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: 10707230
• 负责人: Joan Weinberger Berman
• 金额: $ 75.45万
• 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/10707230
• 关键词: Address; Anhedonia; Anterior; Anxiety; Astrocytes; Biological Response Modifiers; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; CD4 Lymphocyte Count; Cell Separation; 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; Testing; Trauma; Ventral Tegmental Area; Viral; Viral Load result; Vulnerable Populations; Water; Youth; arterial spin labeling; blood-brain barrier crossing; 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; migration; neural circuit; neurobiological mechanism; neuroimaging; neuroinflammation; neuromechanism; neuropsychiatry; novel; response; reward anticipation; reward circuitry; subthreshold depression; suicidal; 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.

项目概要/摘要 响应 RFA-DA-21-250， 我们建议调查 炎症、血脑屏障 (BBB) 通透性 HIV 感染者 (PWH) 和共病抑郁症患者的奖励功能。抑郁症是最常见的 感染者中神经精神疾病的发病率在某些人群中平均患病率高达 78%。令人震惊的是，它 据估计，到 2030 年，全球疾病负担的两大主要原因将是艾滋病毒和抑郁症 失调。这些数据凸显了迫切需要关注神经生物学机制的研究 HIV/抑郁症合并症。我们的建议解决了这一需求。我们提出的模型：(1) HIV 感染诱发 全身炎症[外周血单核细胞（PBMC）、细胞因子]； (2)全身炎症 通过 BBB 迁移 PBMC 亚型延伸至 CNS； (3)血脑屏障完整性破坏 神经炎症会导致奖赏回路发生改变，从而导致感染者抑郁症。支持中 基于该模型，我们课题组率先开展了 PWH 中 BBB 的研究，建立了高度可重复且可靠的模型 人类 BBB 的体外模型，由人脑微血管内皮细胞和 人类星形胶质细胞。我们发现，与健康对照 (HC) 相比，来自 PWH 的特定 PBMC 亚型 尽管病毒载量受到抑制，但仍优先穿过 BBB 模型。在我们的抑郁症研究中，我们 发现快感缺乏——反映奖励缺陷的抑郁症的核心症状——与更差的 抑郁症的结果，包括慢性和自杀倾向。为了更好地描述奖励电路，我们确定了 使用基于纹状体的内在与抑郁和快感缺乏相关的不同静息态网络特征 功能连接和全脑分区数据驱动的图论分析。我们还利用了 奖励侧卫（RFT）和奖励预测误差（RPET）功能磁共振成像任务来检查不同的大脑活动 奖励预期、成就和预测错误。此外，我们报告了之间的关联 循环细胞因子在青年时期具有快感缺失和奖赏神经回路。此外，我们的团队还有 实施动态对比增强 (DCE) MRI 和相衬动脉自旋水提取 标记 (WEPCAST​​) MRI，分别实现体内局部和全局 BBB 通透性。扩展我们的 令人信服的发现专业知识，我们将测试总体假设，即 PWH 表现出系统性增加 炎症和血脑屏障破坏（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 因子设计：1) 100 抑制 PWH； 2) 100名非抑郁孕妇； 3) 50 名抑郁的艾滋病毒患者 消极的人； 4) 50 HC。我们将包括阈下抑郁症以捕获广泛的抑郁症 严重程度。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) 和免疫测定。神经影像将包括 DCE-MRI、WEPCAST​​ 和 fMRI。