Neuroimmune mechanisms involved in the complex co-morbidity Involving OUD, MDD, and HIV

Univ Of Massachusetts Med Sch Worcester, Worcester MA

Investigators

Abstract

The prevalence of co-occurring psychiatric and/or substance use disorders in people living with HIV (PLWH) is a significant health problem. PLWH with a diagnosis of major depressive disorder (MDD) are at increased risk of developing opioid use disorder (OUD). Both MDD and OUD are also major risk factors for acquiring and transmitting HIV. Despite clinical evidence, the mechanisms in the brain that underlie these relationships between HIV and co-occurring MDD and/or OUD are unknown and severely understudied. While these disorders are generally investigated in isolation, very little work has been performed at the intersection of these disorders, especially in human brain. To address this gap, we propose to directly investigate the cellular and molecular mechanisms of co-occurring MDD, OUD, and HIV using a combination of multi-omics and histological approaches in postmortem human brain tissues. Our investigations will focus on a region critically involved in emotional dysregulation, anhedonia, altered motivation, and impaired cognition, hallmarks of each disorder—the subgenual anterior cingulate cortex (sgACC). The sgACC is also critically involved in resilience to stress in various psychiatric disorders including MDD and OUD. With the advent of single cell sequencing technologies, recent studies in postmortem human brain have shed new light on molecular mechanisms across cell types associated with HIV, OUD, or MDD. Further, evidence suggests microglia are primary effectors of proinflammatory and stress-related cascades in brain related to these disorders. Indeed, across HIV, MDD, and OUD, evidence is consistent with a model in which upstream factors (e.g., virus, stress, drugs) impact activity of microglia, which in turn participate in excessive pathologic removal of synapses. But again, those studies were not performed in clinically-relevant populations of individuals with HIV and co-occurring OUD and MDD. Thus, it is important to investigate microglia and dendritic spines not just in each disorder in isolation, but rather at the intersection of OUD, HIV, and MDD. Thus, we designed a cohort which includes 5 groups: 1) subjects with all three disorders (HIV+/OUD+/MDD+); 2) subjects with co-occurring HIV and OUD (HIV+/OUD+/MDD-); 3) subjects with co-occurring HIV and MDD (HIV+/OUD-/MDD+); 4) subjects with only HIV (HIV+/OUD-/MDD-); 5) unaffected comparison subjects (HIV-/OUD-/MDD-). Use of this innovative cohort will provide essential comparisons for disentangling whether co-occurrence of these disorders causes additive or synergistic effects. In Aim 1, we will use single nuclei RNA-sequencing (snRNA-seq) to investigate cell type-specific transcriptional alterations in the sgACC. In Aim 2, we will use snATAC-seq to assess cell type-specific chromatin accessibility alterations and integrate findings with human genetic risk variants for psychiatric, substance use, and psychosocial traits. In Aim 3, we will take a more targeted approach to investigate alterations in microglia and dendritic spines. Collectively, these results will improve our understanding of disease-related mechanisms in the brain, while paving the way for improving on current and new therapies.