/or astrocyte lineages. *** Aim 3. To examine the role of mitochondrial biogenesis in hormone control of hypothalamic progenitors. We found that BPA can dose-dependently increase basal respiration in a mitochondrially-mediated manner in embryonic zebrafish, suggesting that hormone signaling can either directly or indirectly modulate mitochondrial output. Here, we will examine whether mitochondrial biogenesis is a downstream target of hormone signalling in hypothalamic progenitors, and also ask if mitochondrial biogenesis is required for NSC differentiation. *** Impact. This work will provide important insights into the relatively unappreciated role of hormones, which unexpectedly appear to act via mitochondrial biogenesis, in controlling progenitor proliferation and differentiation in the embryonic hypothalamus. Knowledge created from this grant will serve to uncover processes that may be sensitive to EDCs in our environment, which can then be exploited to further understand mechanisms by which contaminants might be affecting developing brains.**