Schmitt Oliver, Eipert Peter, Wang Yonggang, Kanoke Atsushi, Rabiller Gratianne, Liu Jialing
Medical School Hamburg - University of Applied Sciences, Department of Anatomy; University of Rostock, Institute of Anatomy.
SFVAMC, 1700 Owens Street, San Francisco, CA 94158.
bioRxiv. 2023 May 5:2023.05.05.539601. doi: 10.1101/2023.05.05.539601.
Experimental rat models of stroke and hemorrhage are important tools to investigate cerebrovascular disease pathophysiology mechanisms, yet how significant patterns of functional impairment induced in various models of stroke are related to changes in connectivity at the level of neuronal populations and mesoscopic parcellations of rat brains remain unresolved. To address this gap in knowledge, we employed two middle cerebral artery occlusion models and one intracerebral hemorrhage model with variant extent and location of neuronal dysfunction. Motor and spatial memory function was assessed and the level of hippocampal activation via Fos immunohistochemistry. Contribution of connectivity change to functional impairment was analyzed for connection similarities, graph distances and spatial distances as well as the importance of regions in terms of network architecture based on the rat connectome. We found that functional impairment correlated with not only the extent but also the locations of the injury among the models. In addition, via coactivation analysis in dynamic rat brain models, we found that lesioned regions led to stronger coactivations with motor function and spatial learning regions than with other unaffected regions of the connectome. Dynamic modeling with the weighted bilateral connectome detected changes in signal propagation in the remote hippocampus in all 3 stroke types, predicting the extent of hippocampal hypoactivation and impairment in spatial learning and memory function. Our study provides a comprehensive analytical framework in predictive identification of remote regions not directly altered by stroke events and their functional implication.
实验性中风和出血大鼠模型是研究脑血管疾病病理生理机制的重要工具，然而，各种中风模型中诱导的功能损害的显著模式如何与大鼠脑神经元群体水平和介观分区的连接性变化相关，仍未得到解决。为了填补这一知识空白，我们采用了两种大脑中动脉闭塞模型和一种脑出血模型，其神经元功能障碍的程度和位置各不相同。通过Fos免疫组织化学评估运动和空间记忆功能以及海马激活水平。基于大鼠连接组，分析了连接性变化对功能损害的贡献，包括连接相似性、图谱距离和空间距离，以及各区域在网络架构方面的重要性。我们发现，功能损害不仅与模型中的损伤程度有关，还与损伤位置有关。此外，通过动态大鼠脑模型中的共激活分析，我们发现损伤区域与运动功能和空间学习区域的共激活比与连接组中其他未受影响区域更强。使用加权双侧连接组进行动态建模，检测到所有三种中风类型的远程海马体中信号传播的变化，预测了海马体激活不足的程度以及空间学习和记忆功能的损害。我们的研究提供了一个全面的分析框架，用于预测性识别未直接受中风事件影响的远程区域及其功能意义。
