This study will investigate the role of HIV-encoded Tat protein in the central nervous system pathology and behavioral impairment associated with NeuroAIDS. The goal of this project is to contribute to the understanding of NeuroAIDS etiology and pathology by focusing on HIV-Tat protein as a possible contributing factor to the neurological deficits and neurodegeneration seen in HIV infection. Although Tat protein is a single component of HIV infection, previous research demonstrating the neurotoxic and neuromodulatory effects of Tat support its involvement in NeuroAIDS. This study will test the hypothesis that HIV-Tat protein induces neurodegeneration and learning and memory deficits. The hypothesis will be tested using a transgenic mouse with inducible and brain-selective Tat protein expression. Brains will be excised from Tat-induced, uninduced, and C57BI/6 mice for anatomical and diffusion tensor magnetic resonance imaging using a 9.4 T magnet. Reductions in volume and the integrity white matter axonal tracts will be evaluated in the hippocampus and prefrontal cortex and other brain regions considered essential for intact learning and memory. This technology will allow for identification of brain regions and circuitry damaged by Tat protein. Also, mice induced to express Tat will be tested in behavioral assays assessing learning and memory and will be compared to uninduced littermates and C57BI/6 mice. The novel object recognition task will be used to assess recognition memory. The Barnes maze will be used to assess spatial learning and memory by testing the ability of the mice to use spatial cues to locate an escape hole. Overall, this research aims to identify the contribution of HIV-Tat protein to neurodegeneration and behavioral impairment associated with NeuroAIDS.

Public Health Relevance

Evaluating the consequences of HIV-Tat protein activity in the brain could improve our understanding of NeuroAIDS and help identify a target for development of therapeutics to prevent or treat the neurodegeneration and cognitive dysfunction associated with HIV infection. This is particularly important given that antiretroviral drugs are less effective at allaying the effects of HIV in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS064872-02
Application #
7858411
Study Section
Special Emphasis Panel (ZRG1-AARR-H (22))
Program Officer
Wong, May
Project Start
2009-06-01
Project End
2010-06-30
Budget Start
2010-06-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$497
Indirect Cost
Name
Northeastern University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Carey, Amanda N; Liu, Xiaoxu; Mintzopoulos, Dionyssios et al. (2015) Conditional Tat protein brain expression in the GT-tg bigenic mouse induces cerebral fractional anisotropy abnormalities. Curr HIV Res 13:3-9
Paris, Jason J; Singh, Harminder D; Carey, Amanda N et al. (2015) Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice. Behav Brain Res 291:209-18
Paris, Jason J; Carey, Amanda N; Shay, Christopher F et al. (2014) Effects of conditional central expression of HIV-1 tat protein to potentiate cocaine-mediated psychostimulation and reward among male mice. Neuropsychopharmacology 39:380-8
Hoot, Michelle R; Sypek, Elizabeth I; Reilley, Kate J et al. (2013) Inhibition of G??-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward. Behav Pharmacol 24:144-52
Carey, Amanda N; Liu, Xiaoxu; Mintzopoulos, Dionyssios et al. (2013) Conditional Tat protein expression in the GT-tg bigenic mouse brain induces gray matter density reductions. Prog Neuropsychopharmacol Biol Psychiatry 43:49-54
Carey, Amanda N; Sypek, Elizabeth I; Singh, Harminder D et al. (2012) Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse. Behav Brain Res 229:48-56