Enhancing Recovery after Neonatal Stroke

描述（由申请人提供）：最近的研究表明，行为干预可以促进中风后的功能恢复。我们开发了实验模型来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。在一个特征良好的新生啮齿动物中风模型，引起单侧颈动脉结扎，然后中度缺氧暴露在7天龄（P7）大鼠，我们记录了空间学习受损。我们最近还证实了新生儿中风后海马树突长度、分支和棘密度的双侧减少。我们评估了行为干预，新生儿“处理”对脑卒中后认知功能障碍的影响。处理（每日与母体短暂分离）被广泛研究;其影响包括增加突触发生，增加脑源性神经营养因子（BDNF）的产生，以及提高学习率。我们证明，在新生儿中风后，日常处理的治疗导致成年后空间学习的改善。处理的一个局限性是其窝间设计。最近描述的“新生儿新奇”范例复制了许多处理的影响，在一窝内的设计。对缺氧缺血后新奇的初步研究表明，它也会改善成年后的认知结果。在这个提议中，我们将开始确定新生儿中风后行为干预（新生儿新奇）有益效果的神经机制。在P7大鼠中风模型中，我们将确定用2周新奇方案治疗是否导致突触形成增加（目的1），以及缺血后时期BDNF、trkB和ERK 1/2的变化（目的2）。动物将在P7时损伤; 2.5个月。稍后我们将评估突触形成的3种测量：（i）树突形态，（ii）突触素，（iii）NCAM。我们预测，行为干预将扭转中风后突触缺陷。在目标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ERK 1/2的变化。我们假设新生儿新奇和中风都会刺激BDNF的产生，并且中风诱导的BDNF及其下游信号的增加会被行为干预放大。这些实验将为新生儿中风后介导和调节功能恢复的机制提供见解。

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.