Steroid Receptors and Brain Sex Differences

描述（由申请人提供）：在早期大脑发育过程中，类固醇激素暴露可区分男性和女性的大脑。尽管男女之间有许多生理和行为上的差异，但也许最深刻的性别差异是在神经和精神疾病方面。例如，女性更有可能表现出抑郁、多发性硬化症和阿尔茨海默病的迹象。男性更有可能表现出注意力缺陷多动、自闭症和阅读障碍的迹象。由于大脑中的大多数性别差异是早期类固醇激素暴露的结果，因此某些疾病的性别差异可能部分受到发育中的大脑中异常类固醇受体作用的影响。因此，了解类固醇受体的活性如何在发育中的大脑中受到调节是很重要的。以前，人们认为类固醇受体只被类固醇激素激活；然而，最近的数据表明，类固醇受体在没有类固醇的情况下也会被激活，称为配体非依赖性激活。尽管目前有许多研究者在细胞培养实验和成年女性大脑中研究类固醇受体的不依赖于配体的激活，但很少有研究调查类固醇受体的不依赖于配体的激活在大脑发育中的作用。我们计划研究雌激素受体（ER）在发育中的功能作用与配体无关的激活。我们最近的数据表明，在生命的最初几天，多巴胺传递的急剧变化可以通过以配体独立的方式激活ER，从而显著改变社交游戏行为的发育组织。我们相信这些数据不仅令人兴奋，因为它们表明了一种潜在的类固醇激素独立于大脑性别分化的机制，而且它们还研究了社会玩耍行为的发育组织。由于自闭症和阿斯伯格综合症儿童的社交游戏行为严重中断，而啮齿动物的社交游戏行为已被用作研究自闭症的啮齿动物模型，这些数据可能会进一步加深我们对大脑发育过程中两性二态社会障碍发生的理解。

DESCRIPTION (provided by applicant): During early brain development, steroid hormone exposure differentiates male from female brain. Although there are numerous physiological and behavioral differences between men and women, perhaps the most profound sex differences are in neurological and psychiatric disorders. For example, women are more likely to exhibit signs of depression, multiple sclerosis, and Alzheimer's disease. Men are more likely to exhibit signs of attention-deficit hyperactivity, autism, and dyslexia. As most sex differences in the brain are a result of early steroid hormone exposure, it is possible that sex differences in some disorders are partly influenced by abnormal steroid receptor action in developing brain. Therefore it is important to understand how steroid receptor activity is regulated in developing brain. Previously, it was assumed that steroid receptors were only activated by steroid hormones; however, recent data indicate that steroid receptors are also activated in the absence of steroid, referred to as ligand-independent activation. Although numerous investigators are currently studying ligand-independent activation of steroid receptors in cell culture assays and in adult female brain, few studies investigate the role of ligand-independent activation of steroid receptors in brain development. We plan to investigate the functional role ligand-independent activation of estrogen receptors (ER) in developing brain. Our recent data indicate that acute changes in dopamine transmission during the first few days of life can dramatically alter the developmental organization of social play behavior by activating ER in a ligand-independent manner. We believe that these data are not only exciting in that they suggest a potential steroid hormone independent mechanism for sexual differentiation of the brain, but they also investigate the developmental organization of social play behavior. As social play behavior is dramatically disrupted in children with Autism and Asperger's syndrome, and social play behavior in rodents has been used as a rodent model for the study of autism, it is possible that these data will further our understanding of how sexually dimorphic social disorders occur during brain development.