Steroid Receptors and Brain Sex Differences

描述（由申请人提供）：在大脑发育早期，类固醇激素暴露区分男性和女性大脑。尽管男女之间存在许多生理和行为差异，但最深刻的性别差异可能是神经和精神疾病。例如，女性更容易表现出抑郁症、多发性硬化症和阿尔茨海默病的症状。男性更容易表现出注意力缺陷多动症、自闭症和阅读障碍的症状。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，因此某些疾病中的性别差异可能部分受到发育中大脑中异常类固醇受体作用的影响。因此，了解类固醇受体活性在发育中的大脑中是如何调节的是很重要的。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，类固醇受体也被激活，在类固醇的情况下，称为配体非依赖性激活。虽然许多研究人员目前正在研究类固醇受体在细胞培养试验和成年女性大脑中的配体非依赖性激活，但很少有研究调查类固醇受体在大脑发育中的配体非依赖性激活的作用。我们计划研究雌激素受体（ER）的非配体依赖性激活在脑发育中的功能作用。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配体非依赖性方式激活ER来显著改变社会游戏行为的发育组织。我们相信，这些数据不仅令人兴奋，因为它们表明了大脑性别分化的潜在类固醇激素独立机制，而且它们还调查了社会游戏行为的发育组织。由于自闭症和自闭症综合征儿童的社交游戏行为受到严重破坏，啮齿动物的社交游戏行为已被用作自闭症研究的啮齿动物模型，这些数据可能会进一步了解大脑发育期间性二态性社交障碍是如何发生的。

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.