Subcortical Estrogen Effect on The Hippocampus

描述（由申请人提供）：本提案的目的是确定哪些皮层下结构参与雌性大鼠海马体的性腺激素作用。动物研究以及人类观察表明，雌激素对海马体相关的认知功能和阿尔茨海默病患者的症状有有益的影响。这些过程中性腺激素的细胞靶标尚不明确。实验表明，全身激素调节会导致 CA1 海马区锥体细胞树突棘密度发生显着变化。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，调节海马活动的皮质下区域，包括布罗卡内侧隔对角带（MSDB）和乳头上区（SUM），含有核雌激素受体。因此，我们假设性腺激素除了直接作用于海马体之外，还通过影响这些调节海马电活动的含有雌激素受体的皮层下结构来调节海马突触可塑性。最近的观察结果支持了这一观点，即对伞部/穹窿横断卵巢切除 (OVX) 的大鼠全身给予雌激素并不能恢复，但对乳头上区局部给予雌激素会显着增加 CA1 区锥体细胞棘突触密度。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 SUM 的效果是否存在差异？ (b) 参与该过程的 SUM 神经元的递质含量是多少？ (c) MSDB 胆碱能和 GABA 能隔膜海马神经元是否都参与介导海马的雌激素作用？ (d) SUM 神经元是否通过 MSDB 直接或间接介导对海马体的雌激素作用？

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?