Effects of HIV-1 TAT protein and methamphetamine exposure on visual discrimination and executive function in mice

Abstract

Mild neurocognitive impairments are common in people with human immunodeficiency virus (HIV) infection. HIV-encoded proteins, such as trans-activator of transcription (TAT), contribute to neuropathology and cognitive function in medicated subjects. The combination of TAT and comorbid methamphetamine use may further impair neurocognitive function in HIV-positive individuals by affecting dopaminergic systems in the brain. The current study examined the effects of TAT protein expression and methamphetamine exposure on cognitive function and dopamine systems in mice. Transgenic mice with inducible brain expression of the TAT protein were exposed to a binge methamphetamine regimen. TAT expression was induced via a doxycycline-containing diet during the final stage of the regimen and maintained throughout cognitive testing. Learning and executive function were assessed using an operant visual discrimination protocol, with a strategy switch and reversal. TAT expression and methamphetamine exposure improved visual discrimination learning. Combined TAT expression and methamphetamine exposure increased perseverative errors during reversal learning. TAT expression altered reversal learning by improving early stage, but impairing late stage, learning. TAT expression was also associated with an increase in dopamine transporter expression in the caudate putamen. These results highlight that TAT expression and methamphetamine exposure likely affect a range of selective cognitive processes, with some potentially improving function under certain conditions.

Cognition and Related Neural Findings on Methamphetamine Use Disorder: Insights and Treatment Implications From Schizophrenia Research

“…Spatial memory impairments are also observed in self-administrating rats and rats subject to experimenter-led chronic injections (86)(87)(88), with effects lasting up to 3 weeks following abstinence (89). In contrast, a study by Kesby and colleagues (90) found that experimenter-led chronic meth injections may improve learning in mice in a visual discrimination task (90). Taken together, it may be that chronic meth injections may initially improve learning processes but lead to deficits in the long-term, whereas meth self-administration consistently lead to memory impairments.…”

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

“…In the present model, Tat induction activates astrocytes (as well as bystander microglia) in the striatum ( Bruce-Keller et al, 2008 ; Fitting et al, 2010a ; Zou et al, 2011 ) and causes modest gliosis within 48 h following expression ( Bruce-Keller et al, 2008 ) that can be sustained for as long as 1 year ( Dickens et al, 2017 ). In preclinical rodent studies, CNS exposure to HIV-1 Tat induces behavioral impairments similar to HAND, including deficits in pre-attentive filter processing ( Fitting et al, 2006 ; Paris et al, 2015 ), emotionality ( Fu et al, 2011 ; Hahn et al, 2015 , 2016 ; Lawson et al, 2011 ; Paris et al, 2014 , 2016 ), motivation ( Kesby et al, 2018 ), and memory ( Carey et al, 2012 ; Fitting et al, 2013 ; Marks et al, 2016 ).…”

Brain Reward Function after Chronic and Binge Methamphetamine Regimens in Mice Expressing the HIV-1 TAT Protein

“…The present study assessed the transcription of dopamine receptor subtypes after three weeks following the completion of doxycycline administration. Therefore, changes in dopamine receptor expression may result from the TAT protein expression and direct effects induced by TAT on molecules of the dopamine system, including alterations in the dopamine transporter and vesicular monoamine transporter-2 [20,40,41].…”

“…Conditional TAT exposure in mice has been shown to induce cognitive deficits in a range of behavioural tasks [17,18] and reversal learning appears particularly susceptible to TAT-induced impairments [19,20]. In this model, TAT expression alters dopamine levels [19,21] as well as the expression of the dopamine transporter in the brain [20]. Together, these changes may contribute to the observed reward deficits and increased sensitivity to methamphetamine-induced reward enhancement in the context of TAT expression [21].…”

“…In inducible TAT transgenic mice, brain-restricted TAT expression becomes transcriptionally active after exposure to doxycycline, a tetracycline derivative [16]. Conditional TAT exposure in mice has been shown to induce cognitive deficits in a range of behavioural tasks [17,18] and reversal learning appears particularly susceptible to TAT-induced impairments [19,20]. In this model, TAT expression alters dopamine levels [19,21] as well as the expression of the dopamine transporter in the brain [20].…”