Mechanisms of Juvenile Neurogenesis and Post-Stroke Recovery: Determining the Role of Age-Associated Neuroimmune Interactions

项目摘要 局部缺血后的内源性组织再生（通过增强的神经发生或干细胞治疗）已经被证实。 高度寻求，但新生成/新生神经元的低存活率限制了 成人神经发生然而，年轻的受伤大脑具有更大程度的可塑性和修复能力 与成年人相比。在大脑中动脉闭塞的青少年模型中，我们观察到 在缺血后30天的幼年纹状体神经发生中， 电生理结果，我们没有观察到在成人。本报告所述知识方面的差距 目前的建议涉及研究与年龄相关的细胞信号差异， 在青少年缺血性中风后， 在成年人中没有发现。幼年期神经发生的机制尚不清楚，但我们已经确定了 青少年脑卒中急性期的保护性早期免疫反应是 内源性神经元再生和随后的功能恢复。这一发现与报告相反， 在成人中风后急性期的促炎性信号，这通常被认为是有害的 神经元的存活确定幼年神经发生和功能恢复的机制， 确定中风后治疗的新靶点是这项赠款的重点。我们建议将这些结果应用于 成年人刺激神经发生和促进恢复，长期目标是增加神经发生， 与干细胞治疗相结合，以显着改善神经元的存活，替代，和缺血后 青少年和成年人的功能结果。我们计划验证一个核心假设， 大脑与成人大脑不同，新生神经元在受损后的大脑中存活并成熟。 缺血青少年脑，通过支持增强神经网络功能和行为恢复 中风引起的抗炎信号。我们将通过追求以下目标来检验这一假设： 1)神经发生是改善神经元修复和增强缺血后神经元再生所必需的。 行为/电生理结果，2）缺血后抗炎信号对于 神经发生和功能恢复，和3）内源性神经发生可以在青少年中增强， 成年人通过刺激抗炎信号在急性期中风。我们将使用转基因 小鼠、病毒标记、化学遗传学、分子测定、神经行为测试和体内电生理学， 研究青少年脑中神经发生的机制和卒中后随后的功能恢复。 这项研究将极大地提高我们对青少年脑损伤机制的理解。 神经发生和支持新生神经元存活的免疫调节途径， 功能恢复，确定成人和儿童中风治疗的新方法和创新方法。

PROJECT SUMMARY Endogenous tissue regeneration following ischemia (via enhanced neurogenesis or stem cell therapy) has been highly sought, but the low survival rate of newly generated/newborn neurons limited the therapeutic potential of adult neurogenesis. However, the young injured brain has a greater degree of plasticity and capacity for repair compared to the adult. In a juvenile model of middle cerebral artery occlusion, we observe a remarkable increase in neurogenesis in the juvenile striatum at 30d post-ischemia that is coupled with improved behavioral and electrophysiological outcomes, which we did not observe in adults. The gap in knowledge addressed in the current proposal involves investigating the age-associated differences in cellular signaling responsible for enhanced neurogenesis and improved functional recovery following ischemic stroke in juveniles that is not found in adults. The mechanisms of juvenile neurogenesis are not yet understood, but we have identified protective early immune responses in the acute phase of juvenile stroke as a potential mechanism of endogenous neuronal regeneration and subsequent functional recovery. This finding is contrary to reports of proinflammatory signaling in adults during the acute phase after stroke, which is generally seen as deleterious to neuronal survival. Determining the mechanisms of juvenile neurogenesis and functional recovery, and identifying novel targets for post-stroke treatment is the focus of this grant. We propose to apply these results in adults to stimulate neurogenesis and promote recovery, with the long-term goal of augmenting neurogenesis in combination with stem cell therapy to dramatically improve neuronal survival, replacement, and post-ischemic functional outcomes in both juveniles and adults. We plan to test the central hypothesis that the juvenile brain differs from the adult brain, and newborn neurons survive and mature in the damaged post- ischemic juvenile brain, enhancing neural network function and behavioral recovery through support from stroke-induced anti-inflammatory signaling. We will test this hypothesis by pursuing the following aims: 1) neurogenesis is both required and necessary for improved neuronal repair and enhanced post-ischemic behavioral/electrophysiological outcomes, 2) post-ischemic anti-inflammatory signaling is essential for neurogenesis and functional recovery, and 3) endogenous neurogenesis can be enhanced in juveniles and adults through stimulation of anti-inflammatory signaling during the acute phase of stroke. We will use transgenic mice, viral labeling, chemogenetics, molecular assays, neurobehavioral tests, and in vivo electrophysiology to investigate mechanisms of neurogenesis in the juvenile brain and subsequent functional recovery after stroke. The proposed research will greatly improve our understanding of the mechanisms underlying juvenile neurogenesis and the instrumental immunomodulatory pathways supporting newborn neuron survival and functional recovery, identifying new and innovative approaches to stroke treatment in both adults and children.