The present proposal stems from research conducted during previous funding periods that revealed novel and unexpected roles of the chemokine CXCL12, and its primary receptor CXCR4, on central neurons and glia. Specifically, the objectives of this proposal are to characterize the effect of CXCL12 on dendritic spines, which are critically involved in neuroprotection and synaptic plasticity, and to study the modulation of this effect by opiates and HIV proteins. The proposed studies will characterize the molecular mechanisms involved in the dendritic spine changes evoked by CXCL12; determine the effect of opiates and HIV proteins on CXCL12-induced changes; and establish the potential behavioral consequences of these alterations in the context of HIV neuropathology and drug abuse. This will be accomplished using both in vitro and in vivo approaches and various techniques of cellular/molecular neurobiology and behavior. The long-term goal of this research is to identify pharmacological targets for adjuvant neuroprotective treatments that may be used to reduce neurological problems in HIV patients, thus assisting in the clinical management of populations at high risk of neuropathology, such as intravenous drug users. The studies proposed in aim 1 will provide detailed information about the kinetics and mechanisms involved in CXCL12-induced dendritic spine changes and confirm the role of the CXCL12/CXCR4 axis in the regulation of spines in vivo (with a major focus on the prefrontal cortex and hippocampus). We expect the results to support the hypothesis that CXCL12 regulates expression of gene programs that control synapse number, which ultimately results in more spines. Overall, these experiments intend to confirm the role of CXCL12/CXCR4 in maintenance of a healthy dendritic arbor and to inform some of the analysis to be conducted in aim 2 and 3. The experiments in aim 2 are important to determine if morphine and HIV viral proteins (or cellular factors induced by these proteins) affect the CXCL12 regulation of dendritic spines. Along with the results from aim 3, these findings will indicate whether morphine and HIV can precipitate neuronal damage by inhibiting normal function of this homeostatic chemokine. Finally, studies in aim 3 will unveil subtle but important differences in behavioral performance (involving the prefrontal cortex and hippocampus) between WT and HIV-Tg rats that will help us characterize the specific deficits associated with expression of HIV viral proteins in the brain as well as impairment of CXCR4 function caused by morphine/CXCR4 antagonists.
Despite the benefits of current antiretroviral treatments, the neurological complications of HIV infection, which include both neurocognitive and motor/sensory deficits, remain an unmet medical and social need - partly because the biological bases of these complex disorders are still undefined. The studies proposed in this application aim to identify pharmacological targets for adjuvant neuroprotective treatments that may be used to reduce neurological problems in HIV patients, thus assisting in the clinical management of populations at high risk of neuropathology, such as intravenous drug users.
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