Estradiol, GABA and Developing Hippocampal Cells

描述（由申请人提供）：患精神疾病或神经障碍的相对风险因性别而异。男性患自闭症和自闭症谱系障碍、图雷特综合症、口吃、阅读障碍和早期精神分裂症的比例要高得多，所有这些都是在儿童时期发病的。相比之下，女性患重度抑郁症、一般焦虑症、厌食症、暴食症和晚发性精神分裂症的几率要高得多，所有这些疾病都有成人发病。这些性别偏见的生物学基础是完全未知的。通过使用哺乳动物模型探索男性和女性大脑发育的差异，我们可以深入了解疾病性别差异的潜在来源，并确定潜在的治疗和预防目标。此外，海马体是一个特别有趣的大脑区域，因为它在学习和记忆中起着核心作用，包括社会交流，以及调节对压力的反应。此外，海马体的病理与许多精神健康障碍有关。目前的建议侧重于男性和女性出生后海马体的早期发育，以及这种发育如何受到内源性类固醇雌二醇的影响。先前的观察显示，新生雄性比雌性产生更多的新海马细胞，此外，外源性雌二醇可以增加雌性新细胞的数量（Zhang et al., 2008）。我们现在通过测试两个特定的假设来建立这一发现。假设1：雌二醇增加新生儿海马细胞增殖，将通过区分细胞增殖和细胞存活的实验进行验证。假设2：雌二醇通过增强GABA去极化作用促进新生儿海马神经元/胶质细胞增殖和/或存活，这将建立在假设1的基础上，决定新细胞是成为神经元还是胶质细胞，以及这个终点是否取决于我们之前记录的雌二醇诱导的GABA兴奋作用的增强。这些实验的结果将为性别和雌二醇如何以不同的方式协调男性和女性的海马发育从而改变神经元功能和最终行为的综合观点奠定基础。鉴于海马体在许多情感障碍中的核心作用，这些结果将为精神疾病和正常认知功能的起源提供见解。

DESCRIPTION (provided by applicant): The relative risk of developing a mental illness or neurological disorder varies considerably by gender. Males exhibit far higher rates of autism and autism spectrum disorder, Tourette's Syndrome, stuttering, dyslexia, and early onset of schizophrenia, all of which have a childhood onset. In contrast, females suffer much higher incidences of major depressive disorders, general anxiety disorder, anorexia, bulimia, and late onset of schizophrenia, all of which have adult onsets. The biological basis for these gender biases is entirely unknown. By exploring how the brain develops differently in males and females, using a mammalian animal model, we can gain insight into the potential sources of the sex differences in disease and identify potential therapeutic and preventive targets. Moreover, the hippocampus is a brain region of particular interest because of its central role in learning and memory, including social communication, and in regulating the response to stress. In addition, pathologies of the hippocampus are associated with numerous mental health disorders. The current proposal focuses on the early postnatal development of the hippocampus in males versus females and how this development is impacted by the endogenous steroid, estradiol. Previous observations reveal newborn males generate more new hippocampal cells than females, furthermore, the number of new cells can be increased in females by exogenous estradiol treatment (Zhang et al., 2008). We now build on this finding by testing two specific hypotheses. Hypothesis #1: Estradiol increases cell proliferation in the neonatal hippocampus, will be tested by experiments that distinguish cell proliferation from cell survival. Hypothesis #2: Estradiol promotes neuronal/glial proliferation and/or survival in the neonatal hippocampus as a result of enhancing depolarizing GABA action, will build on Hypothesis #1 by determining whether the new cells become neurons or glia and if this endpoint depends on our previously documented estradiol-induced enhancement of excitatory actions of GABA. Results from these experiments will form the foundation for an integrated view of how gender and estradiol coordinate hippocampal development differently in males and females to alter neuronal functioning and ultimately behavior. Given the central role of the hippocampus in many affective disorders, these results will provide insights into the origins of mental illness as well as normal cognitive functioning. PUBLIC HEALTH RELEVANCE: The risk of developing a mental illness or neurological disorder varies considerably by gender. Thus, the current proposal focuses on how the brain develops differently in males and females. By exploring sex differences in brain development, it will be possible to gain insight into the potential sources of the sex differences in disease along with identifying potential therapeutic and preventative treatments.