Critical Period Plasticity Following Neonatal Brain Injury

描述（由申请人提供）：早产和足月分娩窒息导致氧气输送不足导致脑损伤，构成了一个主要且日益严重的全球性健康问题。据估计，美国早产儿每年的社会经济负担超过262亿美元。在大多数早产儿（妊娠< 25周）中，结果很差，导致死亡或终身患病，并伴有运动、感觉、学习、行为和语言残疾，限制了学业成绩和福祉。在开发改善神经系统结局的疗法方面取得的进展有限。该提案的总体目标是了解早期脑损伤对活动依赖性脑发育和皮质可塑性的影响，以开发新的治疗方法，优化脑损伤后的修复和恢复。在第一轮拨款中，我们研究了 早期脑缺氧-缺血（HI）脑损伤小动物模型，以显示亚板神经元，在皮质神经元的形成中具有中枢作用的皮质神经元的瞬时群体 是最脆弱的细胞之一。在早期HI损伤后，动物显示皮质可塑性降低。在本提案中，我们专注于早期，自发的模式化大脑活动所必需的正常活动依赖的发展和完善的皮层电路。活动直接影响无数的发育过程，包括基因和蛋白质表达、细胞分化、迁移、程序性细胞死亡、突触形成和电路完善。活动在发育中的神经系统的许多区域自发地产生，通常采取突发的形式，随后是沉默的时期，这是早产儿脑电图（EEG）的特征--跟踪中断。这些活动的爆发不是随机的，它们包含特定频带中的嵌套振荡，其中一些低于用于人类临床EEG的标准滤波器，因此尚未得到很好的理解。早期脑损伤减少自发神经元活动。我们的中心假设是，不良的神经发育结果后，早期HI脑损伤的结果在很大程度上从受损的活动依赖性发展的神经元和皮层电路。早期活动的操纵可能是一种新的策略，以加强修复和恢复后，早期脑损伤。

DESCRIPTION (provided by applicant): Preterm birth and term birth asphyxia result in brain injury from inadequate oxygen delivery and constitute a major and growing worldwide health problem. Estimates of the annual societal economic burden for the preterm population in the United States exceed $26.2 billion. Poor outcomes are noted in a majority of very premature (< 25 weeks gestation) newborns resulting in death or life-long morbidity with motor, sensory, learning, behavioral and language disabilities that limit academic achievement and well-being. Limited progress has been made to develop therapies that improve neurologic outcomes. The overall objective of this proposal is to understand the impact of early brain injury on activity-dependent brain development and cortical plasticity, in order to develop new treatments that will optimize repair and recovery following brain injury. In the first cycle of this grant, we studied a small animal model of early cerebral hypoxic-ischemic (HI) brain injury to show that subplate neurons, a transient population of cortical neurons with central roles in the formation of cortical circuits, are among the most vulnerable cells. Following early HI injury, animals display reduced cortical plasticity. In the present proposal, we focus on early, spontaneous patterned brain activity necessary for normal activity-dependent development and refinement of cortical circuits. Activity directly influences a myriad of developmental processes including gene and protein expression, cell differentiation, migration, programmed cell death, synapse formation and circuit refinement. Activity arises spontaneously in many areas of the developing nervous system, often taking the form of bursts followed by periods of silence, a characteristic feature of the preterm electroencephalogram (EEG) -- trac¿ discontinu. These bursts of activity are not random, they contain nested oscillations in specific frequency bands, some of which are below standard filters used for human clinical EEG and thus have not been well appreciated. Early brain injury reduces spontaneous neuronal activity. Our central hypothesis is that adverse neurodevelopmental outcome following early HI brain injury results in large part from impaired activity-dependent development of neurons and cortical circuits. Manipulation of early activity may be a new strategy to augment repair and recovery following early brain injury.