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Age-Related Decrease in Tyrosine Hydroxylase Immunoreactivity in the Substantia Nigra and Region-Specific Changes in Microglia Morphology in HIV-1 Tg Rats

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Abstract

Animal models have been used to study cellular processes related to human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorders (HAND). The HIV-1 transgenic (Tg) rat expresses HIV viral genes except the gag-pol replication genes and exhibits neuropathological features similar to HIV patients receiving combined antiretroviral therapy (cART). Using this rat, alterations in dopaminergic function have been demonstrated; however, the data for neuroinflammation and glial reactivity is conflicting. Differences in behavior, tyrosine hydroxylase (TH) immunoreactivity, neuroinflammation, and glia reactivity were assessed in HIV-1 Tg male rats. At 6 and 12 weeks of age, rotarod performance was diminished, motor activity was not altered, and active avoidance latency performance and memory were diminished in HIV-1 Tg rats. TH+ immunoreactivity in the substantia nigra (SN) was decreased at 8 months but not at 2–5 months. At 5 months, astrocyte and microglia morphology was not altered in the cortex, hippocampus, or SN. In the striatum, astrocytes were unaltered, microglia displayed slightly thickened proximal processes, mRNA levels for Iba1 and Cd11b were elevated, and interleukin (Il)1α,Cxcr3, and cell adhesion molecule, Icam, decreased. In the hippocampus, mRNA levels for Tnfa and Cd11b were slightly elevated. No changes were observed in the cortex or SN. The data support an age-related effect of HIV proteins upon the nigrostriatal dopaminergic system and suggest an early response of microglia in the terminal synaptic region with little evidence of an associated neuroinflammatory response across brain regions.

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Funding

This work was supported in part by HHS grants NS079172 and NS074916 to IM and NIH intramural research funding Z01 ES021164-12 and Z01 ES101623-05 to JH.

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  1. Andrew Kraft

    Present address: U.S. Environmental Protection Agency Headquarters, Mail Code 8623R, William Jefferson Clinton Building, 1200 Pennsylvania Avenue, N. W, Washington, D.C., 20460, USA

Authors and Affiliations

  1. Comparative Medicine Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    David R. Goulding

  2. National Toxicology Program Laboratory, National Institute of Environmental Health Sciences (NIEHS), P.O. Box 12233, MD E1-07, Research Triangle Park, NC, 27709, USA

    Andrew Kraft, Christopher A. McPherson & G. Jean Harry

  3. SRC Biosciences, Tampa, FL, USA

    Peter R. Mouton

  4. Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University, Washington, D.C., USA

    Valeria Avdoshina & Italo Mocchetti

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  1. David R. Goulding
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Correspondence to G. Jean Harry.

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Animal studies were done in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals following approved animal protocols from the Animal Care and Use Committee of the National Institute of Environmental Health Sciences.

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Goulding, D., Kraft, A., Mouton, P.R. et al. Age-Related Decrease in Tyrosine Hydroxylase Immunoreactivity in the Substantia Nigra and Region-Specific Changes in Microglia Morphology in HIV-1 Tg Rats. Neurotox Res 36, 563–582 (2019). https://doi.org/10.1007/s12640-019-00077-z

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