ESTROGEN, HIPPOCAMPAL NEUROGENESIS AND LEARNING

雌激素、海马神经发生和学习

• 批准号: 2830712
• 负责人: Elizabeth Gould
• 金额: $ 25.55万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2830712
• 关键词: NMDA receptors; antimitotics; association learning; autoradiography; behavioral /social science research tag; biomarker; bromodeoxyuridine; cell proliferation; conditioning; dentate gyrus; developmental neurobiology; electromyography; estrogens; female; gender difference; granule cell; hippocampus; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory rat; neural plasticity; neurogenesis; neuropharmacology

The dentate gyrus of the hippocampus is unusual because it continues to produce new neurons in adulthood in a variety of mammals, ranging from rodents to primates. Exposure to learning tasks that require the hippocampus for acquisition enhances the survival of adult-generated neurons in the dentate gyrus. In addition, adult female rats produce more new neurons than males, and these sex differences are positively correlated with sex differences in hippocampal-dependent learning. These findings indicate that learning influences the survival of new hippocampal neurons and raise the possibility that adult-generated granule neurons are involved in hippocampal-dependent learning. The broad, long-term objectives of this proposal are to characterize the influence of ovarian steroids and learning on the production, survival and gene expression of hippocampal granule neurons generated in adulthood in both sexes. Moreover, the potential role that new granule neurons play in hippocampal-dependent learning and memory will be explored. Using associative learning paradigms of trace classical eyeblink conditioning and the Morris spatial water maze, the role of hormones and experience in the production and survival of new granule neurons in males and females will be investigated with markers of proliferating cells, such as 3H-thymidine and bromodeoxyuridine, combined with immunocytochemistry for neuronal and glial markers. Combined in situ hybridization and immunocytochemistry will be used to explore changes in expression of genes important for cell survival, synaptic plasticity and/or learning, such as NMDA receptor subunits, BDNF and bcl-2, specifically in adult-generated granule neurons following associative learning. Furthermore, the function of hippocampal granule neurons generated in adulthood will be explored in animals depleted of new neurons by endocrine manipulations or treatment with selective toxins for proliferating neuronal precursors and then tested on tasks that require the hippocampal region for acquisition. This proposal is relevant to disorders or age- and disease-related cognitive decline which can be ameliorated by ovarian steroids. In addition, these studies may provide insight into mechanisms of neuronal regeneration.

海马的齿状回是不寻常的，因为它在各种哺乳动物中继续产生新的神经元，从啮齿动物到灵长类动物。 需要进行海马进行采集的学习任务，可以增强成人产生的神经元在齿状回中的存活。 此外，成年雌性大鼠比男性产生的新神经元更多，并且这些性别差异与海马依赖性学习的性别差异呈正相关。这些发现表明，学习会影响新的海马神经元的生存，并提高了成人生成的颗粒神经元参与海马依赖性学习的可能性。 该提议的广泛，长期的目标是表征卵巢类固醇的影响以及对两性成年产生的海马颗粒神经元的生产，生存和基因表达的影响。 此外，将探索新的颗粒神经元在海马依赖性学习和记忆中起的潜在作用。 Using associative learning paradigms of trace classical eyeblink conditioning and the Morris spatial water maze, the role of hormones and experience in the production and survival of new granule neurons in males and females will be investigated with markers of proliferating cells, such as 3H-thymidine and bromodeoxyuridine, combined with immunocytochemistry for neuronal and glial markers.原位杂交和免疫细胞化学的结合将用于探索对细胞存活，突触可塑性和/或学习重要的基因表达变化，例如NMDA受体亚基BDNF和BCL-2，特别是在成人生成的颗粒神经元中，在联想学习后，特异性地是在成人生成的颗粒神经元中。此外，将在成年期产生的海马颗粒神经元的功能通过内分泌操纵耗尽的动物探索或使用选择性毒素进行耗尽的新神经元的功能，然后对需要进行海马区域进行次要摄入的任务进行测试。 该提议与疾病或与年龄和疾病相关的认知下降有关，这可以被卵巢类固醇改善。 此外，这些研究可能会深入了解神经元再生的机制。