Enhancing Recovery after Neonatal Stroke

描述(申请人提供)：最近的研究表明，行为干预可促进中风后的功能恢复。我们开发了实验模型，研究行为干预对新生儿中风后康复的影响，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。在一个具有良好特征的新生啮齿动物中风模型中，我们记录了7天龄(P7)大鼠的空间学习受损。我们最近还发现，新生儿卒中后，双侧海马树突状细胞长度、分支和脊椎密度减少。我们评估了行为干预、新生儿“处理”对卒中后认知功能障碍的影响。处理(每天与大坝短暂分离)被广泛研究；它的效果包括增加突触生成，增加脑源性神经营养因子(BDNF)的产生，以及提高学习速度。我们证明，在新生儿中风后，日常操作的治疗可以改善成年后的空间学习。搬运的一个限制是它的窝间设计。最近描述的“新生儿新颖性”范例在猫砂内设计中复制了许多处理的效果。对缺氧缺血后新颖性的初步研究表明，它还可以改善成年后的认知结果。在这项提案中，我们将开始确定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，我们将确定使用为期2周的新奇方案治疗是否导致突触形成增加(目标1)，以及脑缺血后时期BDNF、TrkB和ERK1/2的变化(目标2)。动物将在P7；2.5个月。稍后，我们将评估三种突触形成的方法：(I)树突形态，(Ii)突触体素，(Iii)NCAM。我们预测，行为干预将逆转中风后的突触缺陷。在目标2中，我们将评估在卒中后新生儿新事物暴露期间，海马区和大脑皮层脑源性神经营养因子、其受体TrkB及其下游的MAP激酶ERK1/2的变化。我们假设，新生儿的新颖性和卒中都会刺激BDNF的产生，行为干预会放大卒中诱导的BDNF及其下游信号的增加。总之，这些实验将为调节和调节新生儿中风后功能恢复的机制提供洞察力。

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.