Estrogen-mediated mechanisms of stress susceptibility

雌激素介导的应激敏感性机制

基本信息

批准号：
10064640
负责人：
Susan Kathleen Wood
金额：
$ 40.23万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-16 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064640
关键词：
Affect Agonist Amygdaloid structure Anhedonia Automobile Driving Behavior Behavioral Binding Blood Pressure Brain Brain region Cardiac Cardiovascular Diseases Cardiovascular system Conflict (Psychology)Corticotropin-Releasing Hormone Data Depressed mood Depressive disorder Development Electrophysiology (science)Estrogen Receptor beta Estrogen Receptors Estrogen Replacements Estrogens Exhibits Exposure to Female Fright Functional disorder Gene Transfer Genes Genetic Transcription Goals Impairment Incidence Major Depressive Disorder Measures Mediating Mediator of activation protein Menopause Mental Depression Messenger RNA Microdialysis Modeling Mood Disorders Myocardial dysfunction Negative Valence Neuromodulator Neurons Neuropeptides Neurosecretory Systems Ovarian hormone Pathology Pathway interactions Peptides Periodicity Physiological Play Population Predisposition Puberty Rattus Receptor Activation Recording of previous events Regulation Response Elements Rest Risk Risk Factors Rodent Role Series Sex Differences Signal Transduction Site Startle Reaction Stress Sucrose Swimming Sympathetic Nervous System Telemetry Testing Time Translating Virus Woman Women&apos s Group awake base biological adaptation to stress comorbidity depressive symptoms estrogenic in vivo indexing knock-down locus ceruleus structure male men neural circuit neurochemistry neuromechanism novel preference receptor release factor response sex small hairpin RNA social social defeat social stress stress related disorder stress resilience

项目摘要

Project Summary Women are twice as likely as men to suffer from stress-related affective disorders, and as a result, are also at a greater risk of developing comorbid cardiovascular disease. This proposal investigates the estrogen (E)- mediated neural mechanisms that we suggest are initiated in the central amygdala (CeA) to promote innate stress vulnerability to both the emergence of negative valence and exaggerated cardiac sympathetic activation. The proposed series of studies relies on the use of a witness stress paradigm whereby a male or female rodent is located in a protected region of a dominant resident's cage and witnesses a social conflict between the resident and a smaller male intruder. Following stress exposure, females with either intact ovarian hormones, or ovariectomized with E replacement (OVX+E) exhibit negative valence (decreased sucrose preference, increased burying) and exaggerated cardiac sympathetic levels (elevated resting blood pressure) while OVX with vehicle replacement (OVX+V) and intact males are resilient, making this model ideal to study the role of estrogen on increased stress susceptibility. Aim 1 expands upon preliminary data that support the hypothesis that ovarian hormones, in particular E, exacerbate stress susceptibility. These studies will identify sex differences and estrogenic effects on behavioral and sympathetic indices of stress-related pathology. Aim 2 utilizes direct intra-CeA administration of an E receptor (ER) agonist (DPN) or antagonist (PHTPP), to activate or block, respectively, the ERs in the CeA. We hypothesize that inhibiting the ER in this brain region will enhance stress resiliency in the innate susceptible (intact-cycling) and induced susceptible (OVX+E) female groups, while activating the receptor will promote vulnerability in the induced resilient group (OVX). One known effect of E is its ability to increase the stress-related neuropeptide corticotropin-releasing factor (CRF), a peptide that is abundant in the CeA and is capable of inducing enhanced behavioral and sympathetic fear responses. Our data indicate that intact females exhibit increased CRF in the CeA, but only if they have a history of stress exposure. Therefore, Aim 2 will also identify if these ER treatments affect CRF expression in the CeA. Finally, Aim 3 will use virus-mediated gene transfer to reduce CRF levels in the CeA to determine whether the susceptibility-enhancing effects of the E are dependent upon CRF. Moreover, using in vivo microdialysis, studies in Aim 3 will identify whether increased CRF in the CeA has consequences on the major stress sensitive target the locus coeruleus (LC). CRF release and neuronal activity will be measured in the LC during stress/control and will identify if intact females exhibit increased CRF release in the LC and whether this translates to elevated activity. The ability of shRNA CRF knockdown in the CeA to affect LC activity and CRF release will also be assessed. Together, these studies will provide evidence of a targeted mechanism increasing susceptibility to affective disorders and comorbid cardiac dysfunction in females. These studies propose a novel and “translatable” pathway by which E may regulate innate stress vulnerability in women.

项目概要女性患与压力相关的情感障碍的可能性是男性的两倍，因此，她们也处于合并心血管疾病的风险更大该提案研究了雌激素 (E)-。我们建议在中央杏仁核 (CeA) 中启动介导的神经机制，以促进先天性应激易受负价的出现和过度的心脏交感神经激活的影响。拟议的一系列研究依赖于使用证人压力范式，其中男性或女性啮齿动物位于主要居民笼子的保护区内，目睹了之间的社会冲突在压力暴露后，居民和较小的雄性入侵者的卵巢都完好无损。激素或用 E 替代 (OVX+E) 切除卵巢的患者表现出负价（蔗糖减少）偏好、增加埋葬）和夸大的心脏交感神经水平（静息血压升高）而带有车辆更换的 OVX (OVX+V) 和完整的雄性具有弹性，使该模型成为研究的理想选择目标 1 扩展了支持雌激素对压力敏感性增加的初步数据。假设卵巢激素，特别是 E，会加剧应激敏感性，这些研究将确定这一点。性别差异和雌激素对压力相关病理学的行为和交感指数的影响。 2 利用 E 受体 (ER) 激动剂 (DPN) 或拮抗剂 (PHTPP) 直接在 CeA 内给药，分别激活或阻断 CeA 中的 ER，我们发现抑制该大脑区域的 ER。将增强先天易感性（完整循环）和诱导易感性（OVX+E）的应激恢复能力女性群体，同时激活受体将促进诱导弹性群体（OVX）的脆弱性。 E 的已知作用是它能够增加与压力相关的神经肽促肾上腺皮质激素释放因子 (CRF)，这是一种 CeA 中丰富的肽，能够诱导增强的行为和交感恐惧我们的数据表明，完整的雌性在 CeA 中表现出增加的 CRF，但前提是它们具有因此，目标 2 还将确定这些 ER 治疗是否影响 CRF 表达。最后，Aim 3 将使用病毒介导的基因转移来降低 CeA 中的 CRF 水平，以确定 E 的易感性增强作用是否取决于 CRF。微透析，目标 3 中的研究将确定 CeA 中 CRF 的增加是否对主要应激敏感靶标蓝斑 (LC) 将在 LC 中测量 CRF 释放和神经元活动。在应激/控制期间，将确定完整雌性是否在 LC 中表现出增加的 CRF 释放，以及这是否 CeA 中 shRNA CRF 敲低影响 LC 活性和 CRF 的能力。释放也将被评估，这些研究将提供有针对性的机制的证据。这些研究增加了女性对情感障碍和合并心功能障碍的易感性。提出了一种新颖且“可翻译”的途径，E可以通过该途径调节女性先天的压力脆弱性。