ESTROGEN, HIPPOCAMPAL NEUROGENESIS AND LEARNING

海马的齿状回是不寻常的，因为它在成年后继续产生新的神经元，在各种哺乳动物中，从啮齿动物到灵长类动物。 暴露于需要海马体进行获取的学习任务增强了齿状回中成人生成的神经元的存活。 此外，成年雌性大鼠比雄性大鼠产生更多的新神经元，这些性别差异与性别差异呈正相关，在海马依赖性学习。这些发现表明，学习影响新的海马神经元的存活，并提高了成人产生的颗粒神经元参与海马依赖性学习的可能性。 这项建议的广泛的，长期的目标是表征卵巢类固醇和学习的影响，在成年期产生的海马颗粒神经元的生产，生存和基因表达在两种性别。 此外，新的颗粒神经元在海马依赖性学习和记忆中发挥的潜在作用也将被探索。 使用关联学习范式的痕迹经典眨眼条件反射和Morris空间水迷宫，激素和经验的作用，在男性和女性的新颗粒神经元的生产和生存将与增殖细胞的标记物，如3 H-胸苷和溴脱氧尿苷，结合免疫细胞化学的神经元和神经胶质标记物。结合原位杂交和免疫细胞化学将被用来探索重要的细胞存活，突触可塑性和/或学习，如NMDA受体亚单位，BDNF和bcl-2，特别是在成人产生的颗粒神经元的表达变化后，联想学习。此外，成年期产生的海马颗粒神经元的功能将在通过内分泌操作或用选择性毒素处理以增殖神经元前体而耗尽新神经元的动物中进行探索，然后在需要海马区进行采集的任务中进行测试。 这一建议与卵巢类固醇可以改善的疾病或年龄和疾病相关的认知下降有关。 此外，这些研究可能提供深入了解神经元再生的机制。

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.