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

感染者抑郁症发病机制中的炎症、血脑屏障破坏和奖赏功能

• 批准号: 10535898
• 负责人: Joan Weinberger Berman
• 金额: $ 84.46万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535898
• 关键词: Address; Anhedonia; Anterior; Anxiety; Astrocytes; Biological Response Modifiers; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; CD4 Lymphocyte Count; Cells; Chronic; Coculture Techniques; Cognition; Corpus striatum structure; Data; Depressed mood; Depressive disorder; Development; Discipline; Evaluation; Exhibits; Flow Cytometry; Functional Magnetic Resonance Imaging; Functional disorder; HIV; HIV Infections; HIV Seronegativity; Health; Heterogeneity; Human; Immune; Immunology; Immunology procedure; Impairment; In Vitro; Inflammation; Lead; Learning; Machine Learning; Magnetic Resonance Imaging; Measures; Mediating; Mental Depression; Mental Health; Modeling; Nucleus Accumbens; Outcome; Participant; Pathogenesis; Peripheral; Peripheral Blood Mononuclear Cell; Permeability; Persons; Phase; Prevalence; Procedures; Process; Psychiatry; Psychopathology; Reporting; Reproducibility; Research; Rest; Rewards; Role; Sampling Studies; Severities; Side; Suicide; Testing; Trauma; Ventral Tegmental Area; Viral; Viral Load result; Vulnerable Populations; Water; Youth; arterial spin labeling; base; blood-brain barrier disruption; blood-brain barrier permeabilization; brain endothelial cell; burden of illness; causal model; chemokine; clinically relevant; cohort; comorbid depression; computerized; contrast enhanced; cytokine; depressive symptoms; design; graph theory; improved; in vitro Model; in vivo; indexing; neural circuit; neurobiological mechanism; neuroimaging; neuroinflammation; neuromechanism; neuropsychiatry; novel; response; reward anticipation; reward circuitry; subthreshold depression; systemic inflammatory response; targeted treatment

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.

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）渗透率 并奖励艾滋病毒（PWH）和合并抑郁症患者的功能。抑郁是最常见的 PWH中的神经精神疾病，某些队列中的平均患病率高达78％。令人震惊的是 据估计，到2030年，全球疾病燃烧的前两个主要原因将是艾滋病毒和抑郁症 疾病。这些数据凸显了迫切需要研究关注神经生物学机制的研究 艾滋病毒/抑郁症合并症。我们的建议满足了这一需求。我们提出的模型：（1）HIV感染影响 全身性炎症[外周血单核细胞（PBMC），细胞因子]； （2）系统性炎症 通过通过BBB传播PBMC亚型，扩展到中枢神经系统； （3）BBB完整性的破坏 神经炎症导致奖励电路的改变，导致PWH抑郁症。支持 在该模型中，我们的小组在PWH中率先研究了BBB的研究，建立了高度繁殖和可靠的 人类BBB的体外模型，由人脑微血管内皮细胞和 人星形胶质细胞。我们表明，与健康对照（HC）相比，PWH的特定PBMC亚型 在BBB模型中优先翻译，任务抑制了病毒载荷。在我们的抑郁研究中，我们 发现抗抑郁症的核心症状反映奖励定义的核心症状与更糟糕的相关 抑郁症结果，包括慢性和自杀。为了更好地描述奖励电路，我们确定了 使用纹状体基因 功能连通性和全脑拟合数据驱动的图理论分析。我们还利用 奖励侧翼（RFT）和奖励预测错误（RPET）fMRI任务，以检查在不同的大脑活动中 奖励预期，尝试和预测错误。此外，我们报告了 与Anhedonia和年轻人的循环细胞因子既有神经通路”。此外，我们的团队有 实施动态对比增强（DCE）MRI和与相对对比度 - 旋转旋转的水萃取 标记（WEPCAST​​）MRI，分别启用体内区域和全球BBB渗透性。扩展我们 引人入胜的发现专业知识，我们将测试PWH暴露增加全身性的总体假设 炎症和BBB破坏（在体内和体外评估），导致功能障碍和抑郁症。 我们将使用2×2阶乘设计：1）100抑郁型PWH； 2）100个不抑郁的PWH; 3）50个抑郁艾滋病毒 消极的人； 4）50 HC。我们将包括亚阈值抑郁症，以捕获广泛的抑郁症 严重程度。研究程序将评估心理病理学，奖励，动画，创伤，认知，艾滋病毒治疗， CD4+计数，病毒载荷（VL）和免疫测定。神经影像学将包括DCE-MRI，Wepcast和fMRI。