Repeated hippocampal seizures lead to brain-wide reorganization of circuits and seizure propagation pathways

Abstract

Repeated seizure activity can lead to long-term changes in seizure dynamics and behavior. However, resulting changes in brain-wide dynamics remain poorly understood. This is due partly to technical challenges in precise seizure control and invivo whole-brain mapping of circuit dynamics. Here, we developed an optogenetic kindling model through repeated stimulation of ventral hippocampal CaMKII neurons in adult rats. We then combined fMRI with electrophysiology to track brain-wide circuit dynamics resulting from non-afterdischarge (AD)-generating stimulations and individual convulsive seizures. Kindling induced widespread increasesin non-AD-generating stimulation response and ipsilateral functional connectivity and elevated anxiety. Individual seizures in kindled animals showed more significant increases in brain-wide activity and bilateral functional connectivity. Onset time quantification provided evidence for kindled seizure propagation from the ipsilateral to the contralateral hemisphere. Furthermore, a core of slow-migrating hippocampal activity was identified in both non-kindled and kindled seizures, revealing a novel mechanism of seizure sustainment and propagation.