The advent of combination antiretroviral therapy (cART) has shifted HIV-associated neurocognitive disorders (HAND) from more severe deficits to milder neurocognitive losses in learning and executive functions ( Heaton et al., 2011 Saylor et al., 2016). Thus, HIV-1 Tat appears to uniquely and systematically disrupt immune regulation and the inhibitory and excitatory synaptic balance throughout the ACC-BG-thalamocortical circuitry resulting in a loss of behavioral control. Alternatively, IL-1α, CCL5, and IL-13 were decreased in the mediodorsal thalamus despite the absence of synaptic changes.

Tat decreased dendritic spine density and cortical VGLUT1 inputs, while increasing IL-1β, IL-6, CCL5, and CCL11 in the striatum. The interaction of Tat exposure and the resultant time-dependent, selective alterations in CCL4, CXCL1, IL-12p40, and IL-17A levels in the PFC predicted significant decreases in adaptability. The behavioral insufficiencies coincided with decreases in the inhibitory pre- and post-synaptic proteins, synaptotagmin 2 and gephyrin, respectively, in the ACC, and alterations in specific pro- and anti-inflammatory cytokines out of 23 assayed. Furthermore, Tat induced adaptability in response to an environmental stressor and pre-attentive filtering deficits. HIV-1 Tat exposure increased novelty-exploration in response to novel food, flavor, and environmental stimuli, suggesting that Tat triggers increased novelty-exploration in situations of competing motivation (e.g., drive to feed or explore vs. To explore how HIV-1 disrupts executive function, we investigated the effects of 48 h, 2 and/or 8 weeks of HIV-1 Tat exposure on behavioral control, synaptic connectivity, and neuroimmune function in the anterior cingulate cortex (ACC) and associated cortico-basal ganglia (BG)-thalamocortical circuitry in adult, Tat transgenic male mice.

Deficits in prefrontal cortex (PFC)-mediated executive function and the resultant loss of behavioral control are a particularly debilitating consequence of neuroHIV. HIV-1 selectively disrupts neuronal integrity within specific brain regions, reflecting differences in viral tropism and/or the regional differences in the vulnerability of distinct neuronal subpopulations within the CNS.

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