Cognitive dysfunction, including loss of short-term memory, decreased concentration and poor learning, is one of the most common disabilities resulting from traumatic brain injury (TBI). Even mild concussion can result in impairments taking weeks or months to clear. The neuronal basis for these stereotyped deficits is not firmly established, however, recent evidence suggests a possible vulnerability of septal and ventrobasal forebrain cholinergic neurons. My preliminary studies found a 35-40% decrease in these neurons 2 weeks following experimental TBI. This proposal is directed at investigating in detail how forebrain cholinergic innervation is affected by experimental TBI. The main hypothesis to be tested is that concussive injury induces degeneration and dysfunction in these neurons, an that regenerative sprouting or neuronal plasticity eventually leads to at least partial restoration of this innervation. This cycle of degeneration and regeneration is hypothesized to account, at least in part, for the cognitive changes following TBI. We would also anticipate that age-related differences in the vulnerability of these cholinergic neurons account for the greater impairment and more limited recovery seen in aged individuals. Lastly, we would expect that treatments which protect these neurons from initial injury would result in less cognitive impairment after concussion. The experiments will all be conducted using the fluid percussion model of TBI in rats. Both immunohistochemical and quantitative neurochemical techniques will be used to analyze cholinergic innervation. We will also simultaneously analyze the effect of TBI on forebrain catecholaminergic innervation as a control for the selectivity of cholinergic injury. Cognitive impairment will be assessed using the Morris water maze test. This study represents a novel approach to the problem of TBI. The investigation of how individual neuronal systems are affected by TBI should greatly increase our understanding of this complex problem and enable therapies directed at improving outcome.
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