Decreased cholinergic neuronal firing in a mouse model of temporal lobe seizures with impaired consciousness

Abstract Objective Impaired consciousness during seizures significantly impacts the quality of life for individuals with epilepsy, and recent research has introduced the network inhibition hypothesis, suggesting that impaired consciousness results from the active inhibition of subcortical arousal mechanisms. However, direct evidence in awake animals has been lacking. Our study aimed to address this gap by recording the activity of individual neurons in crucial brainstem and basal forebrain nuclei in a novel behaving mouse model. Methods We conducted recordings in head‐fixed mice running on a freely moving wheel with implanted electrodes in the orbitofrontal cortex and hippocampi. Focal limbic seizures were induced by applying current pulses, and simultaneously we obtained juxtacellular single unit activity recordings from arousal nuclei in the brainstem and basal forebrain. Double immunofluorescence was performed postrecording to confirm cell locations and cholinergic identities. Results Our findings revealed that focal seizure activity suppressed behavior based on decreased running wheel speed, and the orbitofrontal cortex exhibited slow waves resembling encephalopathy or deep sleep. Single unit recordings showed diverse firing patterns during seizures, with some neurons reducing firing, others increasing, and some remaining relatively stable. Importantly, cholinergic neurons in the brainstem pedunculopontine and laterodorsal tegmental nuclei exhibited significant reductions in firing during focal limbic seizures. Significance Our findings provide direct evidence that focal limbic seizures are associated with decreased cholinergic neuronal firing in brainstem arousal nuclei, linking subcortical suppression to cortical impairment. Further exploration of these pathways promises a deeper understanding of ictal unconsciousness and potential novel treatments for people with epilepsy.