Genetic and Hormonal Mechanisms of Sex Differences in the Nervous System

尽管它们对许多神经精神疾病和神经疾病具有重要意义，但性行为 大脑的差异以及这些差异背后的机制仍然知之甚少。 重要的是，最近的研究强调了遗传性在神经系统中的关键作用，这是 与荷尔蒙信号共同作用，调节大脑和行为的性分化。 然而，人们对遗传性如何调节神经发育和功能知之甚少。 在这里，我们利用最近描述的单个线虫在功能上的性别差异 感觉神经元对，AWA，以更好地理解这些通路。因为有强有力的证据 将遗传性别与神经功能联系起来的保守机制，这些研究将提供一种 这一机制框架将使未来在哺乳动物系统中进行以候选人为导向的研究成为可能。基座 在大量的初步数据基础上，我们假设细胞自主的“遗传性别”是动态的 调节转化生长因子β信号导致听觉诱发电位的性别差异。在目标1中，我们将 使用两种方法识别指定性二型性状态的转录因子 互补功能基因组学方法。在目标2中，我们将确定监管机制 以遗传性别为靶点来调节AWA功能。最近的数据表明转化生长因子β信号很可能 就是这个机制。在目标3中，我们将确定控制效果时间的机制 AWA上的遗传性交。类固醇激素信号与这一作用有关，表明 类固醇和遗传性之间可能存在着深刻的进化联系。加在一起，这些 研究将提供一个完整的分子-遗传学框架，将遗传性别与终端联系起来 行为的效应者，目前还没有系统中存在的东西。

Though they have important significance for many neuropsychiatric and neurological disorders, sex differences in the brain and the mechanisms that underlie these remain poorly understood. Importantly, recent studies have highlighted the key role of genetic sex in the nervous system, which acts together with hormonal cues to regulate sexual differentiation of the brain and of behavior. However, very little is known about how genetic sex might modulate neural development and function. Here, we take advantage of a recently described sex difference in the function of a single C. elegans sensory neuron pair, AWA, to better understand these pathways. Because there is strong evidence that conserved mechanisms that link genetic sex to neural function, these studies will provide a mechanistic framework that will enable future candidate-driven studies in mammalian systems. Based on extensive preliminary data, we hypothesize that cell-autonomous “genetic sex” dynamically modulates TGFβ signaling to bring about the sex difference in AWA sensory function. In Aim 1, we will identify transcription factors that specify the sexually dimorphic state of the AWA neurons using two complementary functional genomic approaches. In Aim 2, we will identify the regulatory mechanism targeted by genetic sex to modulate AWA function. Recent data indicate that TGFβ signaling is likely to be this mechanism. In Aim 3, we will identify the mechanism that controls the timing of the effects of genetic sex on AWA. Steroid hormone signaling has been implicated in this role, indicating that there may be deep evolutionary connections between steroids and genetic sex. Together, these studies will provide an integrated molecular-genetic framework that links genetic sex to a terminal effector of behavior, something that currently exists in no system.