Selective vulnerability of discrete neural circuits in the striatum to HIV-opiate comorbidity

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Opioid drug abuse exacerbates pathological and behavioral/cognitive deficits of neuroAIDS. HIV-1-associated neurocognitive disorders (HAND) remain evident in nearly half the individuals infected. HIV does not uniformly target the brain. Some brain regions, such as the basal ganglia, a region critical for drug reward and highly enriched in µ opioid receptors (MOR), are greatly affected by HIV-1, while other areas are less affected. Within the basal ganglia, e.g., HIV, Tat and gp120 causes losses in the synaptodendritic complexity of striatal medium spiny neurons (MSNs) and morphine exacerbates these effects; however, despite the pronounced damage to some MSNs, other striatal MSNs appear unaffected. We discovered that dopamine D2 receptor (Drd2) expressing MSNs (D2 MSNs) showed significantly greater structural and functional vulnerability to Tat ± morphine than dopamine D1 receptor (Drd1a) expressing MSNs (D1 MSNs) at 14 d following Tat induction when anxiety-like and learning/memory deficits, but not motor disorders (which occur later). Moreover, despite enhanced overall susceptibility, some D2 MSNs were unaffected suggesting that additional phenotypic differences, e.g., expression of MOR (which differs among D2 MSNs), also contribute to Tat and morphine- induced injury in D2 MSNs. Based on this and other evidence, we hypothesize that phenotypically distinct MSN subtypes are selectively vulnerable to Tat and morphine coexposure and that the structural and functional deficits in specific neural circuits underlie specific behavioral dysfunctions. To address this hypothesis, the following specific aims are proposed in both male and female mice. Aim 1 will examine the nature and timing of synaptodendritic injury in striatal D2 ± MOR MSN subgroups after short (14 d) and prolonged (2 month) Tat and morphine exposure. Drd2-eGFP-MOR-mCherry and Tat interbred mice will be exposed to morphine/Tat for 14 d (when cognitive, but not motor, deficits are evident) or 2 months (when cognitive and motor deficits are present). Aim 2 will examine the nature and timing of delayed D1 ± MOR MSN synaptodendritic injury in Tat tg;Drd1a-tdTomato reporter mice. In Aims 1 and 2, cognitive and motor performance will be correlated with the electrophysiologic and morphologic (3D reconstruction of synapses/dendrites and stereology) findings in D1 ± MOR and D2 ± MOR MSNs. Aim 3 will address the question of why specific MSN subtypes are more vulnerable to HIV Tat ± morphine, which will provide considerable insight into fundamental mechanisms underlying the interactive toxicity. Aim 3 will use in vitro approaches to examine the extent to which dopaminergic, glutaminergic and BDNF (TrkB, p75NTR) receptor signaling might selectively rescue synaptodendritic injury and dysfunction in HIV, Tat, or gp120-exposed D1 ± MOR and D2 ± MOR MSN subtypes. Specific excitotoxic pathways (e.g., Na+ influx via NMDA, ATP depletion, Ca2+ overload), synaptodendritic injury, and survival will be examined to gauge the role of dopaminergic, glutamatergic, and BDNF signaling in mediating MSN subtype vulnerability following HIV and opiate exposure.