基于光遗传学技术研究BDNF/TrkB信号通路在岛叶后区调控心肌梗死后心脏交感神经重构的机制

恶性室性心律失常是心肌梗死（MI）后引起心源性猝死的主要原因。我们前期研究表明：MI后交感神经重构是恶性室性心律失常发生和维持的关键，但梗死引起交感神经重构的神经环路及其受高级中枢调控的机制不明。研究发现BDNF-TrkB通路可能参与了MI后交感神经重构的调控，岛叶皮层后区是调控自主神经活性的关键区域。我们提出“岛叶皮层后区-延髓腹外侧头端-脊髓中间外侧柱-左侧星状神经节-心脏交感神经”神经环路是调控MI后交感神经重构的核心并通过BDNF-TrKB信号通路发挥作用这一科学假说。本项目拟通过：(1)建立大鼠MI模型，利用光遗传学技术从神经形态学、功能学方面验证和明确上述神经环路的组成及功能；(2)研究BDNF-TrkB信号通路关键分子在上述神经环路中的调控作用，阐明中枢调控MI后心脏交感神经重构的分子机制。本研究将为中枢神经系统调控MI后心脏交感神经重构提供理论基础，为临床转化提供科学依据。

Malignant ventricular arrhythmia is the main cause of sudden cardiac death after myocardial infarction(MI). Our previous studies have shown that post-MI sympathetic remodeling is the key to the occurrence and maintenance of malignant ventricular arrhythmias. However, the mechanism of sympathetic nerve remodeling induced by infarction and modulated by the higher center still remains unclear. Current research indicates that the BDNF-TrkB signaling pathway may participate in modulating the post-MI sympathetic remodeling which is regulated by central nerves system, and the posterior insular cortex is a pivotal zone to modulate the autonomic nervous activities. We suppose a scientific hypothesis that “posterior insular cortex-RVLM-IML-LSG-heart” circuit is the vital segment for modulating sympathetic remodeling after MI and it is regulated by the BDNF-TrkB signal pathway. First, our study aims to utilize the optogenetic technology to evaluate the neural circuit constitutions and the remodeling features in a post-infarction rat model from the aspects of neuromorphology and neurofunction. Then, we further elaborate molecular mechanisms to expound how central autonomic system modulates the cardiac sympathetic nerves via invastigating the effects of key molecules in BDNF-TrkB signal pathway in the neural circuit. New discoveries of this study may provide the theoretical foundation for better understanding of how central autonomic nervous system modulates post-MI sympathetic remodeling and present a scientific evidence for clinical transformation and application.