Steroid Receptors and Brain Sex Differences

描述(申请人提供)：在大脑发育的早期，类固醇激素的暴露会区分男性和女性的大脑。尽管男性和女性在生理和行为上有许多差异，但最深刻的性别差异可能是在神经和精神障碍方面。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。由于大脑中的性别差异大多是早期类固醇激素暴露的结果，因此某些疾病中的性别差异可能部分受到发育中大脑中类固醇受体活动异常的影响。因此，了解类固醇受体活性是如何在发育中的大脑中被调节是很重要的。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被激活，称为配体非依赖性激活。尽管目前许多研究人员在细胞培养试验和成年女性脑中研究类固醇受体的配体非依赖性激活，但很少有研究探讨类固醇受体的配体非依赖性激活在脑发育中的作用。我们计划研究雌激素受体(ER)非依赖配体激活在发育脑中的功能作用。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不依赖配体的方式激活ER来极大地改变社会游戏行为的发育组织。我们认为，这些数据不仅令人兴奋，因为它们表明了大脑性别分化的潜在类固醇激素非依赖机制，而且它们还调查了社交游戏行为的发育组织。由于患有自闭症和阿斯伯格综合症的儿童的社交游戏行为被戏剧性地扰乱，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如何发生性二态社交障碍的理解。

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.