Cognitive Recovery and Neuronal Plasticity after Stroke in the Aged

描述(申请人提供)：中风是包括记忆障碍在内的残疾的主要原因。我们的实验室已经证明了一种新的治疗方法，即抗Nogo-A免疫疗法，可以使啮齿动物中风后的感觉运动功能恢复。然而，到目前为止，抗Nogo-A免疫疗法在中风后记忆恢复中的作用还没有得到研究。本研究旨在探讨抗Nogo-A免疫疗法作为改善老年啮齿动物卒中后记忆障碍的治疗干预方法。目的1利用Morris水迷宫确定老年卒中后抗Nogo-A免疫治疗是否能减轻记忆损害。莫里斯水迷宫将被用来评估空间参考和工作记忆。目的2将采用高尔基-考克斯分析来确定卒中后抗Nogo-A免疫治疗是否能诱导参与学习和记忆的两个大脑结构--海马区和内嗅区的树突状可塑性。高尔基-考克斯处理脑的海马神经元(CA1锥体细胞、CAS锥体细胞和DG颗粒细胞)和内嗅皮层(第II层星状细胞、第III层锥体细胞和第V层锥体细胞)中的神经元将通过树突分枝、脊柱密度和脊柱形态的量化来检查结构神经元的可塑性。这些实验与临床实践相关，解决了中风后记忆障碍导致的生活质量显著下降的问题。此外，这些实验的翻译相关性通过对老年啮齿动物进行建模来最大化，在老年人群中，中风是最普遍的。此外，抗Nogo-A免疫疗法是一种有希望的治疗干预措施，可能很快就会转化为中风的临床试验。欧洲已经开始的第一阶段临床试验证明了这一点，该试验旨在测试抗Nogo-A作为脊髓损伤的治疗干预措施。中风是美国残疾的主要原因，在许多情况下，残疾是由包括记忆障碍在内的认知障碍造成的。这项建议将有助于开发治疗认知障碍的方法，包括中风后的记忆障碍。此外，这一建议将导致关于神经元可塑性在中风后大脑修复中的作用的重要信息。

DESCRIPTION (provided by applicant): Stroke is a major cause of disability including memory impairment. Our laboratory has shown that a novel treatment, anti-Nogo-A immunotherapy results in sensorimotor functional recovery after stroke in rodents. However, the role of anti-Nogo-A immunotherapy in memory recovery after stroke has not, as of yet, been investigated. The purpose of this proposal is to investigate anti-Nogo-A immunotherapy as a therapeutic intervention to improve memory impairment after stroke in aged rodents. Aim 1 will employ the Morris water maze to determine whether anti-Nogo-A immunotherapy after stroke in the aged attenuates memory impairment. The Morris water maze will be used to evaluate spatial reference and working memory. Aim 2 will employ Golgi-Cox analysis to determine whether anti-Nogo-A immunotherapy after stroke induces dendritic plasticity in the hippocampus and entorhinal cortex, two brain structures involved in learning and memory. Neurons in the hippocampus (CA1 pyramidal cells, CAS pyramidal cells, and DG granule cells) and entorhinal cortex (layer II stellate cells, layer III pyramidal cells, and layer V pyramidal cells) of Golgi-Cox processed brains will be examined for structural neuronal plasticity by quantification of dendritic arborization, spine density, and spine morphology. These experiments are relevant to clinical practice by addressing the significant decrease in quality of life caused by memory impairment after stroke. In addition, the translational relevance of these experiments is maximized by modeling the elderly human population, in which stroke is most prevalent, with aged rodents. Furthermore, anti-Nogo-A immunotherapy is a promising therapeutic intervention that may be quickly translated into a clinical trial for stroke. This is evidenced by the Phase 1 clinical trial that has begun in Europe to test anti-Nogo-A as a therapeutic intervention for spinal cord injury. Stroke is a major cause of disability in the United States and in many cases the disability is contributed to by cognitive impairments including memory impairments. This proposal will contribute to the development of treatments for cognitive impairments including memory impairments after stroke. In addition, this proposal will lead to important information regarding the role of neuronal plasticity in brain repair after stroke.