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

Abstract

Cerebral white matter changes including tissue water diffusion abnormalities detected with diffusion tensor magnetic resonance imaging (DTI) are commonly found in humans with Human Immunodeficiency Virus (HIV) infection, as well as in animal models of the disorder. The severities of some of these abnormalities have been reported to correlate with measures of disease progression or severity, or with the degree of cognitive dysfunction. Accordingly, DTI may be a useful translational biomarker. HIV-Tat protein appears to be an important factor in the viral pathogenesis of HIV-associated neurotoxicity. We previously reported cerebral gray matter density reductions in the GT-tg bigenic mouse treated with doxycycline (Dox) to conditionally induce Tat protein expression. Presently, we administered intraperitoneal (i.p.) Dox (100 mg/kg/day) for 7 days to GT-tg mice to determine whether induction of conditional Tat expression led to the development of cerebral DTI abnormalities. Perfused and fixed brains from eight GT-tg mice administered Dox and eight control mice administered saline i.p. were extracted and underwent DTI scans on a 9.4 Tesla scanner. A whole brain analysis detected fractional anisotropy (FA) reductions in several areas including insular and endopiriform regions, as well as within the dorsal striatum. These findings suggest that exposure to Tat protein is sufficient to induce FA abnormalities, and further support the use of the GT-tg mouse to model some effects of HIV.

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

“…Although additional in-depth studies of Tat-induced markers of neuroinflammation are needed, the results after 7 days of induction suggest that Tat exposure promotes microglial (and potential astroglial) pathology and inflammation. Moreover, our prior MRI findings support the idea that multiple brain areas are affected by conditional Tat expression [10–11], supporting the evaluation of additional brain regions for future histochemical studies aimed at assessing the magnitude of neuroinflammation over time following Tat induction. Notably, hippocampal inputs to mPFC appear critical for output to PPI-relevant brain regions (including nucleus accumbens) [43].…”

“…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].…”

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model

“…The iTat mouse has been utilized to investigate some of these processes. Among the many reports utilizing the iTat model just within the last decade are studies addressing Tau processing (Kadri et al 2015), host cell cycle regulation (Fields et al 2015b), cell survival (Fan and He 2016b), differentiation (Perry et al 2010; Wheeler et al 2008; Yao et al 2012) and glial activation (Kiebala et al 2010), substance abuse (Fitting et al 2012, 2010; Hauser et al 2009; Mediouni et al 2015; Paris et al 2014a; Zou et al 2011), sex differences (Hahn et al 2015a, b), behavior (Hahn et al 2016; Paris et al 2014b, c, 2015), memory and learning (Carey et al 2012; Fitting et al 2013) and brain changes observed via imaging (Carey et al 2015, 2013). Table 1, while not comprehensive by any means, provides examples of the diversity of studies that have utilized the iTat mouse model.…”

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

“…TAT-expressing mice show neuropathology similar to that observed in HIV-infected humans including apoptosis, astrocytosis, neurodegeneration of the cortex, degeneration of dendrites and inflammation (Kim et al, 2003). Recent imaging studies have revealed reduced gray matter density and cerebral fractional anisotropy abnormalities in multiple brain areas in TAT-expressing mice (Carey et al, 2013, Carey et al, 2015). TAT protein induces dysfunction of dopaminergic neurotransmission in corticolimbic brain circuits (Ferris et al, 2009b, Zhu et al, 2009, Midde et al, 2012, Theodore et al, 2012) that are involved in reward function (Koob and Volkow, 2010).…”