Genetic and Hormonal Mechanisms of Sex Differences in the Nervous System

虽然它们对许多神经精神和神经系统疾病具有重要意义， 大脑中的差异及其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别在神经系统中的关键作用， 与荷尔蒙信号一起调节大脑和行为的性别分化。 然而，很少有人知道遗传性别如何调节神经发育和功能。 在这里，我们利用最近描述的性别差异的功能，一个单一的C。elegans 感觉神经元对，AWA，以更好地了解这些途径。因为有确凿的证据表明 将遗传性别与神经功能联系起来的保守机制，这些研究将提供一个 机制框架，这将使未来的候选人驱动的研究在哺乳动物系统。基于 根据大量的初步数据，我们假设细胞自主的“遗传性别”动态地 调节TGFβ信号，导致AWA感觉功能的性别差异。在目标1中，我们 使用两种方法鉴定指定AWA神经元性二态状态的转录因子， 互补功能基因组方法。在目标2中，我们将确定监管机制 通过遗传性别来调节AWA功能。最近的数据表明，TGFβ信号可能是 成为这个机制。在目标3中，我们将确定控制效应时间的机制 遗传性别的证据类固醇激素信号与此作用有关，表明 类固醇和性别遗传之间可能存在着深层的进化联系。所有这些 研究将提供一个完整的分子遗传学框架，将遗传性别与一个终端联系起来， 行为的效应器，目前不存在于任何系统中的东西。

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.