Frontal lobe syndrome is the hallmark neuropsychiatric response to traumatic brain injury (TBI) in humans. Frontal cortex activity is critically involved in """"""""executive"""""""" cognitive functions including the generation and monitoring of strategic action, functions essential to complex goal-directed behavior that are frequently impaired following TBI. There is extensive evidence that dopaminergic lesions of the frontal cortex, innervated by mesocortical dopamine (DA) projections, can lead to persistent cognitive and behavioral deficits. However, there is a significant gap in the knowledge regarding the mechanisms of frontal lobe syndrome following TBI. DA deficits after TBI may be attributable to oxidant damage caused by autoxidation of DA, or by an imbalance in DA function. There is now extensive experimental evidence that enhancement of motor recovery can be achieved by pharmacologic stimulation of these systems. However, there is a paucity of experimental data examining the dopaminergic mechanisms of frontal cortex mediated cognitive deficits following TBI. The goal of this proposal is to examine the cellular mechanisms of mesocortical dopaminergic deficits after TBI in a rodent model using biochemical indices of DA autoxidation and biochemical, molecular biological and immunohistochemical indices of DA metabolism and neurotransmissions. Neurochemical and immunohistochemical markers of DA neurotransmission in the dopaminergic ventral tegmental/forebrain systems, as well as functional deficits, will be assessed at specific time points following injury suggested by our preliminary data. The effects of therapies that either reduce oxidative damage of DA terminals and /or chronically stimulate DA activity on neurochemical and immunohistologic markers, and on functional performance will be assessed following TBI. Lastly, the relationship between early biochemical markers of DA activity to neurophysiological outcome measures specific to frontal lobe function will be evaluated in severe TBI patients. This project represents the first systematic examination of the mechanisms of induction and recovery of catecholaminergic cognitive deficits after TBI. Our long-term goal is to develop new therapies to attenuate the induction and enhance the recovery of DA-mediated neurobehavioral deficits after TBI.
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