Genetic control of sex differences in the nervous system

描述（由申请人提供）：神经系统和行为的性别差异在动物王国中普遍存在。除了基本的生物学兴趣，这些差异对理解许多心理健康和神经系统疾病的性别偏见具有重要意义。神经系统性别差异的一个有趣但知之甚少的组成部分是通过非依赖性的、细胞内在的“神经性别”在塑造神经系统特征中的作用而产生的。在利用线虫C.在线虫中，我们已经确定了嗅觉行为的强烈性别差异，这种差异是通过细胞内在的、性别依赖的两性共同神经元功能的修饰而产生的。了解这些性别差异背后的机制有很大的潜力，阐明类似的现象在哺乳动物中枢神经系统中发挥作用。在三个具体目标中，我们将（1）确定调节嗅觉性别差异的精确神经灶，并描述这些神经元发育和功能的性别差异;（2）使用候选基因方法以及靶向微阵列研究来确定核心神经系统中的性别调节基因，并确定其功能意义;（3）描述C. elegans成员的保守DM家族的性调节，包括dmd-3，在产生性别差异的嗅觉。总之，这项工作采取了一种创新的方法来阐明保守的分子，遗传和神经机制，通过这些机制，神经性别与神经系统发育和功能的性别差异相结合。公共卫生相关性使用一个微小的土壤蛔虫，我们将研究神经系统发育和功能的性别差异的遗传和细胞调节。这些研究将确定可能在人类心理健康和神经系统疾病中发挥重要作用的基因和机制，如自闭症，情绪障碍和慢性疼痛综合征，这些疾病优先影响一种性别而不是另一种性别。

DESCRIPTION (provided by applicant): Sex differences in the nervous system and in behavior are ubiquitous in the animal kingdom. Beyond their basic biological interest, these differences have important implications for understanding the sex bias that characterizes many mental health and neurological disorders. An intriguing but poorly understood component of nervous system sex differences arises through the actions of hormone-independent, cell-intrinsic "neural sex" in shaping characteristics of the nervous system. In preliminary work using the nematode C. elegans, we have identified robust sex differences in olfactory behavior that arise through cell-intrinsic, sex-dependent modification of the function of neurons common to both sexes. Understanding the mechanisms that underlie these sex differences has great potential to shed light on similar phenomena acting in the mammalian CNS. In three Specific Aims, we will (1) identify the precise neural foci that regulate sex differences in olfaction, and characterize sex differences in the development and function of these neurons; (2) use a candidate-gene approach as well as targeted microarray studies to identify sex-regulated genes in the core nervous system and determine their functional significance; and (3) characterize the role of C. elegans members of the conserved DM family of sexual regulators, including dmd-3, in generating sex differences in olfaction. Together, this work takes an innovative approach to illuminating the conserved molecular, genetic and neural mechanisms by which neural sex is coupled to sex differences in the development and function of the nervous system. PUBLIC HEALTH RELEVANCE Using a tiny soil roundworm, we will examine the genetic and cellular regulation of sex differences in the development and function of the nervous system. These studies will identify genes and mechanisms that may have important roles in human mental health and neurological conditions, such as autism, mood disorders and chronic pain syndrome, that preferentially affect one sex over the other.