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的单一原因，然而，关于区分儿童脑损伤和成人脑损伤的潜在机制，人们所知相对较少。创伤性生物力学损伤对未成熟大脑的影响可以表现为慢性认知和行为问题，并伴有发育潜力的丧失。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一种机制。越来越多的证据表明，儿童脑外伤可导致可塑性受损和神经传递的改变。谷氨酸是中枢神经系统中主要的兴奋性神经递质，与创伤性脑损伤的急性病理生理密切相关，但对正常发育和神经可塑性也至关重要。该应用程序旨在研究未成熟大脑对脑外伤的谷氨酸能反应，特别是涉及n -甲基- d -天冬氨酸（NMDA）受体的谷氨酸能反应。该建议的中心假设是NMDA受体功能障碍是发展性脑损伤后可塑性丧失的基础，并且这种干扰可以通过分子（Specific Aims 1和2）、电生理（Specific Aim 3）和认知（Specific Aim 4）进行测量，使用一个具有良好特征的儿科脑损伤实验模型。通过确定这一重要神经递质系统损伤后的时间变化过程，将有可能确定NMDA受体神经反应性受损的窗口。正确识别这段时间将指导本应用程序的最终目标（具体目标5），即利用增强NMDA受体神经传递的药理学药物来正常化发育中的大脑的分子特征，并减轻行为和认知缺陷。这一建议提供了一个独特的机会来严格测试针对特定年龄的治疗策略，该策略旨在为最易患TBI的患者群体儿童提供有益的治疗。

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.