The Neuroimmunology of Depression in Women Living With HIV
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PROJECT SUMMARY / ABSTRACT In response to RFA-DA-21-116, “Mood Disorders in People Living with HIV: Mechanisms and Pathways”, we propose to investigate neuroimmunological and reward functions to study comorbid depression in women living with HIV (WLWH), a group heavily impacted by depression and its health consequences, yet underrepresented in HIV research. The proposed research will build upon the established Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS) (Dr. Sharma, MPI of Bronx MWCCS) and its unique cohort of phenotypically well-characterized women with and without HIV. Our proposed model is: (1) HIV infection induces systemic inflammation (cytokines, kynurenines); (2) systemic inflammation extends to the CNS inducing oxidative stress [↓glutathione (GSH, antioxidant)] and gamma-aminobutyric acid (GABA, major inhibitory neurotransmitter) deficits; (3) such neurochemical changes alter the reward circuitry, which contribute to the high prevalence of depression in WLWH. In support of this model, our immunological work in the WIHS found increased kynurenine pathway (KP) activity in WLWH compared to women without HIV, and among WLWH, KP activity was higher in WLWH with depression. In our depression non-HIV 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, which predicted future depression severity. Utilizing proton MR spectroscopy, we showed that anhedonia accounted for decreased anterior cingulate cortex (ACC) GABA levels in adolescent depression, and moreover, we documented inverse relationships between cortical GSH and anhedonia severity in depressed adults. Furthermore, we reported associations between circulatory cytokines and kynurenines with both anhedonia and reward neurocircuitry in youth. Extending our compelling findings, we will now test the overall hypothesis that WLWH exhibit increased systemic and CNS inflammation, which leads to reward dysfunction and subsequently depression. We will utilize a 2×2 factorial design: 1) 100 depressed WLWH; 2) 100 non-depressed WLWH; 3) 50 depressed HIV negative women; and 4) 50 non-depressed HIV- negative women. Participants will have comprehensive evaluations at baseline, 6- and 12-months assessing depression, reward, anxiety, trauma, HIV treatment, CD4+ count, and VL. F-MRI (resting-state, RFT, RPET), 1H MRS (GABA, GSH), a reward computerized task and cognitive tests will be done at baseline.
