Progesterone protects normative anxiety-like responding among ovariectomized female mice that conditionally express the HIV-1 regulatory protein, Tat, in the CNS

Abstract

Increased anxiety is co-morbid with human immunodeficiency virus (HIV) infection. Actions of the neurotoxic HIV-1 regulatory protein, Tat, may contribute to affective dysfunction. We hypothesized that Tat expression would increase anxiety-like behavior of female GT-tg bigenic mice that express HIV-1 Tat protein in the brain in a doxycycline-dependent manner. Furthermore, given reports that HIV-induced anxiety may occur at lower rates among women, and that the neurotoxic effects of Tat are ameliorated by sex steroids in vitro, we hypothesized that 17β-estradiol and/or progesterone would ameliorate Tat-induced anxiety-like effects. Among naturally-cycling proestrous and diestrous mice, Tat-induction via 7 days of doxycycline treatment significantly increased anxiety-like responding in an open field, elevated plus maze and a marble-burying task, compared to treatment with saline. Proestrous mice demonstrated less anxiety-like behavior than diestrous mice in the open field and elevated plus maze, but these effects did not significantly interact with Tat-induction. Among ovariectomized mice, doxycycline-induced Tat protein significantly increased anxiety-like behavior in an elevated plus maze and a marble burying task compared to saline-treated mice, but not an open field (where anxiety-like responding was already maximal). Co-administration of progesterone (4 mg/kg), but not 17β-estradiol (0.09 mg/kg), with doxycycline significantly ameliorated anxiety-like responding in the elevated plus maze and marble burying tasks. When administered together, 17β-estradiol partially antagonized the protective effects of progesterone on Tat-induced anxiety-like behavior. These findings support evidence of steroid-protection over HIV-1 proteins, and extend them by demonstrating the protective capacity of progesterone on Tat-induced anxiety-like behavior of ovariectomized female mice.

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

“…The concentration of Dox that was previously demonstrated to optimally express Tat protein in the GT-tg brain (100 mg/kg, i.p. [8,23]), concurrent with impaired learning [23], enhanced anxiety-like behavior [8,9], and potentiated drug reward [31–33] was also the most efficacious concentration observed herein. Notably, effects on ASR and PPI were not linear; rather, acute Tat induction (after 1 day of Dox) or prolonged exposure (after 7 days of Dox) equally potentiated startle and impaired PPI.…”

“…GT-tg bigenic male mice [7] used in behavioral and GFAP protein studies (n=204) were derived at the Torrey Pines Institute for Molecular Studies (Port Saint Lucie, FL) [9] from breeders originally provided by Dr. Johnny J. He.…”

“…To begin to assess the behavioral sequelae associated with central actions of HIV-1 Tat, we have utilized the GT-tg bigenic mouse; a transgenic model that expresses GFAP-driven Tat protein under doxycycline (Dox) regulation in the CNS [7]. Consistent with clinical observations, inducing Tat expression in these mice is associated with elevated anxiety [8,9] and reductions of gray-matter density and fractional anisotropy abnormalities within mood-associated brain regions (including the hippocampus, amygdala, hypothalamus, and striatum [10,11]). Similar Tat-transgenic murine models also demonstrate anxiety-like behavior concurrent with neuronal cell death, astrocytosis, and microglial reactivity in striatal cells [12].…”

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice

“…Female HIV-1 transgenic rats have also been shown to exhibit a range of depression-like behaviors (learned helplessness) and social anxiety (Nemeth et al, 2014). In addition, TAT expression alters other affective behaviors, such as anxiety-like behavior assessed in a variety of behavioral procedures (Paris et al, 2014b, Paris et al, 2014c, Hahn et al, 2015). Our findings demonstrate that expression of the TAT protein alone is sufficient to induce anhedonia and may contribute to comorbid depression in HIV-infected subjects.…”

Conditional Tat Protein Brain Expression in the GT-tg Bigenic Mouse Induces Cerebral Fractional Anisotropy Abnormalities

“…While this effect could be a result of our sample size, right-lateralized brain damage has been associated with behavioral disinhibition syndromes (see [67] for review) as well as increased sensitivity for stress-induced depression or anxiety [68]. Behavioral phenotypes associated with right hemisphere damage/dysfunction thus appear similar to those exhibited by Tat-expressing GT-tg mice [34, 35, 37, 56, 69]. …”