Neural circuit mechanisms of inflexible drug seeking in a model of HIV infection

About This Grant

Project Summary Human immunodeficiency virus (HIV) infection frequently co-occurs with cocaine use disorder (CUD). Despite high rates of psychostimulant use among people living with HIV (PLWH), and the worsening of HIV outcomes by chronic drug exposure - including increased risk for neurocognitive impairment -, targeted therapeutic strategies to reduce drug use in PLWH are lacking. CUD is characterized by difficulty in terminating drug use and high propensity to relapse after even protracted abstinence. This can be modeled in rodents through extinction learning (persistent drug seeking) and reinstatement (relapse to use) models. Extinction and reinstatement are mediated in part by projections to the nucleus accumbens shell (NAcS) from the infralimbic subregion of the medial prefrontal cortex (IL). HIV infection and chronic drug exposure have independent and interactive effects on the brain and behavior, including regulation of reward seeking. Our previous and preliminary findings identify impaired extinction learning in multiple mouse models of HIV infection (humanized mouse model with HIV-1 infection and wild-type mice with EcoHIV infection). We further observe increased cocaine-primed reinstatement in the EcoHIV model. These behavioral changes are accompanied by dysregulation of the IL and NAc. Thus, this proposal will apply in vivo electrophysiology, tract tracing, and circuit-specific chemogenetics to test the overarching hypothesis that EcoHIV infection impacts activity in glutamatergic projections from the IL to the NAcS and that modulation of these projections is sufficient to suppress drug seeking in animals with EcoHIV infection. We propose that alterations in these circuits resulting from infection impair cognitive control of behavior which promotes the maintenance of and susceptibility to relapse to cocaine seeking. Aim 1 will determine the effects of EcoHIV and/or ART on IL encoding of cocaine reward and seeking behavior using in vivo electrophysiology to track neuronal activity across behavior. This Aim will further assess interactive effects of EcoHIV and/or ART exposure with a history of cocaine administration on later neurocognitive performance. Aim 2 will investigate the ability of modulation of ILNAcS circuit activity to suppress cocaine reinstatement in EcoHIV-infected mice. This will be accomplished using chemogenetic modulation of the IL and of IL projections to the NAcS and through local administration of an mGluR2/3 agonist to the NAc. Aim 3 will test the effects of EcoHIV and/or ART on cocaine-associated alterations in activity within IL to NAc circuitry. This will be accomplished using multiplexed tract tracing and immunofluorescent labeling. This Aim will further identify EcoHIV and ART effects on glutamate receptor expression within the prefrontal cortex and NAC using western blot. Together, the results of these experiments will inform the mechanisms by which EcoHIV alters cocaine seeking and taking behavior and expand our understanding of the circuit-level consequences of EcoHIV infection which may support next- generation CUD and HAND therapeutic development for PLWH.