The epidemic spread of human immunodeficiency virus, type I (HIV-1) with its resulting acquired immunodeficiency syndrome (AIDS) and attendant cognitive and affective deficits (AIDS dementia complex - ADC) have made studies of the behavioral and neurobiological effects of retroviral infection imperative. Previous studies have demonstrated that infection of susceptible mice with the LP-BM5 retrovirus mixture progressively induces profound immunosuppression, central nervous system (CNS) invasion, neurological impairment and spatial learning and memory deficits in the Morris water maze. More recent studies have shown that, like HIV-1 infection of humans, LP-BM5 infection of mice profoundly increases CNS levels of the glutamatergic neuronal excitotoxin, quinolinic acid. Moreover, LP-BM5 infection results in alterations in ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. Since glutamatergic pathways and the NMDA receptor have been critically implicated in the neuronal changes-underlying spatial learning, these data suggest that LP-BM5 may impair spatial learning by acting on these sites. This proposal addresses three primary questions: 1. What neuronal mechanisms are involved in LP-BM5-induced spatial learning deficits? 2. Which behaviors relevant to learning does LP-BM5 disrupt? 3. What therapeutic interventions block or reverse LP-BM5 induced learning deficits? It is hypothesized that: 1. LP-BM5 infection results in alterations in the NMDA receptor complex within discrete regions of brain which correspond temporally with the appearance of learning deficits in the water maze; 2. LP-BM5 infection does not disrupt learning and memory in relatively simple tasks but will display increasingly disruptive effects in relatively complex learning paradigms, such as spatial learning tasks and complex operant schedules and; 3. that agents which block the proliferation of LP-BM5, the synthesis of quinolinic acid or act as antagonists at the NMDA receptor complex will block, delay or reverse the spatial learning deficits produced by LP-BM5. Mice will be infected with LP-BM5 and the non-immunosuppressive, but CNS invasive, ecotropic virus and examined in both general behavioral paradigms (open field exploration, elevated plus maze exploration) and learning and memory tasks of graduated difficulty (passive avoidance, active avoidance, water maze and repeated acquisition operant paradigms) to assess the behavioral specificity of LP-BM5 infection. Likewise, LP-BM5 and ecotropic virus infected mice will be sacrificed at several time points over the course of infection and examined post-mortem for effects on CNS and peripheral quinolinic acid levels, the NMDA receptor complex and nicotinic and muscarinic acetylcholine receptors. In addition, animals will be examined post-mortem for cytopathological changes in forebrain structures. Finally, infected mice will be treated with several potential therapeutic agents (quinolinic acid synthesis inhibitors and functional NMDA receptor antagonists) and tested in the water maze in order to determine whether these drugs can block or reverse the spatial learning deficits induced by LP-BM5 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29MH053228-01
Application #
2253248
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Project Start
1994-12-01
Project End
1999-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216