Glioma-induced alterations in neuronal activity and neurovascular coupling during disease progression

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...

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Published inbioRxiv
Main Authors Montgomery, Mary Katherine, Kim, Sharon H, Dovas, Athanassios, Patel, Kripa, Mela, Angeliki, Nelson Humala, Zhao, Hanzhi T, Thibodeaux, David N, Shaik, Mohammed, Ma, Ying, Grinband, Jack, Chow, Daniel S, Schevon, Catherine, Hillman, Elizabeth M C, Canoll, Peter
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 10.09.2019
Subjects
Brain tumors
Cortex
Glioma
Hemodynamics
Hypoxia
Neurological complications
Seizures
Therapeutic applications
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Summary: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 followed 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 in glioma-infiltrated cortex gradually decreased, while neurovascular coupling was also progressively disrupted compared to uninvolved cortex. Over time, mice developed diverse patterns of high amplitude discharges and eventually generalized seizures that begin at the infiltrative margin of the tumors. Interictal and seizure events exhibited positive neurovascular coupling in uninfiltrated cortex, however glioma-infiltrated regions exhibited inverted 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 new biomarkers and therapeutic targets.
DOI:10.1101/763805