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Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat

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Abstract

Rationale

Human immunodeficiency virus (HIV) infection is associated with substantial increases in generalized anxiety. The HIV regulatory protein, transactivator of transcription (Tat), has been implicated in the neuropathogenesis related to HIV-1 infection. However, direct examination of the effect of Tat on behavioral measures of anxiety has not been demonstrated.

Objective

To identify whether expression of the Tat1-86 protein exerts dose-dependent and persistent anxiety-like effects in a whole animal model, the GT-tg bigenic mouse.

Methods

GT-tg mice and C57BL/6J controls were administered doxycycline in a dose- (0, 50, 100, or 125 mg/kg, i.p., for 7 days) or duration- (100 mg/kg, i.p., for 0, 1, 3, 5, or 14 days) dependent manner to induce Tat1-86 in brain. Mice were assessed for anxiety-like behavior in an open field, social interaction, or marble burying task 0, 7, and/or 14 days later. Central expression of Tat1-86 protein was verified with Western blot analyses.

Results

Doxycycline produced no effects on C57BL/6J controls that lacked the Tat1-86 transgene. Among GT-tg mice, doxycycline (100 mg/kg for 3, 5, or 7 days) significantly increased anxiety-like behavior in all tasks, commensurate with enhanced Western blot labeling of Tat1-86 protein in brain, displaying optimal effects with the 7-day regimen. Greater exposure to doxycycline (either 125 mg/kg for 7 days or 100 mg/kg for 14 days) impaired locomotor behavior; whereas lower dosing (below 100 mg/kg) produced only transient increases in anxiety-like behavior.

Conclusions

Expression of HIV-1-Tat1-86 in GT-tg mouse brain produces exposure-dependent, persistent increases in anxiety-like behavior.

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Acknowledgements

We thank Johnny He for the gift of the GT-tg transgenic breeder mice. This work was supported by funding from the National Institute of Mental Health (MH085607 to JPM) and funds from the State of Florida, Executive Office of the Governor's Department of Economic Opportunity. The State of Florida had no involvement in the planning, execution, or presentation of this project in any manner. All experiments herein comply with the current laws of the United States of America.

Conflict of Interest Statement

The authors do not have a financial relationship with the funding organizations, and have no conflicts of interest to report.

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  1. Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL, 34987, USA

    Jason J. Paris, Harminder D. Singh, Michelle L. Ganno, Pauline Jackson & Jay P. McLaughlin

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Paris, J.J., Singh, H.D., Ganno, M.L. et al. Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat. Psychopharmacology 231, 2349–2360 (2014). https://doi.org/10.1007/s00213-013-3385-1

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