Restoration of plasticity after pediatric traumatic brain injury

描述（由申请人提供）：创伤性脑损伤（TBI）是儿童和青少年死亡和残疾的最重要原因，但对区分儿童脑损伤与成人脑损伤的潜在机制知之甚少。据了解，对未成熟大脑的创伤性生物力学损伤可以表现为慢性认知和行为问题，并丧失发育潜力。可塑性被定义为大脑改变细胞和网络结构和功能以应对环境变化的机制。越来越多的证据表明，小儿创伤性脑损伤可导致可塑性受损和神经传递改变。谷氨酸代表中枢神经系统中的主要兴奋性神经递质，并且与TBI的急性病理生理学密切相关，但对于正常发育和神经可塑性也是至关重要的。本申请提出研究未成熟脑中对TBI的神经递质能反应，特别是涉及N-甲基-D-天冬氨酸（NMDA）受体的反应。该建议的中心假设是NMDA受体功能障碍是发育性TBI后可塑性丧失的基础，并且可以使用表征良好的儿科TBI实验模型在分子（特定目的1和2），电生理（特定目的3）和认知（特定目的4）方面测量这种扰动。通过确定损伤后这一重要神经递质系统变化的时间进程，将有可能确定NMDA受体神经反应性受损的窗口。然后，对该时间段的适当鉴定将指导本申请的最终目的（具体目的5），其是利用增强NMDA受体神经传递的药理学试剂来使发育中的大脑的分子谱正常化并减轻行为和认知缺陷。该提案提供了一个独特的机会，可以严格测试针对特定年龄的治疗策略，该策略旨在为最易受TBI影响的患者人群（儿童）带来益处。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the single most important cause of death and disability in children and adolescents, yet relatively little is known about the underlying mechanisms that distinguish pediatric brain injury from that in adults. It is understood the traumatic biomechanical injury to the immature brain can manifest as chronic cognitive and behavioral problems with a loss of developmental potential. Plasticity is defined as a mechanism by which the brain modifies cellular and network structure and function to respond to changes in the environment. There is increasing evidence that pediatric TBI can result in impaired plasticity and alterations in neurotransmission. Glutamate represents the major excitatory neurotransmitter in the central nervous system and is intimately involved in the acute pathophysiology of TBI, but also is critical for normal development and for neural plasticity. This application proposes to investigate the glutamatergic response to TBI in the immature brain, in particular, that which involves the N-methyl-D-aspartate (NMDA) receptor. The central hypothesis of this proposal is that dysfunction at the NMDA receptor underlies the loss of plasticity seen following developmental TBI, and that this perturbation can be measured molecularly (Specific Aims 1 and 2), electrophysiologically (Specific Aim 3) and cognitively (Specific Aim 4), using a well-characterized experimental model of pediatric TBI. By determining the post-injury time course of changes in this important neurotransmitter system, it will be possible to identify the window of impaired neural responsiveness at the NMDA receptor. Proper identification of this time period will then direct the final aim (Specific Aim 5) of this application, which is to utilize pharmacological agents that augment NMDA receptor neurotransmission to normalize the molecular profile of the developing brain and to alleviate behavioral and cognitive deficits. This proposal provides a unique opportunity to rigorously test an age-specific therapeutic strategy that is designed to be beneficial for the patient population most vulnerable to TBI, children.