The Neuroimmunology of Depression in Women Living With HIV

项目总结/摘要 回应RFA-DA-21-116，“艾滋病毒感染者的情绪障碍：机制和途径”， 我们 建议调查神经免疫学和奖励功能，以研究生活在 艾滋病毒感染者（WLWH），一个受抑郁症及其健康后果严重影响的群体，但代表性不足 艾滋病研究。拟议的研究将建立在已建立的多中心艾滋病队列研究的基础上 （MACS）/妇女机构间HIV研究（WIHS）联合队列研究（MWCCS）（Sharma博士，布朗克斯MPI MWCCS）及其独特的表型特征良好的妇女与艾滋病毒。我们提出的 模型是：（1）HIV感染诱导全身炎症（细胞因子，犬尿氨酸）;（2）全身炎症 延伸至CNS，诱导氧化应激[↓谷胱甘肽（GSH，抗氧化剂）]和γ-氨基丁酸 (GABA主要抑制性神经递质）缺陷;（3）这种神经化学变化改变了奖赏回路， 这导致了WLWH中抑郁症的高患病率。为了支持这个模型，我们的免疫学 WIHS的工作发现，与没有艾滋病毒的妇女相比，WLWH中的犬尿氨酸途径（KP）活性增加， 在WLWH中，KP活性以WLWH伴抑郁组较高。在我们的抑郁症非艾滋病研究中，我们 发现快感缺失--抑郁症的一个核心症状，反映了奖励不足--与更糟糕的 抑郁结果，包括慢性和自杀倾向。为了更好地描述奖励回路，我们确定了 使用基于纹状体的内源性神经元研究与抑郁和快感缺乏相关的不同静息态网络特征 功能连接和全脑分组数据驱动的图论分析。我们还利用了 奖励侧翼（RFT）和奖励预测错误（RPET）功能磁共振成像任务，以检查不同的大脑活动， 奖励预期，实现和预测错误，预测未来抑郁症的严重程度。利用质子 磁共振波谱，我们发现，快感缺失占减少前扣带皮层（ACC）GABA 水平，此外，我们记录了皮质GSH和 成年抑郁症患者的快感缺失严重程度。此外，我们报告了循环细胞因子之间的关联， 以及犬尿氨酸在年轻时同时具有快感缺乏和奖赏神经回路。扩展我们令人信服的发现，我们 现在将检验WLWH表现出全身和CNS炎症增加的总体假设，这导致 来奖励功能障碍和随之而来的抑郁症我们将采用2×2析因设计：1）100个受试者 WLWH; 2）100名非抑郁的WLWH; 3）50名抑郁的HIV阴性妇女;和4）50名非抑郁的HIV-1感染者。 消极的女人参与者将在基线、6个月和12个月进行全面评估， 抑郁、奖励、焦虑、创伤、HIV治疗、CD 4+计数和VL。F-MRI（静息状态，RFT，RPET），1H 将在基线时进行MRS（GABA、GSH）、奖励计算机任务和认知测试。

PROJECT SUMMARY / ABSTRACT In response to RFA-DA-21-116, “Mood Disorders in People Living with HIV: Mechanisms and Pathways”, we propose to investigate neuroimmunological and reward functions to study comorbid depression in women living with HIV (WLWH), a group heavily impacted by depression and its health consequences, yet underrepresented in HIV research. The proposed research will build upon the established Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS) (Dr. Sharma, MPI of Bronx MWCCS) and its unique cohort of phenotypically well-characterized women with and without HIV. Our proposed model is: (1) HIV infection induces systemic inflammation (cytokines, kynurenines); (2) systemic inflammation extends to the CNS inducing oxidative stress [↓glutathione (GSH, antioxidant)] and gamma-aminobutyric acid (GABA, major inhibitory neurotransmitter) deficits; (3) such neurochemical changes alter the reward circuitry, which contribute to the high prevalence of depression in WLWH. In support of this model, our immunological work in the WIHS found increased kynurenine pathway (KP) activity in WLWH compared to women without HIV, and among WLWH, KP activity was higher in WLWH with depression. In our depression non-HIV research, we found that anhedonia–a core symptom of depression reflecting reward deficits–was associated with worse depression outcomes, including chronicity and suicidality. To better delineate reward circuitry, we identified distinct resting-state network features associated with depression and anhedonia using striatal-based intrinsic functional connectivity and whole-brain parcellation data-driven graph theory analysis. We additionally utilized the reward flanker (RFT) and reward prediction error (RPET) fMRI tasks to examine distinct brain activity during reward anticipation, attainment, and prediction errors, which predicted future depression severity. Utilizing proton MR spectroscopy, we showed that anhedonia accounted for decreased anterior cingulate cortex (ACC) GABA levels in adolescent depression, and moreover, we documented inverse relationships between cortical GSH and anhedonia severity in depressed adults. Furthermore, we reported associations between circulatory cytokines and kynurenines with both anhedonia and reward neurocircuitry in youth. Extending our compelling findings, we will now test the overall hypothesis that WLWH exhibit increased systemic and CNS inflammation, which leads to reward dysfunction and subsequently depression. We will utilize a 2×2 factorial design: 1) 100 depressed WLWH; 2) 100 non-depressed WLWH; 3) 50 depressed HIV negative women; and 4) 50 non-depressed HIV- negative women. Participants will have comprehensive evaluations at baseline, 6- and 12-months assessing depression, reward, anxiety, trauma, HIV treatment, CD4+ count, and VL. F-MRI (resting-state, RFT, RPET), 1H MRS (GABA, GSH), a reward computerized task and cognitive tests will be done at baseline.