The neurotoxic consequences of opiate drug and HIV-1 interactions on striatal neurons and on the underlying intracellular signaling pathways (autophagy, ER-stress/unfolded protein responses (UPR), apoptosis) resulting in sublethal injury and death will be explored. Accumulating evidence indicates that opioid drug abuse per se directly exacerbates the neuropathology of HIV-1. We have found that (1) opioid drugs exacerbate neuronal injury and death through independent actions on ?-opioid receptor (MOR) expressing neurons, astroglia and microglia;and (2) that neuronal death is preceded by non-lethal changes in synaptodendritic pathology that are presumably reversible. Opiate abuse potentiates the neuropathogenesis of HIV largely/exclusively by synergistically disrupting glial function and dendritic pathology. We hypothesize that opioid-HIV interactive increases in neuron death are preceded by cumulative insults to synaptic organization and function that originate in glia, are non-lethal, and assumed reversible. These reductions in neuronal function likely underlie cognitive impairment in neuroAIDS and represent an important therapeutic target for chronic drug abuse-HIV comorbidity.
Aim 1 will examine opioid and HIV-1-dependent (Tat, gp120, and live virus) sublethal neuronal dysfunction and/or death as a continuum using multiple in vitro models including primary human dissociated neuron, astroglia, and microglial cultures. It is likely that apoptosis, autophagy, and ER-stress/UPR are operative in sublethal injury as well as during neuron death, and these pathways are evaluated and tested for potentially reversible effects.
Aim 2 will identify the extent to which apoptotic, autophagic, and ER-stress/UPR events are associated with opiate-HIV-induced neuronal dysfunction and/or death in vivo. Our ability to visualize/manipulate apoptotic, autophagic, and UPR events in living, cultured neurons will garner new insight into the pathogenesis of opioid abuse/HIV comorbidity and will reveal novel strategies to reverse neuron injury. Our labs were the first to show that opioids, in large part via glial intermediates, exacerbate HIV-induced CNS neuroimmune responses and neuronal injury. Our long-term goal is to define the mechanisms by which opiate drug use or abuse contributes to neurodegeneration accompanying HIVE, and to identify signaling pathways that could be targeted for therapeutic intervention.
This grant tests the innovative concept that chronic opiate abuse and HIV injure neurons and brain circuitry through the competing actions of three interrelated cell stress pathways (apoptotic, autophagic, and ER-stress). We will test whether experimentally manipulating each of these pathways can prevent the types of neuronal injury associated with neurocognitive deficits occurring with drug abuse and/or neuroAIDS.
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|Marks, William D; Paris, Jason J; Schier, Christina J et al. (2016) HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J Neurovirol 22:747-762|
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|Fitting, Sylvia; Knapp, Pamela E; Zou, Shiping et al. (2014) Interactive HIV-1 Tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Naâº influx, mitochondrial instability, and CaÂ²âº overload. J Neurosci 34:12850-64|