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. ? ?
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