Paris Jason J, Singh Harminder D, Carey Amanda N, McLaughlin Jay P
Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, USA.
Northeastern University, Department of Psychology, Boston, MA 02115, USA.
Behav Brain Res. 2015 Sep 15;291:209-218. doi: 10.1016/j.bbr.2015.05.021. Epub 2015 May 22.
Human immunodeficiency virus (HIV) infection is associated with mood disorders and behavioral disinhibition. Impairments in sensorimotor gating and associated neurocognitive disorders are reported, but the HIV-proteins and mechanisms involved are not known. The regulatory HIV-1 protein, Tat, is neurotoxic and its expression in animal models increases anxiety-like behavior concurrent with neuroinflammation and structural changes in limbic and extra-limbic brain regions. We hypothesized that conditional expression of HIV-1 Tat1-86 in the GT-tg bigenic mouse model would impair sensorimotor gating and increase microglial reactivity in limbic and extralimbic brain regions. Conditional Tat induction via doxycycline (Dox) treatment (0-125 mg/kg, i.p., for 1-14 days) significantly potentiated the acoustic startle reflex (ASR) of GT-tg mice and impaired prepulse inhibition (PPI) of this response in a dose-dependent manner when Dox (100mg/kg) was administered for brief (1 day) or prolonged (daily for 7 days) intervals. A greater proportion of active/reactive Iba1-labeled microglia was seen in the anterior cingulate cortex (ACC), dentate gyrus, and nucleus accumbens core when Tat protein was induced under either brief or prolonged expression conditions. Other subregions of the medial prefrontal cortex, amygdala, hippocampal formation, ventral tegmental area, and ventral pallidum also displayed Tat-induced microglial activation, but only the activation observed in the ACC recapitulated the pattern of ASR and PPI behaviors. Tat exposure also increased frontal cortex GFAP. Pretreatment with indomethacin attenuated the behavioral effects of brief (but not prolonged) Tat-exposure. Overall, exposure to HIV-1 Tat protein induced sensorimotor deficits associated with acute and persistent neuroinflammation in limbic/extralimbic brain regions.
人类免疫缺陷病毒（HIV）感染与情绪障碍和行为抑制有关。有报道称感觉运动门控受损及相关神经认知障碍，但所涉及的HIV蛋白和机制尚不清楚。HIV-1调节蛋白Tat具有神经毒性，其在动物模型中的表达会增加焦虑样行为，同时伴有神经炎症以及边缘和边缘外脑区的结构变化。我们假设，在GT-tg双转基因小鼠模型中条件性表达HIV-1 Tat1-86会损害感觉运动门控，并增加边缘和边缘外脑区的小胶质细胞反应性。通过强力霉素（Dox）处理（0-125mg/kg，腹腔注射，持续1-14天）进行条件性Tat诱导，当以短时间（1天）或长时间（连续7天）间隔给予Dox（100mg/kg）时，显著增强了GT-tg小鼠的听觉惊吓反射（ASR），并以剂量依赖方式损害了该反应的前脉冲抑制（PPI）。在短暂或长时间表达条件下诱导Tat蛋白时，在前扣带回皮质（ACC）、齿状回和伏隔核核心中可见更大比例的活跃/反应性Iba1标记的小胶质细胞。内侧前额叶皮质、杏仁核、海马结构、腹侧被盖区和腹侧苍白球的其他亚区也显示出Tat诱导的小胶质细胞激活，但只有在ACC中观察到的激活重现了ASR和PPI行为的模式。Tat暴露还增加了额叶皮质GFAP。用吲哚美辛预处理可减轻短暂（而非长时间）Tat暴露的行为效应。总体而言，暴露于HIV-1 Tat蛋白会导致与边缘/边缘外脑区急性和持续性神经炎症相关的感觉运动缺陷。
