Microglial modulation of neurocircuits in HIV/cocaine comorbidity

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Project Summary: Despite the success of combination antiretroviral therapy (cART), a significant proportion of infected individuals exhibiting neurocognitive decline, and a prior history of substance use disorder (SUD) may result in an exacerbated rate of decline. Thus, prior drug history may be clinically significant in the treatment of neurological HIV-1 infection. The specific aims of the project are: 1) To define the dendritic “spine- targeted” - microglial interactions which produce HIV-1/psychostimulant-induced synaptodendritic loss and spine dysmorphology. Dendritic spine loss is a key pathology of HAND; however, the underlying mechanisms remain largely uncharacterized. We will investigate whether HIV-infected microglia play a key role in spine loss/dysmorphology using an in vitro HIV infection model and psychostimulant drug exposures in sex- specified brain cell cultures. 2) To establish whether a history of psychostimulant abuse drives an accelerated progression of microglial dysfunction and dendritic spine alterations following HIV infection. Dopamine will be assessed both prior to and after EcoHIV-infection in animals with or without a history of cocaine self-administration. The mechanisms by which HIV-infected microglia produce dopaminergic circuit dysfunction will be critically tested using proviral gene excision techniques; cART, and SABV are integral factors of the design. 3) To establish executive function “choice” deficits in EcoHIV-infected animals, and the role of microglial HIV infection, following psychostimulant self-administration. We will establish prior drug history and HIV-1 infection as variables that influence the effect of fronto-striatal circuit dysregulation on choice behavior, thereby identifying factors that may exacerbate resistance to treatment. We will examine synaptodendritic integrity in pyramidal neurons of the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) of the nucleus accumbens given their sensitivity to drug history and/or HIV-1 infection. Targeted proviral gene excision of HIV from microglial cells will be used to determine the role of infected microglial cells in executive function deficits. Thus, this proposal addresses two key questions regarding neuroHIV – 1) does a history of drug dependence alter the progression and clinical outcomes of HIV-1- associated neurocognitive disorders? and 2) how do substances of abuse and HIV interact to produce dendritic spine alterations, one of the key neuropathologies of neuroHIV in the current cART era? The program goal is to identify how microglial HIV infections produce synaptodendritic loss; knowledge that will lead to novel therapeutic strategies for restoring fronto-striatal circuitry.