Sex, Hormones and GABA in Stress Induced Anhedonia in Depression

项目摘要 严重抑郁障碍(MDD)是世界范围内疾病负担的主要原因，女性有2倍于 风险比男性高。尽管如此，人们对与此相关的神经生物学机制知之甚少。 MDD的出现与性别有关，以及在完全缓解后以何种形式持续存在。临床前研究已经 显示出调节失调的下丘脑-垂体-肾上腺(HPA)回路(即，应激回路)和- 抑郁模型中的氨基丁酸(GABA)。关键的是，应力回路容纳了一些最高强度的 大脑中的性二相区域。使用创新的多模式成像方法，拟议的研究 将研究GABA的作用(通过质子磁共振波谱评估；MRS)，功能性 关键应激回路区域的脑活动缺陷，以及性腺和肾上腺激素 了解MDD的性别差异。此外，我们将把这些异常现象与 捕捉关键MDD漏洞的行为(快感缺失和压力敏感性)。目标是调查：(1) 应激环路中性二型区的功能和神经化学特征 临床状态；(2)类固醇激素失调对MDD应激回路的调节作用；(3)性别 在非享乐行为和在压力下无法调节唤醒方面的差异。为此，144人未服药 年龄在18-25岁的年轻人，96名患有当前或缓解的MDD(RMDD)的人将被招募，按性别平均分配。 利用一种新的三体素MRS技术提供更好的时间和空间分辨率，GABA 将同时评估与压力有关的三个性二态区域的传播情况 调节(嘴前扣带回皮质(RACC)、内侧前额叶皮质(MPFC)和海马区 (HIPP))。此外，功能磁共振成像将在建立良好的应激范例期间收集。参与者将 在“无压力”和“有压力”的条件下，也要接受概率奖励任务。性腺和肾上腺 荷尔蒙将在基线和压力/奖励任务中收集，以联系性别依赖荷尔蒙 任务性能和成像数据出现异常。基于我们广泛的初步数据，我们假设 1)与健康女性相比，患有MDD的女性将表现出(1a)激活和(1b)功能失调 应激通路内的连通性，以及(1c)HIPP、mPFC和rACC中较低的GABA信号。此外，我们 预计(1D)预测的性别差异将出现，无论当前MDD状态与缓解的MDD状态如何。(2) 这些神经异常将与类固醇激素水平的生理缺陷有关；以及(3) Hipp、mPFC和rACC中GABA的减少和活性的降低将预示着更大的应激性快感缺乏， 特别是在患有MDD的妇女中。使用范畴分析和量纲分析方法，拟议的 整合了基于实验室的奖励和压力敏感性测量、最先进的成像技术、 荷尔蒙评估有望为性别依赖的表现提供新的见解 MDD的病理生理学。

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.