Deconvoluting Dopaminergic Neuronal-Glial Interactions in the Striatum

About This Grant

More than 50% of people living with HIV (PLWH) encounter cognitive dysfunction, and chronic peripheral pain, in the setting of opioid drug abuse. Neuronal circuitry innervating from the prefrontal cortex to the striatum is important in decision-making. Additionally, dopaminergic projections from the ventral tegmental area (VTA) in the midbrain to the nucleus accumbens (NAc) and dorsal striatum are involved in reward and motivational behaviors. We reported that global suppression of secreted phosphoprotein-1 production (OPN/Spp1) increases the expression of the mitochondrial translocator protein (TSPO) in Iba1+ macrophages/microglia across several key brain regions involved in cognition including the substantia nigra (SN). Interestingly, a subset of tyrosine hydroxylase (TH) reactive neurons co-labeled with TSPO, or were closely positioned near TSPO+ TH- cells in the midbrain region. In this regard, substance use disorders (SUD) in PLWH and in particular methamphetamine (METH) continues to be a consequential comorbid condition impacting viral suppression and health outcomes. Findings using rat and mouse HIV-Tat transgenic models have provided insights about how METH alters the expression of genes required for dopamine synthesis, metabolism, and receptor trafficking, and the role of sex as a modifier. However, our understanding of how dopaminergic neuronal-glial communication is altered in vivo during HIV replication, and METH is not understood likely due to the daunting task of deconvoluting multiple intersecting variables. Moreover, we implicated mammalian target of rapamycin (mTOR) pathway activation by (OPN/Spp1) in a mechanism of neuroprotection. Whether mTOR-OPN/Spp1 signaling plays a role in microglial- dopaminergic neuronal crosstalk in HIV-METH infection-exposure in vivo in is unknown. In this R21 application for high-risk/reward ideas, we propose to use our expertise with HIV-infected humanized mice, SUDs and modeling, to develop a rational approach to mathematical model dynamic dopaminergic neural-glial network circuitry. Our overarching hypothesis is that neuro-glial cells upregulate OPN/Spp1 expression in response to HIV-1 infection, which stimulates mTOR pathway signaling thereby, activating neuroprotective signaling to preserve homeostatic neurocircuitry; with acute co-exposure to METH, these pathways are upregulated and reinforced in a time-dependent manner. We will interrogate gene expression among neurons and glia in the nigrostriatal and meso-limbic brain regions to resolve dopaminergic neuronal-glial interactions using prospectively collected in vivo time course data. The analyses will focus on identifying interactions in the presence of HIV infection, with and without ART and acute administration of METH. Our long-term goal is to gain insights into the therapeutic potentials of resilience from cognitive dysfunction and drug addiction. We expect that findings from this project will advance the understanding of immunomodulation and metabolic reprogramming during co-exposure to HIV-1 and METH and will provide avenues for translational and clinical research aiming at improving mental health and substance use.