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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042196-04
Application #
6872860
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Hicks, Ramona R
Project Start
2002-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$264,480
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Pandya, Jignesh D; Pauly, James R; Sullivan, Patrick G (2009) The optimal dosage and window of opportunity to maintain mitochondrial homeostasis following traumatic brain injury using the uncoupler FCCP. Exp Neurol 218:381-9
Davis, Laurie M; Pauly, James R; Readnower, Ryan D et al. (2008) Fasting is neuroprotective following traumatic brain injury. J Neurosci Res 86:1812-22
Guseva, Maria V; Hopkins, Deann M; Scheff, Stephen W et al. (2008) Dietary choline supplementation improves behavioral, histological, and neurochemical outcomes in a rat model of traumatic brain injury. J Neurotrauma 25:975-83
Pandya, Jignesh D; Pauly, James R; Nukala, Vidya N et al. (2007) Post-Injury Administration of Mitochondrial Uncouplers Increases Tissue Sparing and Improves Behavioral Outcome following Traumatic Brain Injury in Rodents. J Neurotrauma 24:798-811
Kelso, Matthew L; Wehner, Jeanne M; Collins, Allan C et al. (2006) The pathophysiology of traumatic brain injury in alpha7 nicotinic cholinergic receptor knockout mice. Brain Res 1083:204-10
Guseva, M V; Hopkins, D M; Pauly, J R (2006) An autoradiographic analysis of rat brain nicotinic receptor plasticity following dietary choline modification. Pharmacol Biochem Behav 84:26-34
Pauly, J R; Charriez, C M; Guseva, M V et al. (2004) Nicotinic receptor modulation for neuroprotection and enhancement of functional recovery following brain injury or disease. Ann N Y Acad Sci 1035:316-34
Verbois, S L; Scheff, S W; Pauly, J R (2003) Chronic nicotine treatment attenuates alpha 7 nicotinic receptor deficits following traumatic brain injury. Neuropharmacology 44:224-33
Verbois, S L; Hopkins, D M; Scheff, S W et al. (2003) Chronic intermittent nicotine administration attenuates traumatic brain injury-induced cognitive dysfunction. Neuroscience 119:1199-208

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