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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040125-02
Application #
6363969
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Michel, Mary E
Project Start
2000-03-01
Project End
2004-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$296,972
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Carlson, Shaun W; Yan, Hong; Dixon, C Edward (2017) Lithium increases hippocampal SNARE protein abundance after traumatic brain injury. Exp Neurol 289:55-63
Osier, Nicole D; Dixon, C Edward (2016) The Controlled Cortical Impact Model: Applications, Considerations for Researchers, and Future Directions. Front Neurol 7:134
Wagner, Amy K; Sokoloski, Joshua E; Chen, Xiangbai et al. (2009) Controlled cortical impact injury influences methylphenidate-induced changes in striatal dopamine neurotransmission. J Neurochem 110:801-10
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
Wagner, Amy K; Drewencki, Laura L; Chen, Xiangbai et al. (2009) Chronic methylphenidate treatment enhances striatal dopamine neurotransmission after experimental traumatic brain injury. J Neurochem 108:986-97
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
Wagner, A K; Sokoloski, J E; Ren, D et al. (2005) Controlled cortical impact injury affects dopaminergic transmission in the rat striatum. J Neurochem 95:457-65
Wagner, Amy K; Chen, Xiangbai; Kline, Anthony E et al. (2005) Gender and environmental enrichment impact dopamine transporter expression after experimental traumatic brain injury. Exp Neurol 195:475-83
Massucci, Jaime L; Kline, Anthony E; Ma, Xiecheng et al. (2004) Time dependent alterations in dopamine tissue levels and metabolism after experimental traumatic brain injury in rats. Neurosci Lett 372:127-31
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

Showing the most recent 10 out of 18 publications