Estradiol and Hippocampal Development

描述（由申请人提供）：发育事件的终身后果越来越明显。海马体是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大脑区域，并且早在生命的第一周就可以发挥这种作用。出生后早期是大脑性别差异组织的敏感窗口，许多与大脑相关的功能和/或相关的病理表现出强烈的性别偏见。本提案的目的是探索新生雄性大鼠海马中细胞发生率高于雌性大鼠的新观察结果，以及外源性雌二醇治疗增加细胞发生。我们提出，这一时期的细胞发生是独特的胚胎和成人神经发生相比，我们假设，在男性中的更大的速率是建立在这种性别中观察到的较大的海马体的机制。我们还推测，这种早期的神经发生可能是非常早期的学习和持久的母性剥夺的后果的性别差异的基础。我们将确定海马新细胞的来源，并确定是否性别差异和雌二醇对新细胞的影响是增殖和/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/或神经胶质的发育。最后，我们将测试的假设，性别差异去极化GABA的行动和增强这种反应的雌二醇是增加新生儿男性海马细胞增殖和/或生存的机制基础。我们将使用BrdU掺入新细胞，显微注射细胞示踪剂染料，双标记免疫荧光共聚焦显微镜，电生理学的器官型切片培养和单细胞钙成像，以完成九个特定的目标，测试三个不同的假设。这项工作的结果将为预防、干预和治疗发育性神经障碍和疾病以及脑损伤提供新的治疗途径。 公共卫生相关性：海马体是调节认知和情绪的关键大脑区域。影响海马发育的参数对于理解成年功能至关重要，并提供了对海马损伤和疾病的选择脆弱性的见解。本文提出的研究探索了与雌性大鼠相比，新生雄性大鼠海马中细胞发生增加的新观察结果。我们试图阐明介导这种性别差异的细胞机制，作为一种有价值的工具，用于识别新的治疗干预和预防目标。

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.