Role of the Male-Specific Factor Sry in Brain Function

描述（由申请人提供）：男性和女性的大脑是不同的。这些研究的首要目标是了解大脑性别差异的分子机制，重点关注黑质（SN）作为模型。众所周知，睾丸在出生前或出生后分泌的睾丸激素作用于男性大脑，使特定的神经网络男性化，从而导致特定的男性化行为。传统观点认为，性腺雄激素是大脑男性化的唯一因素。在哺乳动物性腺开始产生雄激素之前，大脑中差异基因表达的发现使我们提出了另一种假设。我们建议探索脑功能和行为的性别差异可能部分由遗传因素引起，而不是由性腺产生的。我们已经证实，在成人大脑的两个区域：黑质（SN）和乳状体中，y相关的睾丸决定因子Sry的特异性表达。SN中Sry表达的减少导致酪氨酸羟化酶的强烈减少以及感觉运动障碍。为了了解Sry在SN功能性别差异中的作用，我们将研究Sry在成人大脑中的表达谱，确定Sry表达的细胞类型，测量Sry的表达水平，并测试其是否与TH表达相关（Specific Aim 1）。我们将探讨SN中下调和上调Sry对th阳性神经元及其控制的感觉运动行为的影响，以及男性的Sry作用是否补偿了女性特异性因子的缺乏（或较低水平）。具体来说，我们将测试这个女性因素是否可能是雌二醇，或者X染色体的剂量（特异性目标2）。最后，我们将以NT2N细胞作为多巴胺能神经元模型，阐明Sry对多巴胺能神经元的分子作用机制（Specific Aim 3）。这一建议旨在提高我们对脑功能性别差异的普遍理解。对男性和女性大脑差异的分子机制的描述影响了我们对精神疾病和神经疾病（如帕金森病、注意力缺陷障碍或抑郁症）中性别差异的理解。

DESCRIPTION (provided by applicant): Male and female brains are different. The overarching goal of the proposed studies is to understand the molecular mechanisms of sex differences in the brain, focusing on the substantia nigra (SN) as a model. It is well established that testosterone, secreted by the testes, before or after birth, acts on the male brain to masculinize specific neural networks, which results in specific masculine behaviors. The classical view is that gonadal androgens are the only factors involved in the masculinization of the brain. Discovery of differential gene expression in the mammalian brain before the gonads start producing androgens led us to propose an alternative hypothesis. We propose to explore that sex differences in brain function and behavior may be caused in part by genetic factors not produced by the gonads. We have demonstrated specific expression of the Y-linked, testis-determining factor Sry, in two regions of the adult brain: the substantia nigra (SN) and the mammillary bodies. Reduction of Sry expression in the SN resulted in a strong decrease of tyrosine hydroxylase as well as in sensorimotor impairment. In order to understand the role of Sry in sex differences in SN function, we will investigate the expression profile of Sry in the adult brain, identify the cell types in which Sry is expressed, measure the level of expression of Sry and test whether it correlates with TH expression (Specific Aim 1). We will explore the consequences of down-regulating and upregulating Sry in the SN on TH-positive neurons and the sensorimotor behaviors they control, and whether Sry action in males compensates for the lack (or lower levels) of a female-specific factor. Specifically, we will test if this female factor could be estradiol, or dosage of the X chromosome (Specific Aim 2). Finally, we will elucidate the molecular mechanisms of action of Sry on dopaminergic neurons using NT2N cells as a model of dopaminergic neurons (Specific Aim 3). This proposal intends to improve our general understanding of sex differences in brain function. The characterization of the molecular mechanisms by which male and female brains differ impacts our understanding of sex differences in psychiatric and neurological disorders such as Parkinson's disease, attention deficit disorder, or depression.