Neurodegeneration induced by methamphetamine (METH) abuse and HIV may result in accelerated age-related brain changes leading to exacerbated cognitive deficits in the aged HIV+ population. HlV-induced neurodegeneration involves, in part, the envelope glycoprotein gpl20 and the nonstructural protein Tat. During the previous funding period we showed that gpl 20 expression induced specific deficits in reversal learning and executive function in adult mice and, when combined with METH exposure, resulted in further impairments of spatial learning. We also found that gp120 expression increased dopamine transporter levels in the nucleus accumbens and decreased calbindin levels in the hippocampus that may underlie the observed cognitive deficits. This renewal application will expand the current findings by investigating the impact of aging and METH on cognitive function in the gpl 20 and iTat transgenic mouse models that mimic the chronic and acute effects of HIV on the brain, respectively. Aged mice will be exposed to METH, tested in a battery of cognitive tests (Aim 1) and subjected to neuropathological and imaging analyses (Aim 2) using the TMARC Core resources. It is predicted that aging and METH exposure will augment cognitive deficits induced by gp120 and TAT expression and result in more pronounced neuropathology, increased inflammation and oxidative stress, compared to younger adult mice. The use of identical mouse models and METH exposure within the TMARC will facilitate the interpretation and cross comparisons of the results obtained in this project with data from other projects conducting complementary behavioral and neuropathological testing in mice. This project enhances the translational potential of TMARC by assessing in animals cognitive and neuroimaging measures that are directly analogous to those used in human studies, and cross-inform our future research directions. This project will improve our understanding of the neurobiological mechanisms underiying cognitive deficits in aging individuals with chronic HIV infection and may help identify targets for the development of therapies for neurodegeneration and cognitive deficits in HIV+ METH users.
Aging may accelerate brain damage induced by HIV infection and METH abuse. Such brain damage results in behavioral and cognitive deficits that impair day-to-day function in humans. This project will identify neuropathological mechanisms underlying cognitive deficits associated with age, HIV and METH abuse, and thus may lead to the design of new therapeutic treatments.
|Morgan, Erin E; Iudicello, Jennifer E; Cattie, Jordan E et al. (2015) Neurocognitive impairment is associated with lower health literacy among persons living with HIV infection. AIDS Behav 19:166-77|
|Casaletto, K B; Obermeit, L; Morgan, E E et al. (2015) Depression and executive dysfunction contribute to a metamemory deficit among individuals with methamphetamine use disorders. Addict Behav 40:45-50|
|Maung, Ricky; Hoefer, Melanie M; Sanchez, Ana B et al. (2014) CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120. J Immunol 193:1895-910|
|Morgan, Erin E; Doyle, Katie L; Minassian, Arpi et al. (2014) Elevated intraindividual variability in methamphetamine dependence is associated with poorer everyday functioning. Psychiatry Res 220:527-34|
|Kamat, Rujvi; Brown, Gregory G; Bolden, Khalima et al. (2014) Apathy is associated with white matter abnormalities in anterior, medial brain regions in persons with HIV infection. J Clin Exp Neuropsychol 36:854-66|
|Montoya, Jessica L; Georges, Shereen; Poquette, Amelia et al. (2014) Refining a personalized mHealth intervention to promote medication adherence among HIV+ methamphetamine users. AIDS Care 26:1477-81|
|Desplats, Paula; Dumaop, Wilmar; Cronin, Peter et al. (2014) Epigenetic alterations in the brain associated with HIV-1 infection and methamphetamine dependence. PLoS One 9:e102555|
|Henry, Brook L; Geyer, Mark A; Buell, Mahalah R et al. (2014) Prepulse inhibition in HIV-1 gp120 transgenic mice after withdrawal from chronic methamphetamine. Behav Pharmacol 25:12-22|
|Tatro, Erick T; Purnajo, Intan; Richman, Douglas D et al. (2014) Antibody response to Achromobacter xylosoxidans during HIV infection is associated with lower CD4 levels and increased lymphocyte activation. Clin Vaccine Immunol 21:46-50|
|Iudicello, Jennifer E; Morgan, Erin E; Gongvatana, Assawin et al. (2014) Detrimental impact of remote methamphetamine dependence on neurocognitive and everyday functioning in older but not younger HIV+ adults: evidence for a legacy effect? J Neurovirol 20:85-98|
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