Recovery of cognitive function after traumatic brain injury (TBI) is a dynamic process in which alterations in neurotransmitter systems do not likely occur in isolation. During the previously funded period, we have observed that substantial cholinergic neurotransmission deficits can occur without a chronic (4-week post injury) loss of cholinergic cell bodies. We also have extensive data that TBI causes chronic changes in key dopaminergic proteins that occur concomitantly with these cholinergic changes. Numerous studies have demonstrated that the dopaminergic innervation of medial septum and diagonal band of broca (medial septal area [MSA]) regions that are dense with cholinergic neurons, can affect hippocampal acetylcholine (ACh) release, especially via D about receptor agonists. Furthermore, we have compelling preliminary data that dopaminergic innervation of cholinergic nuclei is reduced after TBI. For this competitive renewal, we propose to logically extend our previous findings to hypothesize that cognitive deficits following TBI may be, at least partially, attributable to decreased DA modulation of septohippocampal cholinergic function. A systematic series of Specific Aims are proposed to test this hypothesis. For this project, we will focus on dopamine (DA) modulation of the selectively vulnerable septohippocampal cholinergic system. This provides us with a prototypical system to examine the effects of TBI on interactive neurotransmitter systems. To better grade an effect of TBI on these systems, we will compare in the MSA the effects of TBI to an established model of DA deafferentation effects, 6-hydroxydopamine (6-OHDA) -induced DA denervation.
Aim 1 will examine the effects of TBI and 6-OHDA lesions on DA modulated ACh release in the hippocampus and DA release in the medial septum.
Aim 1 will also determine whether changes in hippocampal ACh release is associated with altered Dl receptors in the MSA using quantitative autoradiography, and DA-fiber/cholinergic neuron interactions using a tyrosine hydroxylase/choline acetyltransferase double-immunolabeling method following TBI.
Aim 2 will determine the effect of exogenous administration of neurotrophic factors that promote DA neuronal survival on DA biochemical markers, cognitive deficits, as well as hippocampal ACh release and MSA DA release following TBI.
Aim 3 will determine the effects of clinically relevant DA agonist therapies on cognitive deficits, as well as hippocampal ACh release and MSA DA release following TBI. Our LONG TERM GOAL is to develop new therapies to accelerate cognitive recovery following traumatic brain injury.
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