Role of the Male-Specific Factor Sry in Brain Function

描述(申请人提供)：男性和女性大脑不同。拟议研究的首要目标是了解大脑中性别差异的分子机制，重点是以黑质(SN)为模型。众所周知，在出生前或出生后，睾丸分泌的睾酮会作用于男性大脑，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，性腺雄激素是大脑男性化的唯一因素。在性腺开始产生雄激素之前，在哺乳动物大脑中发现了差异基因表达，这让我们提出了另一种假说。我们建议探索大脑功能和行为的性别差异可能部分是由不是由性腺产生的遗传因素造成的。我们已经证明Y连锁的睾丸决定因子Sry在成人大脑的两个区域中有特定的表达：黑质(SN)和乳头体。SN中Sry表达的减少导致酪氨酸羟化酶的强烈降低以及感觉运动障碍。为了了解Sry在SN功能性别差异中的作用，我们将研究Sry在成人脑中的表达谱，鉴定表达Sry的细胞类型，测量Sry的表达水平，并测试其是否与TH的表达相关(特定目标1)。我们将探索在黑质中下调和上调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Sry的行为是否补偿了女性特有因子的缺乏(或更低水平)。具体地说，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(特定目标2)。最后，我们将使用NT2N细胞作为多巴胺能神经元的模型来阐明Sry对多巴胺能神经元的作用的分子机制(特定目标3)。这项建议旨在提高我们对大脑功能性别差异的总体理解。对男性和女性大脑不同的分子机制的表征，影响了我们对精神和神经疾病(如帕金森氏症、注意力缺陷障碍或抑郁症)的性别差异的理解。

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.