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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS033150-09S1
Application #
6828525
Study Section
Special Emphasis Panel (ZRG1)
Project Start
1996-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
9
Fiscal Year
2004
Total Cost
$74,500
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yan, Hong Q; Shin, Samuel S; Ma, Xiecheng et al. (2014) Differential effect of traumatic brain injury on the nuclear factor of activated T Cells C3 and C4 isoforms in the rat hippocampus. Brain Res 1548:63-72
Bales, James W; Wagner, Amy K; Kline, Anthony E et al. (2009) Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis. Neurosci Biobehav Rev 33:981-1003
Yan, Hong Qu; Ma, Xiecheng; Chen, Xiangbai et al. (2007) Delayed increase of tyrosine hydroxylase expression in rat nigrostriatal system after traumatic brain injury. Brain Res 1134:171-9
Wilson, Margaret S; Chen, Xiangbai; Ma, Xiecheng et al. (2005) Synaptosomal dopamine uptake in rat striatum following controlled cortical impact. J Neurosci Res 80:85-91
Kline, Anthony E; Massucci, Jaime L; Ma, Xiecheng et al. (2004) Bromocriptine reduces lipid peroxidation and enhances spatial learning and hippocampal neuron survival in a rodent model of focal brain trauma. J Neurotrauma 21:1712-22
Kline, Anthony E; Massucci, Jaime L; Dixon, C Edward et al. (2004) The therapeutic efficacy conferred by the 5-HT(1A) receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after experimental traumatic brain injury is not mediated by concomitant hypothermia. J Neurotrauma 21:175-85
Dixon, C Edward; Ma, Xiecheng; Kline, Anthony E et al. (2003) Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury. Crit Care Med 31:2222-7
Kline, Anthony E; Bolinger, Bryan D; Kochanek, Patrick M et al. (2002) Acute systemic administration of interleukin-10 suppresses the beneficial effects of moderate hypothermia following traumatic brain injury in rats. Brain Res 937:22-31
Yan, Hong Qu; Kline, Anthony E; Ma, Xiecheng et al. (2002) Traumatic brain injury reduces dopamine transporter protein expression in the rat frontal cortex. Neuroreport 13:1899-901
Kline, Anthony E; Yu, Jianyun; Massucci, Jaime L et al. (2002) Protective effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin against traumatic brain injury-induced cognitive deficits and neuropathology in adult male rats. Neurosci Lett 333:179-82

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