Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse

Abstract

HIV-Tat protein has been implicated in the pathogenesis of HIV-1 neurological complications (i.e., neuroAIDS), but direct demonstrations of the effects of Tat on behavior are limited. GT-tg mice with a doxycycline (Dox)-inducible and brain-selective tat gene coding for Tat protein were used to test the hypothesis that the activity of Tat in brain is sufficient to impair learning and memory processes. Western blot analysis of GT-tg mouse brains demonstrated an increase in Tat antibody labeling that seemed to be dependent on the dose and duration of Dox pretreatment. Dox-treated GT-tg mice tested in the Barnes maze demonstrated longer latencies to find an escape hole and displayed deficits in probe trial performance, versus uninduced GT-tg littermates, suggesting Tat-induced impairments of spatial learning and memory. Reversal learning was also impaired in Tat-induced mice. Tat-induced mice additionally demonstrated long-lasting (up to one month) deficiencies in novel object recognition learning and memory performance. Furthermore, novel object recognition impairment was dependent on the dose and duration of Dox exposure, suggesting that Tat exposure progressively mediated deficits. These experiments provide evidence that Tat protein expression is sufficient to mediate cognitive abnormalities seen in HIV-infected individuals. Moreover, the genetically engineered GT-tg mouse may be useful for improving our understanding of the neurological underpinnings of neuroAIDS-related behaviors.

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

“…The concentration of Dox that was previously demonstrated to optimally express Tat protein in the GT-tg brain (100 mg/kg, i.p. [8,23]), concurrent with impaired learning [23], enhanced anxiety-like behavior [8,9], and potentiated drug reward [31–33] was also the most efficacious concentration observed herein. Notably, effects on ASR and PPI were not linear; rather, acute Tat induction (after 1 day of Dox) or prolonged exposure (after 7 days of Dox) equally potentiated startle and impaired PPI.…”

“…To induce central HIV-1 Tat expression as previously described [7], mice were administered Dox at dosing regimens that have been established to optimize expression of central HIV-1 Tat protein in a manner dependent on Dox exposure (25–125 mg/kg, i.p., once daily for 1 to 14 days) [8,23]. In this animal model, Dox is demonstrated to induce expression of Tat mRNA [7] and protein [8,23] in an exposure-dependent manner where central Tat mRNA correlates with the transgene copy numbers expressed in brain [7].…”

“…In this animal model, Dox is demonstrated to induce expression of Tat mRNA [7] and protein [8,23] in an exposure-dependent manner where central Tat mRNA correlates with the transgene copy numbers expressed in brain [7]. Significant gross physiological changes (e.g., body weight) were not observed in response to Dox exposure with the exception of the two highest dosing regimens (Dox 125 mg/kg, i.p.…”

Effects of Conditional Central Expression of HIV-1 Tat Protein to Potentiate Cocaine-Mediated Psychostimulation and Reward Among Male Mice

“…Tat-induced mice recapitulate many clinical findings of HIV-1 infection, including central macrophage/monocyte infiltration, T-lymphocyte infiltration, and neuronal cell death (Kim et al, 2003). Using Western blot analysis, we previously established that the magnitude of Tat expression correlates with the treatment dose of Dox and duration of Dox administration (Carey et al, 2012). Exposure to Tat protein results in behavioral deficits of learning and memory and reductions of gray-matter density in limbic regions of GT-tg mouse brains as measured with ex vivo magnetic resonance imaging (Carey et al, 2013).…”

Methamphetamine Exposure Combined with HIV-1 Disease or gp120 Expression: Comparison of Learning and Executive Functions in Humans and Mice

“…For example, treating human neuronal cell cultures with a combination of gp120 protein and methamphetamine at physiologically inert doses when given alone led to significantly increased levels of neuronal cell death (Turchan et al, 2001). However, determining the specific role of gp120 in methamphetamineand HIV-induced cognitive impairments is extremely difficult, if not impossible, in humans because of the potential contributions of additional HIV-associated proteins such as TAT (Carey et al, 2012) and Nef (Chompre et al, 2013).…”