Subcortical Estrogen Effect on The Hippocampus

描述(申请人提供)：这项建议的目的是确定哪些皮质下结构参与雌性大鼠海马性腺激素的作用。动物研究和人类观察表明，雌激素对阿尔茨海默氏症患者的海马体相关认知功能和症状有有益的影响。性腺激素在这些过程中的细胞靶点是不明确的。实验证明，系统的激素操作导致CA1区锥体细胞树突棘密度的显着变化。然而，目前还没有令人信服的数据表明，海马CA1区锥体细胞是雌激素的直接靶点。另一方面，调节海马体活动的皮质下区域，包括Broca内侧隔斜角带(MSDB)和乳房上区(SUM)，含有核雌激素受体。因此，我们假设性激素除了直接作用于海马区外，还通过影响这些含有雌激素受体的皮质下结构来调节海马区的电活动，从而调节海马区突触的可塑性。最近的观察结果支持这一观点，即全身应用雌激素对海马伞/穹隆横断卵巢切除(OVX)大鼠没有恢复作用，但乳房上区局部应用雌激素显著增加了CA1区锥体细胞脊突突触密度。为了进一步阐述这些观察结果，将解决以下问题：(A)单侧和双侧雌激素注射的效果是否存在差异？(B)参与这一过程的SUM神经元的递质含量是什么？(C)MSDB胆碱能神经元和GABA能隔-海马神经元是否都参与介导对海马区的雌激素效应？以及(D)SUM神经元是否通过MSDB直接或间接地介导对海马体的雌激素效应？

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?