Subcortical Estrogen Effect on The Hippocampus

皮质下雌激素对海马体的影响

• 批准号: 6541600
• 负责人: CSABA LERANTH
• 金额: $ 27.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6541600
• 关键词: brain electrical activity; brain septal area; brain subcortex; central neural pathway /tract; cholesterol; dendrites; electron microscopy; estrogen analog; estrogen receptors; estrogens; hippocampus; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; laboratory rat; neural plasticity; neuroendocrine system; neurons; ovariectomy; pyramidal cells; scopolamine; sex hormones; stereotaxic techniques; synapses

DESCRIPTION (Provided by applicant): The purpose of this proposal is to determine which subcortical structures are involved in gonadal hormonal actions on the hippocampus, in female rats. Animal studies, as well as human observations demonstrated that estrogen has a beneficial effect on hippocampus-associated cognitive functions and symptoms of Alzheimer's patients. The cellular targets of gonadal hormones in these processes are ill-defined. Experiments demonstrated that systemic hormonal manipulations result in dramatic changes in the density of CA1 hippocampal area pyramidal cell dendritic spines. However, there are no convincing data that hippocampal CA1 area pyramidal cells are the direct targets of estrogen. On the other hand, subcortical areas that regulate the activity of the hippocampus, including the medial septum diagonal band of Broca (MSDB) and supramammillary area (SUM) contain nuclear estrogen receptors. Therefore, we hypothesize that gonadal hormones, in addition to acting directly in the hippocampus, regulate hippocampal synaptic plasticity by affecting these estrogen receptor-containing subcortical structures that regulate hippocampal electric activity. This view is supported by recent observations that systemic estrogen administration to fimbria/fornix-transected ovariectomized (OVX) rats does not restore, but local estrogen administration into the supramammillary area dramatically increases CA1 area pyramidal cell spine synapse density. To further elaborate these observations, the following questions will be addressed: (a) is there a difference between the effect of unilateral versus bilateral estrogen implants into the SUM? (b) What is the transmitter content of SUM neurons involved in this process? (c) Are both the MSDB cholinergic and GABAergic septo-hippocampal neurons involved in mediating estrogenic effect to the hippocampus? and (d) Do SUM neurons mediate estrogenic effect to the hippocampus directly or indirectly, via the MSDB?

描述（由申请人提供）：本提案的目的是确定女性大鼠对海马的性腺激素作用涉及哪些皮下皮结构。动物研究以及人类的观察结果表明，雌激素对阿尔茨海默氏症患者的海马相关的认知功能和症状具有有益作用。在这些过程中，性腺激素的细胞靶标是不明的。实验表明，全身激素的操作导致CA1海马面积锥体细胞树突状棘的密度发生巨大变化。但是，没有令人信服的数据，海马CA1区域锥体细胞是雌激素的直接靶标。另一方面，调节海马活性的皮质下区域，包括Broca（MSDB）的内侧隔膜（MSDB）和超肌区（SUM）含有核雌激素受体。因此，我们假设性腺激素除了直接在海马中作用外，还通过影响这些含有雌激素受体受体的皮层下皮层结构来调节海马电动活性，从而调节海马突触可塑性。最近的观察结果表明，该观点是，全身性雌激素对纤维膜/肌肉转移的卵巢切除术（OVX）大鼠没有恢复，而是恢复了局部雌激素，局部雌激素施用到超乳房上区域会大大增加CA1区域锥体细胞脊柱突触突触密度。为了进一步阐述这些观察结果，将解决以下问题：（a）单侧与双侧雌激素植入物的影响之间是否存在差异？ （b）此过程中涉及的总和神经元的发射器含量是什么？ （c）MSDB胆碱能和GABA能 - 海马神经元是否参与对海马的雌激素作用？ （d）总和神经元是否通过MSDB直接或间接地向海马介导雌激素作用？