HIV-1 Tat promotes age-related cognitive, anxiety-like, and antinociceptive impairments in female mice that are moderate
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ORIGINAL ARTICLE
HIV-1 Tat promotes age-related cognitive, anxiety-like, and antinociceptive impairments in female mice that are moderated by aging and endocrine status Alaa N. Qrareya & Fakhri Mahdi & Marc J. Kaufman & Nicole M. Ashpole & Jason J. Paris
Received: 15 May 2020 / Accepted: 10 September 2020 # American Aging Association 2020
Abstract Hypogonadism is a common comorbidity associated with HIV-1 that is more prevalent among infected individuals over the age of 45. The underlying mechanisms are unknown, but both combined antiretroviral therapeutics and HIV-1 proteins, such as transactivator of transcription protein (Tat), dysregulate steroid-synthetic mechanisms including lipid storage/ synthesis and mitochondrial function. Thus, Tat expression may accelerate age-related comorbidities partly by impairing endocrine function. Few studies exist of Tatmediated behavioral deficits in aged animals and effects of endocrine status have not been investigated. Accordingly, we tested whether conditional Tat expression in aged (~ 1.5 years old), female, Tat-transgenic [Tat(+)] mice increases anxiety-like behavior, impairs cognition, and augments mechanical allodynia, when compared to age-matched controls that do not express
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11357-020-00268-z) contains supplementary material, which is available to authorized users. A. N. Qrareya : F. Mahdi : N. M. Ashpole : J. J. Paris (*) Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, 315 Faser Hall, P.O. Box 1848, University, MS 38677-1848, USA e-mail: [email protected] M. J. Kaufman Department of Psychiatry, McLean Imaging Center, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA N. M. Ashpole : J. J. Paris Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA
Tat protein [Tat(−)]. We further tested whether aged mice that maintained their endocrine status (preestropausal) were more resilient to Tat/age-related comorbidities than peri- or post-estropausal mice. Tat and endocrine aging status exerted separate and interacting effects that influenced anxiety-like and cognitive behaviors. Peri- and post-estropausal mice exhibited greater anxiety-like behavior in the elevated plus-maze and impaired learning in the radial arm water maze compared to pre-estropausal mice. Irrespective of estropause status, Tat(+) mice demonstrated impaired learning, reduced grip strength, and mechanical allodynia compared to Tat(−) mice. Tat exposure reduced circulating estradiol in post-estropausal mice and increased the estradiol-to-testosterone ratio in pre-estropausal mice. Changes in circulating estradiol, testosterone, and progesterone correlated with grip strength. Thus, endocrine status is an important factor in age-related anxiety, cognition, neuromuscular function, and allodynia that can be accelerated by HIV-1 Tat protein. Keywords Aging . Estropause . Gonadal hormones . HIV/AIDS . Hypogonadism . Menopau
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