Critical Period Plasticity Following Neonatal Brain Injury

描述(申请人提供)：早产和足月出生窒息导致脑损伤，由氧气供应不足，并构成一个主要的和日益严重的世界性健康问题。据估计，美国早产儿每年的社会经济负担超过262亿美元。大多数早产儿(妊娠25周)结局不佳，导致死亡或终生患病，并伴有运动、感觉、学习、行为和语言障碍，限制了学业成就和福祉。在开发改善神经学结果的疗法方面取得了有限的进展。这项建议的总体目标是了解早期脑损伤对活动依赖型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。在这笔赠款的第一个周期中，我们研究了一个 早期脑缺氧缺血(HI)脑损伤的小动物模型显示，亚板下神经元是一组在皮质形成中起中心作用的暂时性皮质神经元 电路，是最脆弱的细胞之一。在早期HI损伤后，动物表现出皮质可塑性降低。在目前的提案中，我们将重点放在早期的、自发的模式脑活动上，这是正常活动依赖的发育和皮质环路完善所必需的。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、细胞程序性死亡、突触形成和电路完善。活动自发地出现在发育中的神经系统的许多区域，通常采取爆发后静默的形式，这是早产儿脑电(EEG)的一个特征--轨迹中断。这些突发的活动不是随机的，它们包含特定频段的嵌套振荡，其中一些低于用于人类临床脑电的标准滤波器，因此没有得到很好的认识。早期的脑损伤会减少自发的神经元活动。我们的中心假设是，早期HI脑损伤后的不利神经发育结果在很大程度上是由于神经元和皮质回路活动依赖的发育受损造成的。操纵早期活动可能是促进早期脑损伤后修复和恢复的新策略。

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) -- tracé 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.