Role of the Male-Specific Factor Sry in Brain Function

描述（由申请人提供）：男性和女性的大脑不同。拟议研究的总体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酮作用于男性大脑，使特定的神经网络男性化，从而导致特定的男性行为。经典观点认为，性腺雄激素是参与大脑男性化的唯一因素。在性腺开始产生雄激素之前，哺乳动物大脑中基因表达的差异的发现使我们提出了另一种假设。我们建议探索大脑功能和行为的性别差异可能部分是由非性腺产生的遗传因素引起的。我们已经证明了 Y 连锁睾丸决定因子 Sry 在成人大脑的两个区域：黑质 (SN) 和乳头体中的特异性表达。 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，识别Sry表达的细胞类型，测量Sry的表达水平并测试它是否与TH表达相关（具体目标1）。我们将探讨下调和上调 SN 中的 Sry 对 TH 阳性神经元及其控制的感觉运动行为的影响，以及男性中的 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，我们将测试该女性因素是否可能是雌二醇或 X 染色体的剂量（具体目标 2）。最后，我们将使用 NT2N 细胞作为多巴胺能神经元模型，阐明 Sry 对多巴胺能神经元作用的分子机制（具体目标 3）。该提案旨在提高我们对大脑功能性别差异的总体理解。男性和女性大脑差异的分子机制的表征影响了我们对帕金森病、注意力缺陷障碍或抑郁症等精神和神经疾病中性别差异的理解。

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.