LOSS OF DEVELOPMENTAL PLASTICITY AFTER HEAD INJURY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在美国，儿童因创伤性脑损伤（TBI）而死亡或致残的几率高于任何其他“疾病”。我们已经发现，发育性TBI损害了年轻动物与丰富环境（EE）中的饲养互动并从中受益的能力[4;5]。互动和体验的能力是正常成熟的关键功能;然而，这种“经验依赖性神经可塑性”的机制才刚刚开始被理解。N-甲基-D-天冬氨酸受体（NMDAR）的过度激活发生在TBI后，可导致细胞功能障碍和死亡[6;7]。然而，太少的激活会损害正常发育和从损伤中恢复[8]。NMDAR与一种独特的生长因子--脑源性神经营养因子（BDNF）密切相关。BDNF的增加是对特定环境经历的反应，例如在EE或运动中饲养[9;10;11]，这些增加与增强的可塑性和认知有关。我们提出，早期TBI的结果在发展潜力的减少，这种损害发生的机制，其中NMDAR/BDNF系统的生理激活是由这些分子通路的病理过度刺激错乱。为了研究这一点，提出了以下5个具体目标：（1）表征正常和受伤动物对EE饲养反应的NMDAR/BDNF系统的分子谱：（2）通过在受伤时阻断NMDAR并恢复“正常”的经验依赖性NMDAR/BDNF反应来证明过度的NMDAR激活是有害分子变化的触发因素;（3）通过自主运动激活损伤后的分子可塑性通路;（4）证明恢复正常的NMDAR/BDNF反应导致解剖学和行为改善;以及最后（5）通过运动在损伤后的适当时间内源性地增强可塑性，挽救正常的NMDAR/BDNF反应，并改善神经行为结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.