Role of GPR30 in Estrogen-Mediated Effects on Cholinergic Function and Cognition

动物研究表明，雌激素可以显著提高学习和记忆能力；然而，这些作用背后的机制还不清楚。研究表明，投射到海马区和额叶皮质的神经元，以及使用乙酰胆碱作为神经递质的神经元，在这些效应中发挥着重要作用。本项目的目的是研究一种新的雌激素受体蛋白GPR30是否在胆碱能神经元的功能和学习记忆中起重要的中介作用。研究将在摘除卵巢的大鼠身上进行。组织化学、行为药理学和体内微透析将被用来评估作用于GPR30受体的药物的效果。据预测，选择性激活GPR30受体将显著增强感兴趣胆碱能神经元的功能，以及认知能力。此外，据预测，阻断GPR30受体激活或破坏感兴趣的胆碱能神经元的药物将阻断雌二醇的作用以及与GPR30激活特定相关的作用。这表明，胆碱能神经元表达的GPR30在介导雌二醇的作用中起着重要作用。细胞培养研究也将用于评估对胆碱能神经元内信号通路的影响。这些研究将为GPR30在调节雌激素对胆碱能神经元和认知功能的影响中的作用提供许多新的和有价值的机制信息。这些信息将大大增加我们对卵巢功能丧失以及雌激素替代如何影响认知的理解。博士生和本科生将受益于接受行为药理学、组织化学和体内微透析方法的培训。

Animal studies show that estrogens can significantly enhance learning and memory; however, the mechanisms that underlie these effects are very unclear. Studies suggest that neurons that project to the hippocampus and frontal cortex, and that use acetylcholine as their neurotransmitter, play an important role in these effects. The purpose of this project is to study whether a novel estrogen receptor protein, GPR30, plays an important role in mediating effects on the function of the cholinergic neurons as well as on learning and memory. Studies will be performed in rats that have had their ovaries removed. Histochemistry, behavioral pharmacology, and in vivo microdialysis will be used to evaluate the effects of drugs that act on the GPR30 receptor. It is predicted that selective activation of the GPR30 receptor will significantly enhance the function of the cholinergic neurons of interest, as well as cognitive performance. In addition, it is predicted that drugs which block activation of the GPR30 receptors, or that destroy the cholinergic neurons of interest, will block the effects of estradiol as well as effects associated specifically with GPR30 activation. This would demonstrate that GPR30, which is expressed by the cholinergic neurons, plays an important role in mediating the effects of estradiol. Cell culture studies also will be used to evaluate effects on signaling pathways within the cholinergic neurons. These studies will provide much new and valuable mechanistic information about the role of GPR30 in mediating estrogen effects on the cholinergic neurons and on cognitive performance. This information will add significantly to our understanding of how loss of ovarian function as well as estrogen replacement influences cognition. Doctoral and undergraduate students will benefit by receiving training in methods of behavioral pharmacology, histochemistry, and in vivo microdialysis.