HIV-Tat protein mediation of neuroAIDS central nervous system pathology and behavioral deficits.

摘要

This dissertation investigated the role of HIV-Tat protein in mediating behavioral dysfunction and neurodegeneration associated with NeuroAIDS..;The first study tested if Tat was sufficient to impair learning and memory processes in Tat-induced GT-tg mice compared to the C57Bl/6J parent strain of mice and/or the uninduced GT-tg littermates. The GT-tg mice induced to express Tat demonstrated longer latencies to find an escape hole, committed more total, reference, and working memory errors, and favored a less efficient search strategy during acquisition compared to their uninduced GT-tg littermates, suggesting impaired spatial learning. Tat-induced mice also demonstrated poor probe trial performance, suggesting impaired spatial memory. Furthermore, reversal learning was impaired in Tat-induced mice, as the mice learned a new escape location slower than uninduced littermates. Tat-induced mice also demonstrated deficiencies in novel object recognition (NOR), a behavioral model for a different type of learning and memory performance than the Barnes maze. Tat-induced mice displayed long-lasting (i.e., up to one month) NOR deficits. Furthermore, NOR impairment was dependent on the dose and duration of Dox exposure, suggesting that the amount and duration of exposure to Tat progressively mediated deficits.;The next study tested the hypothesis that Tat can result in increased anxiety depending on the extent of Tat protein expression. Uninduced and Tat-induced GT-tg mice were initially tested in the open field test for anxiety-like behavior 48 h and one week after the completion of Tat induction to determine if any increases in anxiety were transient or persistent. Increases in anxiety-like behavior were apparent in mice induced to express Tat compared to controls, but mice administered the maximum induction regimen (Dox, 100 mg/kg, 7 days) were noted to have a more complex behavioral profile. These data were confirmed in the light-dark box. Mice induced to express Tat using various Dox induction regimens were also tested in the elevated plus maze. Interestingly, Tat-induced mice demonstrated behavioral changes in the elevated plus maze that were suggestive not of anxiety, but of behavioral disinhibition, a behavior commonly observed in patients suffering from dementia.;The third study evaluated the ability of Tat to modulate the rewarding and sensitizing effects of cocaine. Once expressed, Tat produced sensitization to the locomotor effects of acutely administered cocaine, as the locomotor effects induced by a single injection of cocaine were significantly potentiated, a response typically seen only after repeated exposure to cocaine. Furthermore, mice expressing Tat showed a greatly potentiated cocaine-conditioned place preference response as compared to C57Bl/6J or uninduced mice, suggesting that brain expression of Tat protein enhanced the rewarding effects of cocaine. The magnitude of this effect was dependent on the dose and duration of Dox administered and the corresponding Tat induction. We also confirmed that the potentiated preference response was not a transient event, and became extinct at the same rate as that of uninduced littermates. Experiments further demonstrated the effects of Tat on an established reward state, with the induction of Tat protein significantly potentiating the effect of an additional exposure to place conditioning over both prior preference and the response of mice that were uninduced.;The final study tested the hypotheses that Tat protein expression in the central nervous system is associated with decreases in gray matter density, white matter microstructural changes, and histological abnormalities in brain areas known to be affected in NeuroAIDS patients. In the study, brains were excised from Tat-induced, uninduced, and C57Bl/6J mice for ex vivo anatomical histology-grade magnetic resonance imaging using a 9.4 Tesla Varian magnet. Reductions in gray matter density in the amygdala, amygdala-hippocampal area, piriform, perirhinal, and entorhinal cortices were found in the brains of 5 day Tat-induced mice compared to Dox-treated C57Bl/6J mice. Significant loss of white matter microstructural integrity in the insula, endopiriform nucleus, and part of the striatum was observed in the 7 day Tatinduced mice compared to uninduced GT-tg mice, suggesting a progressive effect of Tat protein on white matter, with increasing exposure to Tat resulting in more severe damage. Additionally, limited analysis of histology staining used to detect activated microglia and cell death was performed to correlate in vitro evidence of the toxicity of Tat to in vivo demonstrations of neurodegeneration in our animal model. (Abstract shortened by UMI.)