Neuroinflammation and Behavior in HIV-1 Transgenic Rats Exposed to Chronic Adolescent Stress

Abstract

Highly active antiretroviral therapy (HAART) has improved prognosis for people living with HIV (PLWH) and dramatically reduced the incidence of AIDS. However, even when viral load is controlled, PLWH develop psychiatric and neurological disorders more frequently than those living without HIV. Adolescents with HIV are particularly susceptible to the development of psychiatric illnesses and neurocognitive impairments. While both psychiatric and neurocognitive disorders have been found to be exacerbated by stress, the extent to which chronic stress and HIV-1 viral proteins interact to impact behavior and relevant neuroinflammatory processes is unknown. Determination of the individual contributions of stress and HIV to neuropsychiatric disorders is heavily confounded in humans. In order to isolate the influence of HIV-1 proteins and chronic stress on behavior and neuroinflammation, we employed the HIV-1 transgenic (Tg) rat model, which expresses HIV-1 proteins with a gag and pol deletion, allowing for viral protein expression without viral replication. This Tg line has been characterized as a model of HAART-controlled HIV-1 infection due to the lack of viral replication but continued presence of HIV-1 proteins. We exposed male and female adolescent HIV-1 Tg rats to a mixed-modality chronic stress paradigm consisting of isolation, social defeat and restraint, and assessed behavior, cerebral vascularization, and neuroinflammatory endpoints. Stress, sex, and presence of the HIV-1 transgene impacted weight gain in adolescent rats. Female HIV-1 Tg rats showed decreases in central tendency during the light cycle in the open field regardless of stress exposure. Both male and female HIV-1 Tg rats exhibited decreased investigative behavior in the novel object recognition task, but no memory impairments. Adolescent stress had no effect on the tested behaviors. Microglia in female HIV-1 Tg rats exhibited a hyper-ramified structure, and gene expression of complement factor B was increased in the hippocampus. In addition, adolescent stress exposure increased microglial branching and junctions in female wild-type rats without causing any additional increase in HIV-1 rats. These data suggest that the presence of HIV-1 proteins during development leads to alterations in behavioral and neuroinflammatory endpoints that are not further impacted by concurrent chronic adolescent stress.

Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury

“…Others have identified regions that contain hyper-ramified morphologies in situ , which may be similar to our hyper-complex category. Hyper-ramified morphologies were previously identified in female mouse brain tissue 41 , 42 or in mice with chronic stress 43 – 45 . In chronic stress, a hyper-ramified/hyper-complex morphology has not been correlated to neuropathological indicators of injury, such as IL1-β, CD68, or caspase, but instead increased expression of β1-integrin 44 .…”

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

“…Notably, the reduction of aversive environmental conditions (e.g., brightly lit open space) may explain the lack of Tat-induced changes in the marble burying test used to assess compulsive-like behavior, which diverge from previous studies in which marble burying assessed anxiety-like behavior and Tat induction increased marble burying behavior ( Paris et al, 2014 , 2016 ). HIV-1 transgenic rats spent less time exploring the center of an open field with an overhead light, but more time exploring an open field when the center is dark ( Rowson et al, 2016 ), suggesting changes in environmental stimuli can alter behavioral control or anxiety-like behaviors.…”

Synaptic Connectivity in Medium Spiny Neurons of the Nucleus Accumbens: A Sex-Dependent Mechanism Underlying Apathy in the HIV-1 Transgenic Rat

“…Women represent approximately half of the individuals living with HIV-1 (UNAIDS, 2016 ), yet remain underrepresented in both clinical and preclinical studies (Maki and Martin-Thormeyer, 2009 ; Maki et al, 2015 ). More recent clinical studies have systematically evaluated sex differences in HIV-1 associated neurocognitive disorders, revealing greater neurocognitive impairment in HIV-1 seropositive women relative to HIV-1 seropositive men (Royal et al, 2016 ; Maki et al, 2018 ); results which were translationally modeled in the HIV-1 Tg rat (e.g., McLaurin et al, 2016 , 2017 ; Rowson et al, 2016 ). To date, however, no clinical or preclinical study has systematically evaluated sex differences in HIV-1 associated apathy.…”