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.

项目总结/文摘