Corticolimbic circuit and neuroimmune mechanisms of comorbid HIV and cocaine use - Project Summary/Abstract Cocaine use disorders (CUDs) and human immunodeficiency virus (HIV) are persistent public health concerns worldwide. Psychostimulants such as cocaine can facilitate viral replication and neuroinvasion into the central nervous system, which can exacerbate HIV-associated neurocognitive dysfunction that is observed even among those virally suppressed under antiretroviral therapy (ART). Unlike other addictive substances, cocaine does not have effective FDA-approved medications for helping individuals reduce their cocaine use or maintain long-term abstinence. Moreover, it is possible that comorbidities such as HIV may impair the efficacy of medications that may be otherwise effective at treating CUDs (e.g., Namba et al., 2023, Addiction Neuro.). Taken together, identifying the unique cellular- and circuit-specific mechanisms underlying drug seeking and relapse-like behavior in the context of HIV is imperative for developing targeted and effective treatments for vulnerable subpopulations of individuals, such as PLWH suffering from CUDs. This proposal aims to elucidate corticostriatal and neuroimmune mechanisms underlying HIV-induced dysregulation of reward seeking, with the ultimate goal of identifying novel CUD treatment targets for PLWH. My preliminary work has revealed that mice infected with the chimeric HIV construct, EcoHIV, display potentiated cocaine-seeking behavior, impaired extinction learning, as well as dysregulated peripheral and corticolimbic neuroimmune function. A wide breadth of studies demonstrate that activity of neuronal projections from the infralimbic cortex (IL) region of the prefrontal cortex (PFC) to the nucleus accumbens shell (NAcSh) are necessary for both the acquisition and expression of extinction learning and facilitate refraining from drug seeking. As well, PFC dysfunction is also heavily implicated in HIV at both the clinical and preclinical level. In Aim 1 of this proposal, I will use circuit-specific, closed-loop optogenetics to stimulate the IL→NAcSh circuit to rescue EcoHIV-induced deficits in extinction learning in male and female mice. Given the putative role of microglia in HIV-associated neuropathology, I will also explore EcoHIV- and cocaine-induced plasticity of NAcSh microglia in Aim 2. Here, I will employ a combination of designer receptors exclusively activated by designer drugs (DREADDs) expressed specifically in microglia with quantitative microglial morphometry to 1) characterize how microglial morphology changes due to cocaine and EcoHIV infection and 2) determine whether Gi-coupled DREADD stimulation on microglia suppresses EcoHIV- induced potentiation of cocaine seeking. This research has the potential to reveal novel corticolimbic circuit and neuroimmune mechanisms underlying HIV-induced dysregulation of reward-seeking behavior, which will advance our understanding of, and identification of treatment targets for, comorbid HIV and CUDs. Throughout the proposed training period, I will be trained in techniques such as mouse stereotaxic surgery, closed-loop optogenetics, chemogenetics, and quantitative imaging and analysis of microglial morphology.
