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

Autor:	Nass SR; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, P.O. Box 980613, VA, 23298-0613, USA., Hahn YK; Department of Anatomy and Neurobiology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, P.O. Box 980709, Richmond, VA, 23298-0709, USA., McLane VD; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, P.O. Box 980613, VA, 23298-0613, USA., Varshneya NB; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, P.O. Box 980613, VA, 23298-0613, USA., Damaj MI; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, P.O. Box 980613, VA, 23298-0613, USA., Knapp PE; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, P.O. Box 980613, VA, 23298-0613, USA.; Department of Anatomy and Neurobiology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, P.O. Box 980709, Richmond, VA, 23298-0709, USA.; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, P.O. Box 980059, Richmond, VA, 23298-0059, USA., Hauser KF; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, P.O. Box 980613, VA, 23298-0613, USA.; Department of Anatomy and Neurobiology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, P.O. Box 980709, Richmond, VA, 23298-0709, USA.; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, P.O. Box 980059, Richmond, VA, 23298-0059, USA.
Jazyk:	angličtina
Zdroj:	Brain, behavior, & immunity - health [Brain Behav Immun Health] 2020 May; Vol. 5. Date of Electronic Publication: 2020 Apr 29.
DOI:	10.1016/j.bbih.2020.100077
Abstrakt:	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. Competing Interests: Declaration of competing interest The authors declare they have no conflicts of interest.
Databáze:	MEDLINE
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