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

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      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.

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      Most cited references 45

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      HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.

      This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups). The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
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        Epidemiology of women and depression.

         R Kessler (2003)
        Depression is the leading cause of disease-related disability among women in the world today. Depression is much more common among women than men, with female/male risk ratios roughly 2:1. Recent epidemiological research is reviewed. Implications are suggested for needed future research. The higher prevalence of depression among women than men is due to higher risk of first onset, not to differential persistence or recurrence. Although the gender difference first emerges in puberty, other experiences related to changes in sex hormones (pregnancy, menopause, use of oral contraceptives, and use of hormone replacement therapy) do not significantly influence major depression. These observations suggest that the key to understanding the higher rates of depression among women than men lies in an investigation of the joint effects of biological vulnerabilities and environmental provoking experiences. Advancing understanding of female depression will require future epidemiologic research to focus on first onsets and to follow incident cohorts of young people through the pubertal transition into young adulthood with fine-grained measures of both sex hormones and gender-related environmental experiences. Experimental interventions aimed at primary prevention by jointly manipulating putative biological and environmental risk factors will likely be needed to adjudicate between contending causal hypotheses regarding the separate and joint effects of interrelated risk factors.
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          Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.

          With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011.
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            Author and article information

            Affiliations
            1Molecular and Systems Pharmacology Graduate Studies Program, Emory University , Atlanta, GA, USA
            2Neuroscience Graduate Studies Program, Emory University , Atlanta, GA, USA
            3Neuroscience and Behavioral Biology, Emory College , Atlanta, GA, USA
            4Department of Physiology, Emory University , Atlanta, GA, USA
            5Department of Psychiatry and Behavioral Science, Emory University , Atlanta, GA, USA
            Author notes

            Edited by: Stefan Oskar Reber, University of Ulm, Germany

            Reviewed by: Yvonne Nolan, University College Cork, Ireland; Roser Nadal, Universitat Autònoma de Barcelona, Spain

            *Correspondence: Gretchen N. Neigh, gretchen.mccandless@ 123456vcuhealth.org

            Specialty section: This article was submitted to Affective Disorders and Psychosomatic Research, a section of the journal Frontiers in Psychiatry

            Contributors
            Journal
            Front Psychiatry
            Front Psychiatry
            Front. Psychiatry
            Frontiers in Psychiatry
            Frontiers Media S.A.
            1664-0640
            20 June 2016
            2016
            : 7
            27378953
            4913326
            10.3389/fpsyt.2016.00102
            Copyright © 2016 Rowson, Harrell, Bekhbat, Gangavelli, Wu, Kelly, Reddy and Neigh.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 6, Tables: 7, Equations: 0, References: 47, Pages: 14, Words: 9345
            Categories
            Psychiatry
            Original Research

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