Cognitive Dysfunction after TBI: Role of alpha7 nAChrs

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Trauma to the CNS initiates acute and secondary cascades of biochemical and metabolic changes often results in a state of persistent neurological dysfunction. Understanding the neurochemical alterations that occur following damage to the CNS is critical for the development of therapeutic strategies that can prevent and/or remediate the detrimental effects of trauma. The neurobiological basis for the protracted memory deficit that commonly occurs following traumatic brain injury (TBI) is not clearly understood although a number of studies have suggested that deficits in the CNS cholinergic system play a prominent role. However, most of the previous studies have focused on muscarinic, rather than nicotinic cholinergic receptor mechanisms. This is surprising since deficits in the nicotinic receptor system have been repeatedly associated with the cognitive deficit that occurs to neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. Our initial studies clearly demonstrate that a cortical contusion injury (CCI) causes significant and widespread defects in hippocampal and cortical alpha 7 nicotinic receptor (nAChr) expression. The working hypothesis of the proposed studies is that changes in the CNS alpha7 nAChr's contribute significantly to head trauma- induced cognitive dysfunction. Furthermore, we predict that pharmacological modulation of alpha7 neuronal nicotinic receptors will have neuroprotective and cognitive-enhancing properties in head-injured rats. The Specific Aims of this proposal will evaluate: 1) the time course of changes in alpha7 protein and message expression following TBI 2) neuroprotective actions of nicotinic receptor antagonists administered in the acute phase of TBI, 3) cognitive enhancing properties of nicotine and selective alpha7 agonists administered acutely (or chronically) in the delayed phase of TBI 4) the effects of TBI on deficits in auditory sensory gating and 5) restoration of sensory gating following treatment with nicotine and other selective alpha7 agonists.