PROJECT 4 (P4)

Neurodegeneration induced by METH abuse and HIV may result in accelerated age-related brain changes leading to exacerbated cognitive deficits in the aged HIV+ population. HIV-induced neurodegeneration involves, in part, the envelope glycoprotein gp120 and the nonstructural protein Tat. During the previous funding period we showed that gp120 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 aims to expand the current findings by investigating the impact of aging and METH on cognitive function in the gp120 and inducible (i)Tat transgenic (tg) mouse models that mimic the chronic and acute effects of HIV on the brain, respectively. Aged mice are 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, which will cross-inform our future research directions. This project will improve our understanding of the neurobiological mechanisms underlying 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.