Almost two million people sustain traumatic brain injury each year in the United States alone, with most reporting deficits in working memory. Working memory involves the """"""""online"""""""" storage of information necessary for performing cognitive operations. The prefrontal cortex, which is required for working memory, is highly developed in humans and its function is often impaired by brain trauma. Studies performed in humans, monkeys and rodents have shown that dopamine signaling plays a critical role in working memory. Either too little or too much dopamine receptor D1 stimulation impairs working memory performance. Recently, a few studies have examined the expression of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase (TH), and the plasma membrane dopamine transporter (DAT) in rat frontal cortex following traumatic brain injury (TBI). However, very little is known about how TBI affects the normalcy of dopamine signaling in the prelimbic/infralimbic (PL/IL) cortices, structures required for working memory performance in rodents. This proposal will test the overall hypothesis that enhanced D1 receptor-mediated signaling in the PL/IL cortices is causally related to TBI-associated working memory deficits. Consequently, attenuation of dopamine synthesis or D1 receptor-activated events in these areas will alleviate these deficits..
The Specific Aims of the proposal are: 1) To determine if dopamine biosynthesis in the PL/IL cortices is increased following TBI and to assess its role in working memory deficits. 2) To determine if TBI alters tissue dopamine content, or receptor levels in the PL/IL cortices and to assess the contribution of dopamine to working memory deficits, and 3) To determine if dopamine-activated intracellular events in the PL/IL cortices ifollowing TBI contributes to working memory deficits. An understanding of the mechanisms by which TBI alters dopamine signaling is critical for the development of mechanism-based intelligent pharmacological treatments for working memory deficits for brain trauma patients.
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