LOSS OF DEVELOPMENTAL PLASTICITY AFTER HEAD INJURY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在美国，儿童死于创伤性脑损伤(TBI)或致残的几率比其他任何“疾病”都要高。我们发现，发育性脑外伤削弱了幼年动物与丰富环境中的饲养互动并从中受益的能力(EE)[4；5]。相互作用和体验的能力是正常成熟的关键功能；然而，人们才刚刚开始了解这种依赖于经验的神经可塑性的机制。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，太少的激活可能会损害正常发育和迟钝的损伤恢复[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中养育或锻炼[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，早期脑损伤导致发育潜力降低，这种损害是通过NMDAR/BDNF系统的生理激活被这些分子通路的病理性过度刺激而错乱的机制发生的。为了研究这一点，提出了以下5个具体目标：(1)表征正常和损伤动物对EE饲养的NMDAR/BDNF系统的分子特征；(2)证明过度的NMDAR激活是有害的分子变化的触发因素，在损伤时阻断NMDAR，恢复“正常”的经验依赖的NMDAR/BDNF反应；(3)通过自愿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反应可导致解剖学和行为学的改善；最后通过运动在伤后适当时间内源性增强可塑性，挽救正常的NMDAR/BDNF反应，改善神经行为结局。

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.