Estradiol and Hippocampal Development

描述（由申请人提供）：发展事件对一生的影响越来越明显。海马体是大脑中整合外部刺激以促进学习和记忆或诱导压力和焦虑的关键区域，它可能早在生命的第一周就发挥了一定的作用。产后早期是大脑性别差异组织的敏感窗口期，许多海马相关功能和/或相关病理表现出强烈的性别偏见。本研究的目的是探索与雌性相比，雄性新生大鼠海马中更高的细胞发生率，以及外源性雌二醇治疗增加细胞发生的新观察结果。我们提出，与胚胎和成人神经发生相比，这一时期的细胞发生是独特的，我们假设，在男性中观察到的更高的速率是建立更大海马的机制。我们还推测，这种早期神经发生可能是早期学习和母亲剥夺持久后果的性别差异的基础。我们将确定海马新细胞的来源，并确定性别差异和雌二醇对新细胞的影响是否是增殖和/或细胞存活变化的结果。我们将进一步确定细胞发生是否促进神经元和/或胶质细胞的发育。最后，我们将验证一个假设，即性别差异在去极化GABA的作用和雌二醇增强这种反应是新生儿雄性海马细胞增殖和/或存活增加的机制基础。我们将使用BrdU掺入新细胞、细胞跟踪染料显微注射、双标记免疫荧光共聚焦显微镜、器官型切片培养的电生理学和单细胞钙成像来完成九个特定目标，测试三个不同的假设。这项工作的结果将为发育性神经障碍、疾病和脑损伤的预防、干预和治疗提供新的治疗途径。

DESCRIPTION (provided by applicant): The life long consequences of developmental events is becoming increasingly apparent. The hippocampus is a critical brain region for integrating external stimuli to promote learning and memory or induce stress and anxiety, and it may serve this role in some capacity as early as the first week of life. The early postnatal period is a sensitive window for the organization of brain sex differences and many hippocampal-related functions and/or associated pathologies exhibit strong gender biases. The goal of this proposal is to explore the novel observation of higher rates of cell genesis in the neonatal male rat hippocampus compared to the female, and an increase in cell genesis by exogenous estradiol treatment. We propose that this period of cell genesis is unique compared to embryonic and adult neurogenesis and we hypothesize that the greater rate in males is the mechanism establishing the larger hippocampus observed in this sex. We also speculate that this early neurogenesis may underlie sex differences in very early learning and enduring consequences of maternal deprivation. We will identify the source of origin of new cells to the hippocampus and determine whether the sex difference and effect of estradiol on new cells are the result of changes in proliferation and/or cell survival. We will further determine whether cell genesis promotes the development of neurons and/or glia. Finally, we will test the hypothesis that sex differences in depolarizing GABA action and enhancement of this response by estradiol is the mechanistic basis for increased cell proliferation and/or survival in the neonatal male hippocampus. We will use BrdU incorporation into new cells, microinjection of cell tracker dye, double label immunofluorescent confocal microscopy, electrophysiology of organotypic slice cultures and single cell calcium imaging to complete nine specific aims that test three distinct hypotheses. Results of this work will provide new therapeutic avenues for prevention, intervention and treatment of developmental neurological disorders and diseases and brain damage. PUBLIC HEALTH RELEVANCE: The hippocampus is a critical brain region regulating cognition and emotionality. Parameters that impact on hippocampal development are essential to understanding adult function and provide insight into the select vulnerability of the hippocampus to damage and disease. The studies proposed here explore the novel observation of increased cell genesis in the newborn male rat hippocampus compared to that of the female. We seek to elucidate the cellular mechanisms mediating this sex difference as a valuable tool for the identification of new targets for therapeutic intervention and prevention.