Estradiol, GABA and Developing Hippocampal Cells

描述(由申请人提供)：发生精神疾病或神经障碍的相对风险因性别而有很大差异。男性自闭症和自闭症谱系障碍、多发性抽动症、口吃、阅读障碍和早发性精神分裂症的发病率要高得多，所有这些都是从童年开始的。相比之下，女性患抑郁症、焦虑症、厌食症、暴食症和精神分裂症晚发的几率要高得多，所有这些都有成人发病。这些性别偏见的生物学基础是完全未知的。通过使用哺乳动物动物模型探索男性和女性大脑发育的不同，我们可以洞察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，海马体是一个特别令人感兴趣的大脑区域，因为它在学习和记忆(包括社会交流)以及调节对压力的反应方面发挥着核心作用。此外，海马体的病理与许多精神健康障碍有关。目前的建议集中在男性和女性出生后早期海马体的发育，以及内源性类固醇雌激素如何影响这一发育。先前的观察表明，新生的男性比女性产生更多的新海马细胞，此外，外源性雌二醇治疗可以增加女性新细胞的数量(Zhang等人，2008年)。我们现在通过测试两个具体的假设来建立这一发现。假设1：雌二醇促进新生海马区的细胞增殖，这将通过区分细胞增殖和细胞存活的实验来检验。假设2：雌激素通过增强去极化GABA的作用而促进新生海马神经元/神经胶质细胞的增殖和/或存活，将建立在假设1的基础上，确定新细胞是成为神经元还是胶质细胞，以及这一终点是否依赖于我们先前报道的雌激素诱导的GABA兴奋作用的增强。这些实验的结果将形成一个综合的观点的基础，即性别和雌二醇如何以不同的方式协调男性和女性的海马体发育，以改变神经元功能和最终的行为。鉴于海马体在许多情感障碍中的中心作用，这些结果将为了解精神疾病的起源以及正常的认知功能提供洞察力。 公共卫生相关性：患精神疾病或神经障碍的风险因性别而有很大差异。因此，目前的建议侧重于男性和女性大脑发育的不同。通过探索大脑发育中的性别差异，将有可能洞察疾病中性别差异的潜在来源，以及确定潜在的治疗和预防方法。

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.