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

项目总结 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)一直是 备受追捧，但新生/新生神经元的低存活率限制了治疗潜力 成人神经发生。然而，年轻受伤的大脑具有更大程度的可塑性和修复能力 与成人相比。在大脑中动脉闭塞的幼年模型中，我们观察到显著的增加 在缺血后30d幼年纹状体的神经发生中，与改善的行为和 电生理结果，这是我们在成年人身上没有观察到的。解决的知识差距在 目前的建议涉及调查与年龄相关的负责细胞信号的差异。 用于促进青少年缺血性中风后的神经再生和改善功能恢复， 在成年人身上没有。幼年神经发生的机制尚不清楚，但我们已经确定 青少年卒中急性期保护性早期免疫反应的潜在机制 内源性神经元再生和随后的功能恢复。这一发现与以下报道相反 成人卒中后急性期的促炎信号，通常被认为是有害的 为了神经元的生存。确定幼年神经发生和功能恢复的机制，以及 确定中风后治疗的新靶点是这笔赠款的重点。我们建议将这些结果应用于 成人刺激神经发生和促进恢复，长期目标是增强 与干细胞治疗相结合，显著改善神经元存活、替代和缺血后 青少年和成年人的功能结果。我们计划测试一个中心假设，即青少年 大脑不同于成人大脑，新生神经元在受损的后脑中存活和成熟 青少年脑缺血，通过支持增强神经网络功能和行为恢复 来自中风诱导的抗炎信号。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功能所必需的。 行为/电生理结果，2)缺血后抗炎信号是必不可少的 神经发生和功能恢复，以及3)内源性神经发生可以在青少年和 成人在中风急性期通过刺激抗炎信号。我们将使用转基因技术 小鼠、病毒标记、化学遗传学、分子分析、神经行为测试和体内电生理学 研究中风后青少年脑内神经发生和随后的功能恢复的机制。 建议的研究将极大地提高我们对青少年发病机制的理解。 神经发生和支持新生神经元存活的工具性免疫调节途径 功能恢复，确定成人和儿童中风治疗的新的和创新的方法。

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.