Depression and anxiety are prevalent mood disorders symptomatic of the syndrome described as "NeuroAIDS," and pose significant problems for the treatment and well-being of HIV-positive patients. Unfortunately, the biological mechanisms linking HIV-related neuropathology to the dysfunction of neuronal circuitry and the progression of behavioral mood disorders are not well understood. Recent evidence suggests that HIV-accessory proteins such as Tat may spread throughout the brain from HIV-infected cells, producing neurotoxicity and changes in neuronal activity that could account for the behavioral changes. We hypothesize that Tat protein expression is sufficient to produce neurodegeneration and dysfunction of neuronal circuitry mediating mood, resulting in an increase of depression- and anxiety-like behaviors. This proposal utilizes the GT-tg transgenic mouse and its doxycycline-gene induction strategy for a controlled, selective expression of Tat protein in the brain. Induced GT-tg bigenic mice will be used to test the hypothesis with behavioral and imaging studies that Tat-mediated increases in depression- and anxiety-like behaviors are correlated with Tat-induced alterations in brain structure and function in regions associated with depression and anxiety, including the amygdala, anterior cingulate, orbitofrontal cortex and hippocampus. Behavioral studies with these mice will assess how Tat expression affects depression-like behaviors with the forced swim stress and social aversion tests. Behavioral experiments also will examine effects of Tat expression on anxiety-like behaviors using the open field, elevated plus maze, light-dark box, acoustic startle and marble burying tests. Assays of Tat mRNA and protein levels will correlate expression of Tat to the observed changes in behavior. In preliminary studies, Tat-induced mice spent less time than uninduced littermates in social interactions and more time immobile in forced swim stress tests, suggestive of a Tat-mediated increase in depression-like behavior. Tat-induced mice also demonstrated increased anxiety-related behaviors, with less time spent in open-field environments and a 3-fold increase in marble burying. Concurrently, we will examine the effects of Tat protein on brain structure and cell death using ex vivo magnetic resonance imaging (MRI) at ultra high magnetic field strength and TUNEL staining for apoptosis in Tat-induced animals. Preliminary ex vivo structural imaging studies documented significant reductions in the grey matter density of amygdala and hippocampus in Tat-expressing mice. Additionally, we will use BOLD functional MRI with corticosterone challenge to identify functional changes in brain regions associated with mood disorders resulting from varying levels of induction and duration of exposure to Tat protein and the response to a challenge dose of corticosterone. Overall, this project seeks to prove that functional and structural deficits can be detected in the brain circuitry of Tat-induced animals, thereby defining mechanisms by which Tat may mediate the mood disorders characteristic of NeuroAIDS.
The prevalence of mood disorders in people with HIV is high, and this comorbidity increases morbidity and mortality. We hypothesize that mood disorders associated with HIV infection are mediated by the neuronal dysfunction and neurodegeneration induced by the HIV-accessory protein, Tat. We will test this theory using a transgenic mouse model enabling selective, controlled Tat protein expression in brain to study behaviors relevant to depression and anxiety along with brain structure and function, using magnetic resonance neuroimaging. The findings will begin to clarify whether Tat protein should be a target for new treatments that block or reduce HIV-related neuropathology and mood disorders.
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|Carey, Amanda N; Sypek, Elizabeth I; Singh, Harminder D et al. (2012) Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse. Behav Brain Res 229:48-56|