PROJECT SUMMARY Substance use disorders (SUDs) occur in the HIV-infected population at nearly twice the rate of the uninfected population. Nearly 50% of HIV+ individuals will develop HIV-associated neurocognitive disorders (HAND) characterized by impairments in memory and attention, deficits in executive control over behavior, and reductions in cognitive flexibility. Deficits in cognitive control over behavior may maintain addiction by promoting compulsive drug seeking and poor combined antiretroviral therapy (cART) adherence which further exacerbates disease progression. Despite the potential contribution of HIV infection to compulsive drug seeking, little research has investigated the neural mechanisms underlying this relationship as animal models of progressive HIV infection are limited. Many neurocognitive impairments observed in HAND are likely mediated by impairments in corticostriatal structure and function. Individuals with HIV show structural and functional impairments in the prefrontal cortex (PFC). Animal models of HIV infection exhibit spine loss and reductions in dendritic branching in prefrontal subregions. SUDs are associated with similar changes to the PFC, including cortical atrophy and aberrant dendritic morphology. The dopaminergic system appears to be particularly vulnerable to dysregulation by HIV infection. Alterations in dopamine (DA) signaling in corticostriatal circuits likely contribute to impairments in behavioral and cognitive flexibility. Indeed, PFC DA mediates the ability to flexibly regulate behavior, including compulsive-like reward seeking that persists despite adverse consequences. This proposal will determine whether progressive HIV-infection promotes compulsive-like cocaine seeking and alters corticostriatal regulation of drug seeking. To do this, humanized mice infected with HIV will be trained in a modified conditioned place preference task which allows assessment of reward-related learning and compulsive-like behavior. We will further determine whether HIV infection alters the ability of DA D2/D3 receptor agonists to reduce compulsive- like behaviors. Additionally, we will determine whether HIV interacts with exposure to a reward-paired context to drive changes in corticostriatal activity, as measured by expression of a putative marker of neural activity and of PSA-NCAM, a modified form of a cell adhesion molecule critically involved in DA-induced plasticity. This will enable direct investigation into the relationship between neuronal consequences of HIV infection with changes in reward learning and compulsive cocaine seeking. The development of this novel mouse model of HIV infection- induced changes in neurocognitive function and drug seeking will enable further elucidation of the precise neural circuits and substrates that are altered following HIV, and how these changes contribute to drug seeking. Future research using this model will investigate the impact of cART and existing treatment strategies on n...