Dopamine modulation for the treatment of chronic dysfunction due to traumatic brain injury

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Project Summary/Abstract More than 2.8 million traumatic brain injuries (TBIs) occur annually, making this one of the most pressing challenges facing the medical community. Survivors of TBI often experience chronic psychiatric symptoms such as increased risky decision-making and impulsivity, yet there are no treatments specific to this large population. These deficits affect individuals across all aspects of everyday life, often leading to reduced quality of life for caregivers or those surrounding the person. A potential major contributor to this enduring dysfunction is reduced dopamine neurotransmission, which mediates many core motivated behaviors in humans and animals. Because of reductions in dopamine, these changes may alter the efficacy of rehabilitative efforts and therapeutic drugs, making patients with TBI a special population in this regard. Thus, the goal of this project is to investigate potential treatments for psychiatric-like deficits arising from chronic TBI, focusing on modulation of dopamine systems, with the hypothesis that augmentation of dopamine will improve function. This will be investigated across three aims, each with different treatment modalities, using a rat model of TBI. Proposed studies will use an analog of the Iowa Gambling Task, known as the Rodent Gambling Task, to concurrently assess risky decision-making and impulsivity after TBI. Aim 1 will investigate changes in sensitivity to environmental contingencies to understand shifts in efficacy of rehabilitative training in humans. A series of experiments will determine whether cueing of outcomes, a known means of stimulating dopamine responses, can rescue decision-making ability. Aim 2 will test the efficacy of multiple therapeutic drugs. It will compare how effective receptor-specific drugs are compared with general dopaminergic agents and what specific changes occur to brain levels of dopamine-related proteins in the chronic injury period. Aim 3 will evaluate the efficacy and mechanism of transcranial direct-current stimulation (tDCS) as a form of neural modulation. Prior research has suggested that tDCS increases dopamine levels, but parameters have not been explored for brain-injured subjects. To verify that dopamine is driving beneficial effects of tDCS, chemogenetic inhibition of dopamine cells will be performed in the frontal cortex. These studies will advance fundamental understanding of mechanisms of dysfunction after TBI, identify the efficacy of three different therapeutic modalities, and determine the degree to which dopamine represents a relevant clinical target for chronic dysfunction after injury.