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Regulation of Neurotransmitter Action by Steroid Hormones in Females

类固醇激素对女性神经递质作用的调节

基本信息

批准号：
9036844
负责人：
ISTVAN MODY
金额：
$ 192.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036844
关键词：
4-vinylcyclohexene diepoxide Address Affect Alzheimer&apos s Disease Animals Behavior Behavioral Brain Breast Cancer Cell Butyric Acids Cells Chemicals Cognition Cognitive Complex Coupled Coupling Disease Electrophysiology (science)Emotional Endothelial Growth Factors Receptor Engineering ErbB4 gene Estradiol Event Female Functional disorder GPER gene GTP-Binding Proteins Genetically Engineered Mouse High Prevalence Hippocampal Formation Hormonal Hormonal Change Hormones Human Impaired cognition In Vitro Interneuron function Interneurons Knowledge Light Mediator of activation protein Memory Memory Disorders Memory impairment Menopause Menstrual cycle Methodology Modeling Molecular Mood Disorders Mus NRG1 gene Neuraxis Neuregulin 1 Neurobehavioral Manifestations Neurologic Neurons Neurotransmitters Ovarian Ovarian Cycles Ovarian Follicle Ovarian hormone Parvalbumins Pathway interactions Phase Physiological Postmenopause Postpartum Period Prefrontal Cortex Pregnancy Process Progesterone Protein Tyrosine Kinase Puberty Regulation Role Short-Term Memory Signal Transduction Staging Syndrome System Testing Time Tissues Woman cognitive task gamma-Aminobutyric Acid genetic manipulation improved in vivo information processing insight memory recall neurosteroids novel novel strategies optogenetics psychiatric symptom public health relevance receptor research study steroid hormone

项目摘要

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.

性状（由申请方提供）：卵巢激素17β-雌二醇（E2）和孕酮（PROG）及其神经活性代谢物水平的变化对中枢神经系统（CNS）具有重要作用。许多中枢神经系统的影响涉及记忆和情绪障碍，如绝经后的妇女，或在月经周期的特定阶段经常出现的认知和精神症状。然而，人们对卵巢激素水平的大幅波动如何影响行为期间大脑中神经元集合的协调以及如何在细胞或分子水平上发生特定异常知之甚少。该建议的重点是小清蛋白阳性（PV+）中间神经元（IN）作为与卵巢激素水平改变相关的认知和情绪状态的集体介质的功能。这些细胞和它们控制的网络与锐波波纹（SPW-R）和γ振荡（30-120 Hz）密切相关，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，以改变SPW-R、γ振荡活动和/或θ（5-10 Hz）和γ振荡之间的相位-振幅耦合。将研究两种新机制：PV+ IN的含δ亚基的γ-氨基丁酸受体（δ-GABAAR）作为PROG衍生神经类固醇（NS）靶点的功能;以及G蛋白偶联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（ErbB 4）形成的E2信号级联。将在小鼠中检查卵巢激素变化的两个时期。第一个是生理性卵巢周期，其中E2和PROG水平在4-6天的典型周期内快速上下摆动。第二个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）对小原始和初级卵泡的选择性磨损，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认知和工作记忆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。复杂的电生理学和光遗传学实验在体内和体外，遗传操作，药理学方法从未测试过对神经元合奏的影响，以及首次在这种情况下进行的形态学/免疫组织化学研究将在该提案中收敛。这种多方面的新颖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转化潜力，因为它们将为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，PMS和经前焦虑障碍，PMDD）的患者提供可能的治疗方法，并可能为认知能力下降和绝经后女性散发性阿尔茨海默病（AD）的高患病率提供解释。