The goal of this proposal is to describe the cellular mechanisms of reorganization of two central cholinergic systems and their temporal relationships to recovery of spatial memory function following experimental traumatic brain injury in the rat. We will assess neurochemical and immunohistochemical cholinergic markers in the septal- hippocampal and nucleus basalis- neurocortical systems, as well as Morris water maze deficits, at specific time points following injury. Lastly, we will assess the effects of therapies that enhance cholinergic neurotransmission on specific neurochemical and immunohistologic markers, and on spatial memory performance. We have substantial published and preliminary data to suggest that chronic deficits in cholinergic neurotransmission deficits are attributable to reduction in the ability of cholinergic neurons to synthesize Ach, rather than a loss of cholinergic neurons. Reduced ach synthesis may be due to a reduction in choline transport, the rate-limiting step for the synthesis of ACh. Our general hypothesis is that severer traumatic brain injury (TBI) in rates produces long-term disturbances in central acetylcholine (ACh) neurotransmission which contribute to spatial memory deficits. To test this hypothesis, we have organized the proposed research into three sequential series of aims.
the first Aim will determine the time course of three functionally distinct periods of recovery of spatial memory deficits following TBI. The first is an interval of """"""""overt"""""""" spatial memory deficits that is characterized by performance deficits that are detectable by routine behavioral assessments. The second interval is characterized by deficits that are """"""""covert"""""""" or undetectable in the absence of secondary pharmacological challenges does not differ between injured and non- injured animals.
Aim 1 will be accomplished by measuring duration and magnitude of increased sensitivity to varying doses of an anticholinergic drug and an NMDA antagonist in the Morris water maze paradigm. The studies in Aim 1 are necessary to provide a rational basis for the selection of the post-traumatic time points use in Aim 2.
The second Aim will systematically employ immunohistochemical, biochemical, and pharmacological techniques to determine if deficits of hippocampal and cortical cholinergic neurotransmission following TBI result from a low of cholinergic neurons or a loss of the cholinergic neuron's ability to function properly. We will evaluate loss of cholinergic neurons by measuring immunohistologic changes in ChAT and low-affinity NGF receptor- positive neurons in the medial septal and nucleus basalis regions. Changes in cholinergic terminal density will be assessed by autoradiographic binding of [3H]hemicholinium to the high-affinity choline uptake site. We will evaluate the ability of cholinergic neurons to function properly by measuring (1) levels of ChAT enzyme activity, (2) the capacity of in vitro tissue slices to synthesize and release acetylcholine, (3) in vivo ACh release using microdialysis, and (4) binding characteristics of muscarinic receptors and uptake sites. The last aim will determine whether chronic increases in cholinergic tone produced by administration of a cholinesterase inhibitor tetrahydrominoacridine (tacrine) will attenuate behavioral and neurochemical deficits in cholinergic neurotransmission in the hippocampus and cortex. 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 #
5R01NS033150-03
Application #
2416357
Study Section
Neurology A Study Section (NEUA)
Program Officer
Cheung, Mary Ellen
Project Start
1996-05-01
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
053785812
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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