LOSS OF DEVELOPMENTAL PLASTICITY AFTER HEAD INJURY

头部受伤后发育可塑性丧失

• 批准号: 7369389
• 负责人: DAVID A HOVDA
• 金额: $ 1.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369389
• 关键词: LOSS; DEVELOPMENTAL; PLASTICITY; AFTER; HEAD

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.

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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。与其他任何“疾病”相比，美国的儿童被创伤性脑损伤（TBI）杀死或残疾的机会更高。我们已经发现，发育性TBI损害了幼小动物与养育环境（EE）（EE）[4; 5]相互作用和受益的能力。互动和经验的能力是正常成熟的关键功能。但是，这种“依赖经验的神经可塑性”的机制才被开始理解。 N-甲基-D-天冬氨酸受体（NMDAR）的过度激活发生在TBI之后，可导致细胞功能障碍和死亡[6; 7]。但是，太少的激活会损害正常发育和受伤的钝性恢复[8]。 NMDAR与独特的生长因子，脑衍生的神经营养因子（BDNF）密切相关。 BDNF的增加是响应特定的环境经历而发生的，例如在EE或运动中饲养[9; 10; 11; 11]，这些增加与增强的可塑性和认知有关。我们建议早期TBI导致发育潜力的降低，并且这种损害是通过一种机制发生的，在这种机制中，NMDAR/BDNF系统的生理激活因这些分子途径的病理过度刺激而破坏了。为了研究这一点，提出了以下5个特定目标：（1）表征NMDAR/BDNF系统的分子谱，以响应正常和受伤的动物中的EE饲养； （2）证明过多的NMDAR激活是通过在损伤时阻止NMDAR并恢复“正常”经验依赖性的NMDAR/BDNF响应来阻止NMDAR的触发因素； （3）通过自愿运动在伤害后激活分子塑性途径； （4）证明恢复正常的NMDAR/BDNF响应会导致解剖和行为改善；最后（5）通过运动后在适当的时间内增强可塑性，挽救正常的NMDAR/BDNF响应并改善神经行为的结果。