Conditional Tat protein expression in the GT-tg bigenic mouse brain induces gray matter density reductions

Abstract

Tat (Trans-activator of transcription) is implicated in the neuropathogenesis of HIV-1 infection and known to contribute to neuronal damage and learning and memory impairments. However, direct neuroanatomical demonstration of Tat pathobiology is limited. GT-tg bigenic mice with a doxycycline (Dox)-inducible and brain-selective tat gene were used to test the hypothesis that conditional induction of Tat activity in brain can induce gray matter density abnormalities. Ultra high spatial resolution ex vivo magnetic resonance imaging (MRI) combined with a voxel based morphometry (VBM) analysis revealed gray matter density reductions in the sublenticular extended amygdala, the amygdala, the amygdala-hippocampal area, piriform and peri-/entorhinal cortices, and hypothalamus, in Tat-expressing GT-tg mice compared to Dox-treated C57Bl/6J mice. These neuroanatomical abnormalities are consistent with regions expected to be abnormal based on behavioral deficits exhibited by Tat-expressing mice (Carey et al., 2012). These experiments provide the first neuroimaging evidence that conditional Tat protein expression in the GT-tg bigenic mouse model alters brain structure. The findings warrant future studies to further characterize effects of conditional Tat expression on brain structure. Such studies may improve our understanding of the neurological underpinnings of neuroAIDS and the neurodegeneration associated with HIV-1 infection, potentially leading to new treatments.

Figure 1. GT-tg mice treated with Dox (5 days) exhibited gray matter density reductions in several brain areas

The brains of the 5-day Dox-induced GT-tg mice exhibited gray matter density reductions versus Dox-treated C57Bl/6J mice. Gray matter abnormalities (red voxels overlaid on composite brain) were identified in the sublenticular extended amygdala (1), piriform cortex (2), amygdala (3), hypothalamus (4) peri-/entorhinal cortex (5), and amygdala-hippocampal area (6) (whole brain p ≤ 0.05, multiple comparisons and cluster-corrected t-tests). Coronal brain sections are shown from roughly +0.74 mm to −4.20 mm Bregma (n = 8/group).

Figure 2. Post-hoc region of interest (ROI) analysis

A composite ROI was identified using the volumes identified in the VBM whole brain analysis in 4 adjacent coronal slices (Figure 1, slices 6–9) as differing between 5-day Dox-induced GT-tg mice and 7-day Dox-treated C57Bl/6J mice. Mean gray matter densities in this composite ROI were calculated for each of the 4 experimental groups. There was a significant gray matter density reduction in the composite ROI of 5-day (p = 0.000055) and 7-day (p = 0.003523) Dox-induced groups compared to 7-day Dox-treated C57Bl/6J mice (controls). Gray matter densities in control groups (7-day Dox-treated C57Bl/6J and uninduced GT-tg mice) did not differ in the composite ROI. (Legend: * = different from 7-day Dox-treated C57Bl/6J mice at p < 0.004167 (corrected); † = different from uninduced GT-tg mice at p = 0.0273 (uncorrected); Kruskal-Wallis H-test with post hoc testing).