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

项目摘要/摘要 响应RFA-DA-21-250， 我们建议调查 炎症、血脑屏障(BBB)通透性 以及艾滋病毒(PWH)患者和共病抑郁症患者的奖励功能。抑郁症是最常见的 威尔斯亲王的神经精神疾病，在一些队列中的平均患病率高达78%。令人震惊的是，它 据估计，到2030年，全球疾病负担的前两大原因将是艾滋病毒和抑郁症 精神错乱。这些数据突显了迫切需要集中研究以下神经生物学机制 艾滋病毒/抑郁症共病。我们的建议满足了这一需求。我们提出的模型：(1)HIV感染诱导 全身炎症[外周血单核细胞、细胞因子]；(2)全身炎症 通过血脑屏障使PBMC亚型迁移至中枢神经系统；(3)血脑屏障完整性中断 神经炎症导致奖赏回路的改变，导致PWH的抑郁。在支持中 在该模型中，我们课题组首创了PWH中血脑屏障的研究，建立了具有高度重复性和可靠性的 人血脑屏障的体外模型，包括人脑微血管内皮细胞和人血脑屏障的联合培养 人类星形胶质细胞。我们发现，与健康对照组(HC)相比，PWH患者的特定PBMC亚群 优先跨血脑屏障模型转生，尽管病毒载量受到抑制。在我们的抑郁症研究中，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。此外，我们报告了两者之间的联系 循环细胞因子与快感缺乏和青年奖赏神经回路。此外，我们团队还拥有 实施动态增强磁共振成像和water-extraction-with-phase-contrast-arterial-spin- 标记(WEPCAST)磁共振成像，分别实现体内局部和全球血脑屏障通透性。扩展我们的 令人信服的发现专业知识，我们将检验PWH表现出系统性增强的总体假设 炎症和血脑屏障破坏(在体内和体外评估)，导致奖赏功能障碍和抑郁。 我们将采用2×2析因设计：1)100个抑郁的PWH；2)100个非抑郁的PWH；3)50个抑郁的HIV 阴性者；4)50例HC。我们将包括阈值下抑郁症，以捕获广泛的抑郁症 严肃性。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， CD4+计数、病毒载量(VL)和免疫分析。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.