Optogentic control of epileptic seizures in a network mapped by simultaneous calcium recordings and fMRI

该项目采用了一种新颖独特的光遗传学，基于纤维的钙记录和功能磁共振成像（fMRI）的组合，以研究人类失神癫痫大鼠模型中的神经元网络，来自斯特拉斯堡的遗传失神癫痫大鼠（GAERS），并探索光遗传学干预干预癫痫发作的策略。在德国，癫痫影响着50多万人，但大脑中异常网络活动的确切机制仍然难以捉摸。钙记录允许癫痫发作检测和深入分析和解释同时获得的功能磁共振成像数据。将推导特定脑区和/或癫痫发作阶段的血流动力学反应。更重要的是，线扫描功能磁共振成像允许读出皮质层特定的血流动力学反应功能。基于准确的血流动力学反应函数，将推导出具有高度空间和时间特异性的癫痫发作地图，揭示异常网络活动的节点和潜在的重要远程癫痫发作瓶颈。在这些瓶颈点的脑切片实验将系统地研究和优化光遗传学方法，即沉默兴奋性神经元或激活神经元，以中断癫痫发作。成功的策略随后将通过同步光遗传学-钙记录-fMRI转移并应用于体内模型。因此，对癫痫网络的神经元和血液动力学活性（包括远程脑区域的潜在阻塞点）的全面评估将成为可能，并且将确定干扰癫痫发作的最有前途的光遗传学方法。

This project employs a novel and unique combination of optogenetics, fiber-based calcium recordings and functional magnetic resonance imaging (fMRI) to investigate neuronal networks in a rat model of human absence epilepsy, the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and to explore strategies for optogenetic interventions to interfere with epileptic seizures. Epilepsy affects more than half a million people in Germany, but the exact mechanisms of aberrant network activity in the brain remains elusive. Calcium recordings allow for seizure detection and in depth analysis and interpretation of simultaneously acquired fMRI data. Hemodynamic responses will be derived for specific brain regions and/or seizure phases. Even more, line scanning fMRI allows for read out of cortical layer-specific hemodynamic response functions. Based on accurate hemodynamic response functions, seizure maps with high spatial and temporal specificity will be derived revealing nodes of aberrant network activity and potentially essential, remote seizure choke points. Brain slice experiment at these choke points will systematically investigate and optimize optogenetic approaches, namely silencing of excitatory neurons or activating neurons, to interrupt seizures. Successful strategies will subsequently be transferred and applied in the in vivo model by simultaneous optogenetic-calcium recording-fMRI. Thus, a comprehensive assessment of both neuronal and hemodynamic activity of the epileptic network, including potential choke points at remote brain regions will become possible, and the most promising optogenetic approach to interfere with seizures will be identified.