Laboratory for Functional Optical Imaging, Zuckerman Mind Brain Behavior Institute, Departments of Biomedical Engineering and Radiology, Columbia University, New York, NY 10027, USA.
Department of Pathology and Cell Biology, Irving Cancer Research Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Cell Rep. 2020 Apr 14;31(2):107500. doi: 10.1016/j.celrep.2020.03.064.
Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption, and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we follow glioma progression in awake Thy1-GCaMP6f mice using in vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity gradually decreases in glioma-infiltrated cortical regions, while neurovascular coupling becomes progressively disrupted compared to uninvolved cortex. Over time, mice develop diverse patterns of high amplitude discharges and eventually generalized seizures that appear to originate at the tumors' infiltrative margins. Interictal and seizure events exhibit positive neurovascular coupling in uninfiltrated cortex; however, glioma-infiltrated regions exhibit disrupted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring novel biomarkers and therapeutic targets.
弥漫性浸润性神经胶质瘤已知会导致皮质功能改变、血管破裂和癫痫发作。这些神经并发症带来了重大的临床挑战，但它们与疾病进展的潜在机制和因果关系尚未得到充分描述。在这里，我们使用体内宽场光学映射在清醒的 Thy1-GCaMP6f 小鼠中跟踪神经胶质瘤的进展，以监测神经元活动和功能血液动力学的变化。在神经胶质瘤浸润的皮质区域，自发神经元活动的双侧同步性逐渐降低，而与未受累的皮质相比，神经血管耦合逐渐被破坏。随着时间的推移，小鼠表现出多种形式的高振幅放电，最终发展为全身性癫痫，这些癫痫似乎起源于肿瘤的浸润边缘。发作间期和发作事件在未浸润的皮质中表现出正的神经血管耦合；然而，浸润性胶质瘤区域表现出破坏的血液动力学反应，导致癫痫诱发的缺氧。这些结果揭示了神经胶质瘤进展过程中发生的复杂生理相互作用的全景图，并为探索新的生物标志物和治疗靶点提供了新的机会。
