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

Abstract

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. Deficits in prefrontal cortex (PFC)-mediated executive function and the resultant loss of behavioral control are a particularly debilitating consequence of neuroHIV. 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. 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. fear of novel, brightly lit open areas). Furthermore, Tat induced adaptability in response to an environmental stressor and pre-attentive filtering deficits. 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. 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. Tat decreased dendritic spine density and cortical VGLUT1 inputs, while increasing IL-1β, IL-6, CCL5, and CCL11 in the striatum. Alternatively, IL-1α, CCL5, and IL-13 were decreased in the mediodorsal thalamus despite the absence of synaptic changes. 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.

Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice

“…These data were in contrast to previous literature that found distinct memory and cognitive impairments (36,43,58,59). It is possible that differences observed in behavioral trends in this study compared to previous reports could be attributed to different readouts in a test, such as MWM conducted over 4 days in this study vs. 18 days in a previous study (43), or due to differences in two strains of Tat mice, which differ in Tat copy number (42). Additionally, two induction paradigms present different handling requirements and it is not known if additional handling of mice during injection may change their response to behavior.…”

“…HIV-1 proteins including Tat and glycoprotein120 (gp120) are implicated in direct or indirect mechanisms that manifest into anxiety-like symptoms ( 52 ). Indeed, several previous reports investigated Tat-induced anxiety and/or stress, including sex-specific differences, in transgenic HIV-1 Tat rodent models ( 42 , 43 , 48 , 53 ). Since our investigations did not focus on sex-specific changes, we did not test for sex as a confounding variable for anxiety.…”

“…injections was based previous reports that depicted dynamic dose- and frequency-dependent changes in Tat expression ( 36 , 38 ). In contrast, studies employing DOX-containing chow ranging from 3 weeks to 1 year have emphasized on the paradigm mimicking a chronic, low level inflammation, and leading to detrimental effects including reduced brain volume, increased ventricular volume, gliosis, inflammatory cytokine expression, and neuronal damage ( 42 , 43 , 48 , 50 ). In this regard, our study provides a first direct comparison of Tat expression by two DOX administration methods.…”

“…HIV-1 Tat is a key protein involved in neuronal dysfunction (28,29), BBB disruption (22), oxidative stress (30,31), elevating MMPs (32,33), and possesses chemokine-like abilities that promote immune infiltration into the brain (26,34). Several investigations using HIV-1 Tat based transgenic models elucidated effects of acute Tat expression, i.e., a few days after Tat induction (35)(36)(37)(38)(39)(40)(41), while the effects of prolonged Tat expression were seldom tested until recently (42,43). It is imperative to test how duration of Tat expression alters its direct and indirect neurotoxic effects since Tat is known to be produced by infected cells during early as well as late stages, even in the presence of ART.…”

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

“…Further, the proinflammatory effects of HIV-1 Tat at C-C chemokine receptor type 5 (CCR5) desensitize MOR or δ-opioid receptors (DOR [ 51 – 53 ]), an effect that appears to contribute to decreased antinociceptive potency of morphine in Tat transgenic mice [ 54 ]. Interestingly, recent research has demonstrated long-term immune tolerance to repeated inflammatory insult within resident microglia in the CNS, which could impact the response to morphine after chronic Tat exposure [ 55 – 58 ].…”