Light, Kindling, Action! Brain-Wide Circuit Changes After Optogenetic Hippocampal Kindling Revealed by Functional Magnetic Resonance Imaging
An optogenetic kindling model through repeated stimulation of ventral hippocampal CaMKII neurons in adult rats is developed and 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.
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 in vivo 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 nonafterdischarge (AD)-generating stimulations and individual convulsive seizures. Kindling induced widespread increases in nonADgenerating 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.