Children in the United States have a higher chance of being killed or disabled by a traumatic brain injury (TBI) than by any other """"""""disease"""""""". We have discovered that developmental TBI impairs the ability of young animals to interact with and benefit from rearing in an enriched environment (EE) [4;5]. The ability to interact and experience is a critical function underlying normal maturation;however, the mechanisms of this 'experience-dependent neuroplasticity'are only beginning to be understood. Excessive activation of the N- methyl-D-aspartate receptor (NMDAR) occurs following TBI and can lead to cell dysfunction and death [6;7]. However, too little activation can impair normal development and blunt recovery from injury [8]. The NMDAR is intimately involved with a unique growth factor, brain-derived neurotrophic factor (BDNF). Increases in BDNF occur in response to specific environmental experiences, such as rearing in an EE or exercise [9;10;11], and these increases are associated with enhanced plasticity and cognition. We propose that early TBI results in a reduction of developmental potential, and that this impairment occurs via a mechanism where physiological activation of the NMDAR/BDNF system is deranged by a pathological overstimulation of these molecular pathways. To study this, the following 5 specific aims are put forth: (1) to characterize the molecular profile of the NMDAR/BDNF system in response to EE rearing in normal and injured animals;(2) to demonstrate that excessive NMDAR activation is the trigger for deleterious molecular changes by blocking the NMDAR at the time of injury and restoring the 'normal'experience-dependent NMDAR/BDNF response; (3) to activate molecular plasticity pathways post-injury through voluntary exercise;(4) to demonstrate that restoring a normal NMDAR/BDNF response results in anatomical and behavioral improvements;and finally (5) to endogenously enhance plasticity at the appropriate time post-injury through exercise, rescue the normal NMDAR/BDNF response, and improve neurobehavioral outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027544-13
Application #
7540964
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Hicks, Ramona R
Project Start
1990-04-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
13
Fiscal Year
2009
Total Cost
$300,039
Indirect Cost
Name
University of California Los Angeles
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dennis, Emily L; Babikian, Talin; Giza, Christopher C et al. (2018) Neuroimaging of the Injured Pediatric Brain: Methods and New Lessons. Neuroscientist 24:652-670
Dennis, Emily L; Babikian, Talin; Alger, Jeffry et al. (2018) Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study. Hum Brain Mapp :
Sta Maria, Naomi S; Reger, Maxine L; Cai, Yan et al. (2017) D-Cycloserine Restores Experience-Dependent Neuroplasticity after Traumatic Brain Injury in the Developing Rat Brain. J Neurotrauma 34:1692-1702
Dennis, Emily L; Rashid, Faisal; Jahanshad, Neda et al. (2017) A NETWORK APPROACH TO EXAMINING INJURY SEVERITY IN PEDIATRIC TBI. Proc IEEE Int Symp Biomed Imaging 2017:105-108
Dennis, Emily L; Faskowitz, Joshua; Rashid, Faisal et al. (2017) Diverging volumetric trajectories following pediatric traumatic brain injury. Neuroimage Clin 15:125-135
Reid, Aylin Y; Bragin, Anatol; Giza, Christopher C et al. (2016) The progression of electrophysiologic abnormalities during epileptogenesis after experimental traumatic brain injury. Epilepsia 57:1558-1567
Harris, N G; Verley, D R; Gutman, B A et al. (2016) Disconnection and hyper-connectivity underlie reorganization after TBI: A rodent functional connectomic analysis. Exp Neurol 277:124-138
Kamins, Joshua; Giza, Christopher C (2016) Concussion-Mild Traumatic Brain Injury: Recoverable Injury with Potential for Serious Sequelae. Neurosurg Clin N Am 27:441-52
Dennis, Emily L; Rashid, Faisal; Villalon-Reina, Julio et al. (2016) Multi-modal Registration Improves Group Discrimination in Pediatric Traumatic Brain Injury. Brainlesion (2016) 10154:32-42
Harris, N G; Verley, D R; Gutman, B A et al. (2016) Bi-directional changes in fractional anisotropy after experiment TBI: Disorganization and reorganization? Neuroimage 133:129-143

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