The Neuroimmunology of Depression in Women Living With HIV

项目摘要/摘要 关于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赏功能，以研究生活在女性中的共病抑郁症 艾滋病毒(WLWH)，这一群体受到抑郁症及其健康后果的严重影响，但代表性不足 在艾滋病研究方面。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)/妇女机构间艾滋病毒研究(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感染和不感染艾滋病毒的妇女队列。我们的建议 模型是：(1)HIV感染引起全身炎症(细胞因子、犬尿氨酸)；(2)全身炎症 延伸到中枢神经系统引起的氧化应激[谷胱甘肽(↓，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奖赏回路， 这导致了WLWH中抑郁症的高患病率。为了支持这一模式，我们的免疫学 WIHS的研究发现，与未感染艾滋病毒的女性相比，WLWH的犬尿氨酸途径(KP)活性增加， 在WLWH中，伴有抑郁的WLWH的KP活性较高。在我们的抑郁症非艾滋病毒研究中，我们 研究发现，快感缺乏--反映奖赏不足的抑郁症的核心症状--与更糟糕的情况有关 抑郁结果，包括慢性病和自杀倾向。为了更好地描述奖励回路，我们发现 基于纹状体的内源性研究发现抑郁症和快感缺乏相关的不同的静息状态网络特征 功能连通性和全脑分割数据驱动图论分析。我们还利用了 奖励侧翼(RFT)和奖励预测误差(RPET)fMRI任务，以检查不同的大脑活动 奖励预期、成就和预测错误，它们预测未来抑郁的严重程度。利用质子 磁共振波谱显示快感缺乏是前扣带回(ACC)GABA降低的原因 青春期抑郁症的水平，此外，我们记录了皮质GSH和GSH之间的反向关系 抑郁症成人快感缺乏的严重程度。此外，我们还报道了循环细胞因子之间的联系。 而犬尿氨酸在青年时期既有快感缺乏又有奖赏神经回路。扩展我们令人信服的发现，我们 现在将检验WLWH表现出全身和中枢神经系统炎症增加的总体假设，这导致 奖励功能障碍和随后的抑郁症。我们将采用2×2析因设计：1)100人抑郁 WLWH；2)100名非抑郁WLWH；3)50名抑郁的HIV阴性妇女；以及4)50名非抑郁的HIV- 消极的女人。参与者将在基线、6个月和12个月评估时进行全面评估 抑郁、奖励、焦虑、创伤、HIV治疗、CD4+计数和VL。F-MRI(静息状态、RFT、RPET)，1H MRS(GABA，GSH)，一项奖励计算机化任务和认知测试将在基线上进行。

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.