Regulation of Neurotransmitter Action by Steroid Hormones in Females

 描述(申请人提供)：卵巢激素17β-雌二醇(E2)和孕酮(PROG)水平的变化，以及它们的神经活性代谢产物，对中枢神经系统(CNS)有重要作用。许多中枢神经系统的影响涉及记忆和情绪障碍，比如绝经后的女性，或者在月经周期的特定阶段经常出现的认知和精神症状。然而，关于卵巢激素水平的大幅波动如何影响行为过程中大脑中神经元群的协调，以及如何在细胞或分子水平上接踵而至的特殊异常，人们知之甚少。这项建议侧重于小白蛋白阳性(PV+)中间神经元(INS)作为与卵巢激素水平变化相关的认知和情绪状态的集体调节因子的功能。这些细胞及其控制的网络关键地参与了尖波波动(SPW-R)和γ振荡(30-120赫兹)，这是记忆回忆、认知和信息处理所必需的大脑节律。我们假设E2和Prog通过不同的机制作用于PV+INS，从而改变SPW-R、γ-振荡活动和/或θ(5-10 Hz)和γ-振荡之间的相位-幅度耦合。两个新的机制将被研究：PV+INS的δ亚单位含γ氨基丁酸受体(δ-GABAARs)作为编程神经类固醇(NS)靶标的功能；以及由G蛋白偶联的E2受体(GPER-1)→神经调节蛋白1(NRG-1)→内皮生长因子受体酪氨酸激酶(ErbB4)形成的E2信号级联反应。将在小鼠身上检查两个时期的卵巢激素变化。第一个是生理卵巢周期，在这个周期中，雌二醇和催乳素水平在4-6天的典型周期中迅速上下波动。第二种是真正的人类更年期小鼠模型，即工业化学品4-乙烯基环己烯二环氧化物(VCD)选择性地磨损小的原始卵泡和初级卵泡，对其他组织的影响可以忽略不计。这些研究将为卵巢激素对潜在认知和工作记忆的神经元振荡作用的第一个全面和统一的模型提供实验基础。在体内和体外进行的复杂的电生理学和光遗传学实验、遗传操作、从未被测试过对神经元整体的影响的药理学方法，以及首次在这方面进行的形态/免疫组织化学研究将汇聚在这一提议中。这一多方面和新颖的方法有望为卵巢激素变化对女性大脑的作用提供独特的见解。这些研究具有很高的翻译潜力，因为它们将阐明数百万患有月经周期相关神经和精神功能障碍(经前综合征和经前焦虑症)的可能治疗方法，并可能为绝经后女性认知能力下降和散发性阿尔茨海默病(AD)的高发病率提供解释。

 DESCRIPTION (provided by applicant): Changing levels of the ovarian hormones 17β-estradiol (E2) and progesterone (PROG), together with their neuroactive metabolites, have essential actions on the central nervous system (CNS). Many of the CNS effects involve memory and mood disorders such as those found in women after menopause, or the cognitive and psychiatric symptoms frequently present during specific stages of the menstrual cycle. Yet, little is known about how large swings in ovarian hormone levels affect the coordination of neuronal ensembles in the brain during behavior and how particular abnormalities may ensue at the cellular or molecular level. This proposal focuses on the function of parvalbumin-positive (PV+) interneurons (INs) as collective mediators of cognitive and emotional states associated with altered ovarian hormone levels. These cells and the networks they control are critically involved in sharp-wave ripples (SPW-R) and γ-oscillations (30-120 Hz), brain rhythms essential for memory recall, cognition, and information processing. We hypothesize that E2 and PROG act on PV+INs through distinct mechanisms to alter SPW-R, γ-oscillatory activity, and/or phase-amplitude coupling between θ (5-10 Hz) and γ-oscillations. Two novel mechanisms will be investigated: the function of δ subunit- containing γ-amino-butyric-acid receptors (δ-GABAARs) of PV+INs as a target for PROG-derived neurosteroids (NS); and the signaling cascade formed by the G-protein coupled E2 receptor (GPER-1) → neuregulin 1 (NRG-1) → endothelial growth factor receptor tyrosine kinase (ErbB4), for E2. Two periods of ovarian hormonal alterations will be examined in mice. The first is the physiological ovarian cycle in which E2 and PROG levels rapidly swing up and down over a typical cycle period of 4-6 days. The second is a genuine model of human menopause in mice, that is, the selective attrition of small primordial and primary ovarian follicles by the industrial chemical 4-vinylcyclohexene diepoxide (VCD) that has negligible effects on other tissues. These studies will provide the experimental underpinnings of the first comprehensive and unifying model of ovarian hormone action on neuronal oscillations underlying cognition and working memory. Sophisticated electrophysiological and optogenetic experiments in vivo and in vitro, genetic manipulations, pharmacological approaches never before tested for effects on neuronal ensembles, and morphological/immunohistochemical studies carried out for the first time in this context will converge in the proposal. This multifaceted and novel approach is expected to provide unique insights into the actions of ovarian hormonal changes on the female brain. The studies have a high translational potential as they will shed light on possible treatments for millions suffering from menstrual cycle-related neurological and psychiatric dysfunction (pre-menstrual syndrome, PMS, and pre-menstrual dysphoric disorder, PMDD), and may provide explanation for the cognitive decline and high prevalence of sporadic Alzheimer's disease (AD) in post-menopausal women.