Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

• Published in: Behavioural brain research Vol. 291; pp. 209 - 218
• Main Authors: Paris, Jason J., Singh, Harminder D., Carey, Amanda N., McLaughlin, Jay P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.09.2015
• Subjects: Acoustic startle reflex; Animals; Brain - immunology; Brain - pathology; Calcium-Binding Proteins - metabolism; Disease Models, Animal; Doxycycline; Glial Fibrillary Acidic Protein; Glial fibrillary acidic protein (GFAP); HIV-1; Human immunodeficiency virus; Human immunodeficiency virus 1; Ionized calcium-binding adaptor protein 1; Male; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins - metabolism; Microglia - pathology; Microglia - physiology; Nerve Tissue Proteins - metabolism; NeuroAIDS; Prepulse inhibition; Sensory Gating - immunology; tat Gene Products, Human Immunodeficiency Virus - genetics; tat Gene Products, Human Immunodeficiency Virus - metabolism; Trans-activating transcriptor; Glial fibrillary acidic protein (GFAP); Acoustic startle reflex; Trans-activating transcriptor; Ionized calcium-binding adaptor protein 1; NeuroAIDS; Prepulse inhibition
• DOI: 10.1016/j.bbr.2015.05.021
• ISSN: 0166-4328

•Low or high exposure to Tat amplified startle and impaired prepulse inhibition.•Low or high Tat activated microglia in mPFC and extra/limbic brain regions.•GFAP increased in mPFC concurrent with low or high Tat.•Indomethacin pretreatment mitigated effects of brief (not prolonged) Tat exposure. 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 (0–125mg/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.