LOSS OF DEVELOPMENTAL PLASTICITY AFTER HEAD INJURY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在美国，儿童因创伤性脑损伤（TBI）而死亡或致残的几率高于其他任何“疾病”。我们发现，发展性脑损伤会损害幼龄动物与丰富环境（EE）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“经验依赖的神经可塑性”的机制才刚刚开始被理解。脑外伤后n -甲基- d -天冬氨酸受体（NMDAR）过度激活，可导致细胞功能障碍和死亡[6；7]。然而，过少的激活会损害正常发育和损伤后的恢复。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体验的反应，例如在情感表达或运动中饲养[9;10；[11]，这些增加与增强的可塑性和认知能力有关。我们认为，早期脑外伤会导致发育潜力的降低，这种损害是通过NMDAR/BDNF系统的生理激活被这些分子途径的病理性过度刺激所扰乱的机制发生的。为此，我们提出了以下5个具体目标：(1)研究正常动物和受伤动物在情感表达饲养过程中NMDAR/BDNF系统的分子特征；(2)通过在损伤时阻断NMDAR并恢复“正常的”经验依赖的NMDAR/BDNF反应，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反应会导致解剖和行为的改善；最后(5)在损伤后适当时间通过运动内源性增强可塑性，恢复正常的NMDAR/BDNF反应，改善神经行为转归。

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.