Impact of Estrogens and Menopause on Interacting Monoamine Neurotransmitters in t

描述(由申请者提供)：我们的目标是了解雌激素影响大脑和认知表现的机制。雌激素在大脑中有许多有益的作用；然而，雌激素调节这些作用的机制在许多方面都是未知的。我们假设，这些效应在很大程度上反映了特定大脑区域中多个相互作用的神经递质通路的影响。特别是，我们假设卵巢功能的丧失会导致大脑中特定单胺能通路的多个同时减少，而作用于特定雌激素受体的选择性激动剂可以逆转这些影响，并将神经递质通路恢复到生理正常状态。在过去的十年里，姚博士的(合伙)实验室专注于开发技术来量化多种低分子量氧化还原活性化合物(例如单胺、单胺代谢物、氨基酸、氧化应激标志物等)。在生物组织中。这是使用最先进的高压液相色谱与16通道库仑多电极阵列系统(HPLC-CMEAS)和毛细管气相色谱与火焰离子化检测器(GC-FID)相结合来实现的。这项技术的威力在于能够同时评估皮考莫范围内不同生化途径的多种代谢物。使用手术和自然更年期的动物模型，我们将应用这项技术来评估更年期和选择性雌激素受体激动剂治疗对特定脑区内多条神经递质通路的影响。更年期的模型将包括卵巢切除(手术更年期的模型)和4-乙烯基环己烯二环氧化物(VCD；自然更年期的模型)治疗。雌激素治疗将包括连续sc给予17ss-雌二醇(E2)、G-1(选择性GPR30激动剂)、PPT(选择性ER激动剂)和DPN(选择性ERss激动剂)。每日5g，持续1周或卵巢功能丧失后6周。来自海马体、额叶皮质和纹状体的组织将被解剖并分析单胺、单胺代谢物、氨基酸神经递质和胆碱乙酰转移酶(胆碱能神经元的标志)的水平。这项研究将详细描述在两种更年期模型中大脑特定区域发生的神经化学相关化合物的变化，以回应选择性激素治疗。这项研究还将首次评估选择性GPR30激动剂对这些靶点的影响，并将它们与选择性ER和ERss激动剂的效果进行比较。这一发现将使人们更清楚地了解与不同类型更年期相关的神经化学变化，并将为女性接受雌激素治疗提供更好的策略。

DESCRIPTION (provided by applicant): Our goal is to understand mechanisms by which estrogens affect the brain and cognitive performance. Estrogens have many beneficial effects in the brain; however, the mechanisms by which estrogens mediate these effects are in many ways unknown. We hypothesize that these effects reflect in large part effects on multiple interacting neurotransmitter pathways in specific brain regions. In particular, we hypothesize that loss of ovarian function results in multiple and simultaneous decreases in specific monoaminergic pathways in the brain, and that selective agonists acting at specific estrogen receptors can reverse these effects and restore the neurotransmitter pathways to a physiologically normal state. Over the past decade, Dr. Yao's (co-PI) laboratory has focused on developing technologies to quantify multiple low-molecular weight redox-active compounds (e.g., monoamines, monoamine metabolites, amino acids, markers of oxidative stress, etc...) in biological tissues. This is accomplished using state-of-the-art high-pressure liquid chromatography coupled with a 16-channel Coulometric Multi-Electrode Array System (HPLC-CMEAS) and capillary gas chromatography with a flame-ionization detector (GC-FID). The power of this technology is the ability to assess multiple metabolites from different biochemical pathways simultaneously in the picomol range. Using animal models of both surgical and natural menopause, we will apply this technology to evaluate the effects of 'menopause' and treatment with selective estrogen receptor agonists on multiple neurotransmitter pathways within specific brain regions. Models of menopause will include ovariectomy (a model of surgical menopause), and treatment with 4-vinylcyclohexene diepoxide (VCD; a model of natural menopause). Estrogen treatments will include 17ss-estradiol (E2), G-1 (a selective GPR30 agonist), PPT (a selective ER¿ agonist) and DPN (a selective ERss agonist) administered continuously sc. at 5 ¿g/day for 1 week or six weeks following loss of ovarian function. Tissues from the hippocampus, frontal cortex, and striatum will be dissected and analyzed for levels of monoamines, monoamine metabolites, amino acid neurotransmitters, and choline acetyltransferase (a marker of cholinergic neurons). This study will provide a detailed description of the changes in neurochemically relevant compounds that occur in specific regions of the brain, in two models of menopause, in response to selective hormone treatments. The studies also will be the first to evaluate the effects of a selective GPR30 agonist on these targets and to compare them with the effects of selective ER¿ and ERss agonists. The findings will provide a much clearer understanding of the neurochemical changes associated with different types of menopause and will lead to better strategies for approaching estrogen therapy in women.