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）：发展精神疾病或神经系统疾病的相对风险因性别而异。男性患自闭症和自闭症谱系障碍、抽动秽语综合症、口吃、诵读困难和早发精神分裂症的比例要高得多，所有这些疾病都是在儿童时期发病的。相比之下，女性患严重抑郁症、广泛性焦虑症、厌食症、暴食症和迟发性精神分裂症的发病率要高得多，所有这些疾病都在成年后发病。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的大脑发育差异，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。目前的建议集中在海马体在男性与女性的出生后早期发展，以及这种发展是如何受到内源性类固醇，雌二醇的影响。先前的观察揭示了新生雄性比雌性产生更多的新海马细胞，此外，通过外源性雌二醇处理可以增加雌性中新细胞的数量（Zhang et al.，2008年）。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：将通过区分细胞增殖与细胞存活的实验来测试Ehrs增加新生海马中的细胞增殖。假设#2：由于增强去极化GABA作用，雌二醇促进新生海马中神经元/神经胶质细胞增殖和/或存活，将通过确定新细胞是否成为神经元或神经胶质以及该终点是否取决于我们先前记录的雌二醇诱导的GABA兴奋作用增强来建立假设#1。这些实验的结果将为性别和雌二醇如何协调男性和女性海马发育的不同以改变神经元功能并最终改变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，这些结果将为了解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：患精神疾病或神经系统疾病的风险因性别而异。因此，目前的建议集中在男性和女性的大脑发育不同。通过探索大脑发育中的性别差异，将有可能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方法。