In the intact central nervous system, cellular energy production is an efficient process which balances energy demands by matching fuel consumption and delivery. This tight relationship between energy production and cerebral blood flow is necessitated by the high metabolic demands of the brain. From our previous work, it is apparent that experimental traumatic brain injury produces a breakdown of this critical balance resulting in a pathologic imbalance between glucose metabolism, oxygen consumption and cerebral blood flow. Specifically, the acute metabolic response to neural injury is characterized by an immediate increase in glucose metabolism and a reduced oxidative capacity for glucose metabolism. Paradoxically, this marked increase in glucose metabolism following traumatic brain injury is accompanied by a persistent decrease in cerebral blood flow. The proposed studies reconcile these provocative findings and provide support for the hypothesis that the uncoupling between metabolism and blood flow profoundly affects the long-term viability of injured neurons and determines the eventual outcome after he ad injury. Thus, we hypothesize that experimental traumatic brain injury induces a state in which: i) glucose metabolism increases dramatically for the first several hours in an attempt to re-establish neuronal homeostasis, and ii) insufficient amount of energy (ATP) is produced by damaged neurons to meet this increased energy demand due to a compromised cellular metabolic machinery and dysfunctional neurovascular system.
The specific aims of this project are: i) to determine whether injury- induced uncoupling of glucose metabolism and cerebral blood flow results in delayed cell death, ii) to determine the physiological cause for this uncoupling, and iii) to determine the cellular mechanism by which injured neurons undergo delayed cell death following traumatic brain injury. In order to implement these specific aims, we will utilize state of the art techniques including double-label autoradiography, video image of neurovascular changes, long-term electrophysiological recordings using chronically-implanted microelectrodes, chronic microdialysis of neurochemical and ionic changes, and quantitative morphometrics. The completion of these studies will provide new and much needed insights into the mechanisms by which cortical contusions evolve into wide-spread lesions, and the ways we can alter or reverse the pathophysiologic response in order to improve functional outcome following head injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Michel, Mary E
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Fukushima, Masamichi; Lee, Stefan M; Moro, Nobuhiro et al. (2009) Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury. J Neurotrauma 26:1095-110
Prins, Mayumi L; Hovda, David A (2009) The effects of age and ketogenic diet on local cerebral metabolic rates of glucose after controlled cortical impact injury in rats. J Neurotrauma 26:1083-93
Aoyama, Naoki; Lee, Stefan M; Moro, Nobuhiro et al. (2008) Duration of ATP reduction affects extent of CA1 cell death in rat models of fluid percussion injury combined with secondary ischemia. Brain Res 1230:310-9
Nuwer, Marc R; Hovda, David A; Schrader, Lara M et al. (2005) Routine and quantitative EEG in mild traumatic brain injury. Clin Neurophysiol 116:2001-25