Estradiol, GABA and Developing Hippocampal Cells

雌二醇、GABA 和发育中的海马细胞

• 批准号: 8003728
• 负责人: jerald michael bowers
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003728
• 关键词: Adult; Animal Model; Anorexia; Anxiety Disorders; Autistic Disorder; Behavior; Biological; Brain; Brain region; Bulimia; Cell Proliferation; Cell Survival; Cells; Childhood; Development; Disease; Dyslexia; Estradiol; Exhibits; Female; Foundations; Gender; Gilles de la Tourette syndrome; Hippocampus (Brain); Incidence; Learning; Major Depressive Disorder; Memory; Mental disorders; Mood Disorders; Neonatal; Neuroglia; Neurons; Newborn Infant; Pathology; Preventive; Relative Risks; Risk; Role; Schizophrenia; Sex Bias; Sex Characteristics; Source; Steroids; Stress; Stuttering; Testing; Therapeutic; autism spectrum disorder; base; cognitive function; early onset; gamma-Aminobutyric Acid; insight; interest; male; nervous system disorder; postnatal; public health relevance; research study; response; social communication

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.

描述（由申请人提供）：患有精神疾病或神经系统疾病的相对风险因性别而异。雄性表现出更高的自闭症和自闭症谱系障碍，图雷特综合征，口吃，阅读障碍和精神分裂症早期发作的率，所有这些都有童年的发作。相比之下，女性的主要抑郁症，普通焦虑症，厌食症，贪食症和精神分裂症晚期发作的发生率更高，所有这些都有成人的进攻。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大脑在男性和女性中的发展方式，我们可以深入了解疾病中性别差异的潜在来源，并确定潜在的治疗和预防靶标。此外，海马是一个特别感兴趣的大脑区域，因为它在学习和记忆中的核心作用，包括社会交流以及调节对压力的反应。此外，海马的病理学与多种心理健康障碍有关。当前的提案着重于男性与女性海马的早期产后发展，以及这种发育如何受到内源性类固醇雌二醇的影响。先前的观察结果表明，新生雄性产生的新海马细胞比女性更多，此外，通过外源性雌二醇治疗，女性可以增加新细胞的数量（Zhang等，2008）。现在，我们通过检验两个特定的假设来建立这一发现。假设1：雌二醇会通过将细胞增殖与细胞存活区分开来测试新生儿海马中的细胞增殖。 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.这些实验的结果将构成对男性和女性的性别和雌二醇坐标如何不同以改变神经元功能并最终行为的综合观点的基础。鉴于海马在许多情感障碍中的核心作用，这些结果将为精神疾病的起源以及正常的认知功能提供见解。 公共卫生相关性：患一种精神疾病或神经系统疾病的风险因性别而异。因此，当前的提案着重于男性和女性的大脑如何发展。通过探索大脑发育中的性别差异，可以深入了解疾病中性别差异的潜在来源，同时识别潜在的治疗和预防治疗。