Inflammation, BBB disruption, and Reward Function in the Pathogenesis of Depression among PWH

项目总结/摘要 响应RFA-DA-21-250， 我们建议调查 炎症，血脑屏障（BBB）通透性 和奖励功能在艾滋病毒（PWH）和共病抑郁症的人。抑郁症是最常见的 威尔斯亲王医院的神经精神病患病率最高，在某些组别中，平均患病率高达78%。令人担忧的是， 据估计，到2030年，全球疾病负担的两大主要原因将是艾滋病毒和抑郁症。 紊乱这些数据突出了研究的迫切需要，重点是神经生物学机制的基础 HIV/抑郁症共病。我们的建议满足了这一需要。我们提出的模型：（1）HIV感染诱导 全身炎症[外周血单核细胞（PBMC），细胞因子];（2）全身炎症 通过PBMC亚型通过BBB的迁移延伸到CNS;（3）破坏BBB的完整性 和神经炎症导致奖励回路的改变，导致PWH的抑郁症。支持 在这个模型中，我们的团队开创了PWH中BBB的研究，建立了一个高度可重复和可靠的 人BBB的体外模型，包括人脑微血管内皮细胞的共培养物， 人类星形胶质细胞我们发现，与健康对照组（HC）相比，PWH的特异性PBMC亚型 尽管病毒载量受到抑制，但它优先穿过BBB模型。在我们的抑郁症研究中，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。此外，我们报告了 循环细胞因子与青少年快感缺乏和奖赏神经回路。此外，我们的团队还 实施动态对比增强（DCE）MRI和水提取与相位对比动脉自旋， 标记（WEPCAST）MRI，分别实现体内区域和整体BBB渗透性。扩展我们 令人信服的研究结果的专业知识，我们将测试的整体假设，PWH表现出增加系统性 炎症和BBB破坏（体内和体外评估），导致奖励功能障碍和抑郁症。 我们将采用2×2析因设计：1）100例抑郁性PWH; 2）100例非抑郁性PWH; 3）50例抑郁性HIV 阴性者; 4）50 HC。我们将包括阈下抑郁症，以捕捉广泛的抑郁症 严重性。研究程序将评估精神病理学，奖励，焦虑，创伤，认知，艾滋病毒治疗， CD 4+计数、病毒载量（VL）和免疫测定。神经成像将包括DCE-MRI、WEPCAST和fMRI。

PROJECT SUMMARY/ABSTRACT In response to RFA-DA-21-250, we propose to investigate inflammation, blood-brain-barrier (BBB) permeability and reward functions in people with HIV (PWH) and comorbid depression. Depression is the most common neuropsychiatric illness among PWH, with an average prevalence of up to 78% in some cohorts. Alarmingly, it is estimated that by 2030, the top two leading causes of disease burden globally will be HIV and depressive disorders. These data highlight the urgent need for research focusing on neurobiological mechanisms underlying HIV/depression comorbidity. Our proposal addresses this need. Our proposed model: (1) HIV infection induces systemic inflammation [peripheral blood mononuclear cells (PBMC), cytokines]; (2) systemic inflammation extends to the CNS through transmigration of PBMC subtypes through the BBB; (3) disruption of BBB integrity and neuroinflammation lead to alterations in the reward circuitry, contributing to depression in PWH. In support of this model, our group has pioneered the study of BBB in PWH, establishing a highly reproducible and reliable in vitro model of the human BBB, comprised of a co-culture of human brain microvascular endothelial cells and human astrocytes. We showed that compared to healthy controls (HC), specific PBMC subtypes from PWH preferentially transmigrate across the BBB model, despite suppressed viral load. In our depression 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. Furthermore, we reported associations between circulatory cytokines with both anhedonia and reward neurocircuitry in youth. In addition, our team has implemented dynamic contrast-enhanced (DCE) MRI and a water-extraction-with-phase-contrast-arterial-spin- tagging (WEPCAST) MRI, enabling in vivo regional and global BBB permeability, respectively. Extending our compelling findings expertise, we will test the overall hypothesis that PWH exhibit increased systemic inflammation and BBB disruption (assessed in vivo and in vitro), leading to reward dysfunction and depression. We will utilize a 2×2 factorial design: 1) 100 depressed PWH; 2) 100 non-depressed PWH; 3) 50 depressed HIV negative people; and 4) 50 HC. We will include subthreshold depression to capture a wide range of depression severity. Study procedures will assess psychopathology, reward, anxiety, trauma, cognition, HIV treatment, CD4+ count, viral load (VL), and immune assays. Neuroimaging will include DCE-MRI, WEPCAST and fMRI.