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|Title:||HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors|
William G. Branton
Amber M. Paul
Glen B. Baker
University of Alberta
University of Calgary
|Keywords:||Immunology and Microbiology;Neuroscience|
|Citation:||Brain, Behavior, and Immunity. Vol.40, (2014), 74-84|
|Abstract:||Background: Neuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties. Methods: Transgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection. Results: Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p< 0.05). Tg animals showed increased CCL2 expression with concurrent IFN-α suppression in striatum compared with Wt littermates (p< 0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p< 0.05). Conclusions: HIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis. © 2014.|
|Appears in Collections:||Scopus 2011-2015|
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