Sex, Hormones and GABA in Stress Induced Anhedonia in Depression

抑郁症中压力引起的快感缺乏中的性、激素和 GABA

• 批准号: 9175370
• 负责人: JILL M GOLDSTEIN
• 金额: $ 70.62万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-10 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175370
• 关键词: Adolescence; Adolescent; Adrenal Glands; Adrenal hormone preparation; Adult; Age; Amygdaloid structure; Anhedonia; Animals; Anterior; Arousal; Behavior; Brain; Characteristics; Clinical; Data; Development; Dimensions; Disease remission; Estradiol; Fasting; Feedback; Functional Magnetic Resonance Imaging; Functional disorder; Glucocorticoids; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Hippocampus (Brain); Hormonal; Housing; Hyperactive behavior; Hypothalamic structure; Image; Imaging Techniques; Incidence; Investigation; Laboratories; Life; Link; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Major Depressive Disorder; Measures; Medial; Mental Depression; Metabolism; National Institute of Mental Health; Neurobiology; Participant; Physiological; Physiology; Pituitary Gland; Pituitary Hormones; Prefrontal Cortex; Prevalence; Progesterone; Protons; Recruitment Activity; Regulation; Research Domain Criteria; Resolution; Rewards; Risk; Risk Factors; Role; Sex Characteristics; Signal Transduction; Steroids; Stress; Symptoms; Task Performances; Techniques; Testing; Testosterone; Time; Woman; Work; base; biological adaptation to stress; brain abnormalities; brain circuitry; burden of illness; cingulate cortex; depression model; gamma-Aminobutyric Acid; high risk men; hypercortisolemia; improved; innovation; insight; men; neurobiological mechanism; neurochemistry; novel; pre-clinical; preclinical study; prenatal; relating to nervous system; response; sex; steroid hormone; trait; transmission process; young adult; young woman

Project Summary Major depressive disorder (MDD) is the leading cause of disease burden worldwide and women have a 2-fold risk higher than men. Despite this, little is known about the neurobiological mechanisms associated with the sex-dependent emergence of MDD and in what form they persist after full remission. Preclinical studies have demonstrated dysregulated hypothalamic pituitary adrenal (HPA) circuitry (i.e., stress circuitry) and gamma- aminobutyric acid (GABA) in depression models. Critically, the stress circuitry houses some of the most highly sexually dimorphic regions in the brain. Using an innovative multi-modal imaging approach, the proposed study will investigate the role of GABA (assessed by proton magnetic resonance spectroscopy; MRS), functional brain activity deficits within key stress circuitry regions, as well as gonadal and adrenal hormones in understanding sex differences in MDD. Further, we will link these abnormalities to fundamental dimensions of behaviors (anhedonia and stress sensitivity) that capture key MDD vulnerabilities. Goals are to investigate: (1) functional and neurochemical features of sexually dimorphic regions within the stress circuitry irrespective of clinical state; (2) moderating effects of steroid hormonal dysfunction on stress circuitry in MDD; and (3) sex differences in anhedonic behavior and inability to regulate arousal under stress. To this end, 144 unmedicated young adults ages of 18-25, 96 with current or remitted MDD (rMDD), will be recruited, equally divided by sex. Capitalizing on a novel triple-voxel MRS technique affording improved temporal and spatial resolution, GABA transmission will be simultaneously assessed from three sexually dimorphic regions implicated in stress regulation (rostral anterior cingulate cortex (rACC), medial prefrontal cortex (mPFC), and hippocampus (HIPP)). In addition, functional MRI will be collected during a well-established stress paradigm. Participants will also undergo a probabilistic reward task under “no-stress” and “stressful” conditions. Gonadal and adrenal hormones will be collected during baseline and stress/reward tasks to relate sex-dependent hormonal abnormalities to task performance and imaging data. Based on our extensive preliminary data, we hypothesize that: 1) Relative to healthy women, women with MDD will show dysregulated (1a) activation and (1b) functional connectivity within the stress circuitry, and (1c) lower GABA signaling in HIPP, mPFC, and rACC. Further, we expect that (1d) predicted sex differences will emerge irrespective of current vs. remitted MDD status. (2) These neural abnormalities will be associated with physiological deficits in steroid hormone levels; and (3) Reduced GABA and lower activity in HIPP, mPFC, and rACC will predict greater stress-induced anhedonia, particularly among MDD women. Using categorical and dimensional analytic approaches, the proposed integration of laboratory-based measures of reward and stress sensitivity, state-of-the-art imaging techniques, and hormonal assessments promises to provide novel insights in the sex-dependent manifestation and pathophysiology of MDD.

项目摘要 重度抑郁症（MDD）是全球疾病负担的主要原因，女性有2倍的抑郁症风险。 风险高于男性。尽管如此，人们对与脑缺血相关的神经生物学机制知之甚少。 MDD的性别依赖性出现以及在完全缓解后以何种形式持续存在。临床前研究已经 表现出下丘脑垂体肾上腺（HPA）回路失调（即，应力电路）和伽马- 氨基丁酸（GABA）在抑郁症模型。重要的是，压力电路中有一些最高的 大脑中的两性异形区域使用创新的多模态成像方法， 将研究GABA的作用（通过质子磁共振波谱评估; MRS），功能 关键压力回路区域内的大脑活动缺陷，以及性腺和肾上腺激素， 了解MDD的性别差异。此外，我们将把这些异常与 行为（快感缺乏和压力敏感），这些行为捕获了关键的MDD漏洞。目的是调查：（1） 功能和神经化学特征的性二型区域内的压力电路，无论 临床状态;（2）类固醇激素功能障碍对MDD中压力回路的调节作用;（3）性别 在快感缺失行为和压力下无法调节唤醒方面的差异。为此，144名未接受药物治疗的 将招募年龄为18-25岁、96岁的患有当前或缓解的MDD（rMDD）的年轻成年人，按性别平均分配。 利用一种新的三体素MRS技术，提供了改善的时间和空间分辨率，GABA 传播将同时从三个与压力有关的性二态性区域进行评估 调节（头端前扣带皮层（rACC）、内侧前额叶皮层（mPFC）和海马 （HIPP））。此外，将在完善的应激模式下收集功能性MRI。参与者将 在“无压力”和“有压力”的条件下也经历概率奖励任务。性腺和肾上腺 将在基线和压力/奖励任务期间收集激素，以将性别依赖性激素 任务表现和成像数据异常。根据我们广泛的初步数据，我们假设 1）相对于健康女性，患有MDD的女性将表现出失调的（1a）激活和（1b）功能性 压力回路内的连接，和（1c）降低HIPP，mPFC和rACC中的GABA信号。我们还 预期（1d）无论当前MDD状态与缓解MDD状态如何，预测的性别差异都会出现。（二） 这些神经异常将与类固醇激素水平的生理缺陷相关;以及（3） GABA的减少和HIPP、mPFC和rACC的活性降低将预示着更大的应激诱导的快感缺失， 尤其是MDD女性。使用分类和维度分析方法，建议 整合实验室奖励和压力敏感性的措施，最先进的成像技术， 激素评估有望为性别依赖性表现提供新的见解， MDD的病理生理学