PROJECT SUMMARY The public health burden of mood disorders, such as depression, anxiety, and apathy, among people with HIV (PWH) remains high, despite control of the virus. Neuropsychiatric disorders or symptoms (NPS), afflict 30- 60% of PWH and have risen in prevalence, owing to increased longevity in the combination antiretroviral therapy era. Furthermore, mood disorders and cognitive impairment frequently co-occur in PWH, are often treatment- resistant, and present substantial challenges to clinical care overall, due to adverse impacts on adherence to treatment, quality of life, and functional status. However, the causative mechanisms underlying NPS in virally suppressed (VS) PWH, and new therapeutic targets, remain elusive. Mood disorders in people without HIV are known to involve altered iron metabolism, and our preliminary studies implicate iron imbalances in cognitive impairment and depression in PWH. Iron is essential for neurotransmitter balance, synthesis and maintenance of myelin by oligodendrocytes, and energy metabolism in the brain. Iron regulation is disrupted by HIV infection, neuro-inflammation, and a leaky blood-brain barrier (BBB). It is unknown, however, whether HIV-related changes in iron transport influence brain iron accumulation, which is linked to many cognitive disorders. Quantitative Susceptibility Mapping magnetic resonance imaging (QSM/MRI) is a powerful, state-of-the-art neuroimaging technique which can address this research gap by providing the means to quantify regional brain iron deposition (or load). Specifically, we will 1) Determine alterations in regional brain iron load in VS-PWH versus HIV-negative individuals, and the contribution of these alterations to reward and cognitive processes, and 2) Determine the contributions of brain iron, oligodendrocyte iron-delivery proteins, and altered myelin and dopamine/serotonin homeostasis to disrupted reward and cognitive processes in VS-PWH versus HIV-negative individuals. The project will employ existing QSM data and behavioral metrics in RDoC cognitive systems from participants in an ongoing NIH-funded study, to which we will add behavioral measures in reward processing and biomarkers of iron delivery, myelin maintenance and mono-amines relevant to frontostriatal function. We will test the central hypotheses that higher brain iron load in frontostriatal regions will significantly contribute to changes in reward as well as cognitive processes, which are strongly reliant on prefrontal regions (cognitive control, working memory, attention) in PWH. Findings from this study will provide the basis for future in-depth mechanistic investigations of mood disorders in VS-PWH and suggest potential therapeutic targets.