Hormone control of embryonic brain development

概述。下丘脑是大脑中一个小而强大的区域，负责产生荷尔蒙，这些荷尔蒙控制着诸如口渴、睡眠、情绪、性欲和饥饿等生理功能。尽管对荷尔蒙靶标和激素激增有相当多的了解，但对产生荷尔蒙靶标和荷尔蒙激增的神经元的个体发育知之甚少。我们最近发现，下丘脑祖细胞对内源性激素(如雌二醇、雌二醇)和类似激素的化学物质(如双酚A、双酚A)做出反应，这表明激素可能在胚胎大脑发育过程中发挥了未被认识的神经营养作用。 使用培养中的小鼠下丘脑神经干细胞(NSCs)作为我们的模型系统，这里我们将检验我们的假设，即在胚胎大脑发育期间，下丘脑NSCs对激素做出反应，影响增殖和/或分化，或同时影响三个目标： 目的1.确定激素是否影响下丘脑NSC的增殖和/或自我更新。我们已经证明，弱雌激素激动剂BPA可以导致斑马鱼下丘脑性早熟。在这一目标中，我们试图通过询问小鼠下丘脑NSCs是否在自我更新能力或细胞周期退出方面显示变化，或两者兼而有之，试图了解激素可能如何改变下丘脑前体细胞的行为。 目的2.研究激素暴露是否影响分化。我们之前在斑马鱼上的工作表明，双酚A可以诱导下丘脑神经发生，但没有研究它们对神经胶质形成决定的影响。在这里，我们将使用体内和体外的方法来测试激素是否可以影响下丘脑前体细胞分化为神经元、少突胶质细胞和/或星形胶质细胞的能力。 目的3.探讨线粒体生物发生在下丘脑前体细胞激素调控中的作用。我们发现BPA能以线粒体介导的方式剂量依赖性地增加斑马鱼胚胎的基础呼吸，这表明激素信号可以直接或间接地调节线粒体的输出。在这里，我们将研究线粒体生物发生是否是下丘脑前体细胞激素信号的下游靶点，并询问线粒体生物发生是否是神经干细胞分化所必需的。 冲击力。这项工作将为激素在控制胚胎下丘脑的祖细胞增殖和分化中相对未被认识的作用提供重要的见解，激素出人意料地似乎通过线粒体生物发生发挥作用。通过这笔赠款创造的知识将有助于揭示我们环境中可能对内分泌细胞敏感的过程，然后可以利用这些过程来进一步了解污染物可能影响发育中的大脑的机制。

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., ß-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.