Enhancing Recovery after Neonatal Stroke

描述（由申请人提供）：最近的研究表明，行为干预可以促进脑卒中后的功能恢复。我们建立了实验模型，研究行为干预对新生儿中风后恢复的影响，使我们能够更多地了解未成熟大脑损伤后可塑性的潜在机制。通过单侧颈动脉结扎和中度缺氧暴露，我们在7天大（P7）大鼠的新生儿中风模型中发现，空间学习能力受损。我们最近也证实了新生儿中风后双侧海马树突长度、分支和脊柱密度的减少。我们评估了新生儿“处理”行为干预对脑卒中后认知缺陷的影响。处理（每天与大坝短暂分离）得到了广泛的研究；它的作用包括增加突触发生，增加脑源性神经营养因子（BDNF）的产生，提高学习率。我们证明，在新生儿中风后，日常处理治疗导致成年后空间学习能力的提高。Handling的一个限制是它的间隔设计。最近描述的“新生儿新颖性”范式在窝内设计中复制了许多Handling的效果。缺氧后缺血性新颖性的初步研究表明，它也可以改善成年期的认知结果。在本提案中，我们将开始确定在新生儿中风后行为干预（新生儿新颖性）有益效果的神经机制。在P7大鼠卒中模型中，我们将确定用2周的Novelty方案治疗是否会导致突触形成增加（Aim 1），以及缺血后时期BDNF、trkB和ERK1/2的变化（Aim 2）。动物将在P7受到伤害；2.5小时后，我们将评估突触形成的3种测量方法：(i)树突形态，（ii）突触素，（iii） NCAM。我们预测行为干预将逆转脑卒中后突触缺陷。在Aim 2中，我们将评估中风后新生儿新奇暴露期间海马和皮质BDNF、其受体trkB和下游MAP激酶ERK1/2的变化。我们假设新生儿新奇性和中风都会刺激BDNF的产生，并且中风引起的BDNF及其下游信号的增加将被行为干预放大。总之，这些实验将提供深入了解调解和调节新生儿中风后功能恢复的机制。

DESCRIPTION (provided by applicant): Recent studies suggest that behavioral interventions enhance functional recovery after stroke. We developed experimental models in which to study the impact of behavioral intervention on recovery after neonatal stroke, to enable us to learn more about underlying mechanisms of post-injury plasticity in the immature brain. In a well-characterized neonatal rodent stroke model, elicited by unilateral carotid ligation followed by moderate hypoxia exposure in seven-day-old (P7) rats, we documented that spatial learning is impaired. We recently also demonstrated bilateral decreases in hippocampal dendritic length, branching and spine density after neonatal stroke. We evaluated the impact of the behavioral intervention, neonatal "Handling" on the post-stroke cognitive deficit. Handling (brief daily separation from the dam) is extensively studied; its effects include increased synaptogenesis, increased Brain-Derived Neurotrophic Factor (BDNF) production, and improved learning rates. We demonstrated that, after neonatal stroke, treatment with daily Handling resulted in improved spatial learning in adulthood. A limitation of Handling is its between-litter design. The recently described "Neonatal Novelty" paradigm replicates many of Handling's effects in a within-litter design. Preliminary studies of post-hypoxic-ischemic Novelty suggest it also leads to improved cognitive outcome in adulthood. In this proposal, we will begin to identify the neural mechanisms that underlie the beneficial effect of behavioral intervention (Neonatal Novelty) after neonatal stroke. In the P7 rat stroke model, we will determine whether treatment with a 2-week Novelty protocol results in increased synapse formation (Aim 1), and changes in BDNF, trkB and ERK1/2 in the post-ischemic period (Aim 2). Animals will be lesioned on P7; 2.5 mo. later we will evaluate 3 measures of synapse formation: (i) dendritic morphology, (ii) synaptophysin, (iii) NCAM. We predict that behavioral intervention will reverse post-stroke synaptic deficits. In Aim 2 we will evaluate changes in hippocampal and cortical BDNF, its receptor trkB and the downstream MAP kinase ERK1/2, during post-stroke Neonatal Novelty exposure. We hypothesize that both Neonatal Novelty and stroke will stimulate BDNF production and that the stroke-induced increase in BDNF and its downstream signaling will be amplified by the behavioral intervention. Together these experiments will provide insights into the mechanisms that mediate and modulate functional recovery after neonatal stroke.