Mechanisms of Impaired Arousal and Sensory Processing in a Behaving Mouse Model of Absence Seizures

About This Grant

PROJECT ABSTRACT Absence seizures, characterized by rhythmic 3–4 Hz spike-and-wave discharges (SWDs) on electroencephalography, represent a significant neurological burden affecting thousands of children worldwide. These brief (5-10 second) periods of impaired responsiveness and loss of consciousness are associated with lasting cognitive, sensory, and learning deficits. Despite this clinical impact, the cellular and network mechanisms underlying impaired consciousness and arousal during absence seizures remain poorly understood, limiting options for therapeutic development in pediatric epilepsy. Prior research in rat models of absence seizures has attempted to address this gap and has partially recapitulated the behavioral impairments seen in patients by training rats on behavioral tasks as proxy indicators of consciousness. However, these studies were performed in freely moving rats, limiting the use of advanced cellular and optical methods that require head fixation. Given the broad availability of genetic and molecular tools in mouse models and the feasibility of studying mice in awake, head-fixed conditions, establishing a behaving head-fixed model of absence seizures would be extremely valuable. To this end, this project will use the heterozygous SCN8A mouse model, a well-characterized genetic model of absence seizures, in combination with an awake, behaving head-fixed task paradigm, to elucidate mechanisms of disrupted arousal and auditory processing during SWDs. Aim 1 will optimize a lick-on-cue behavioral paradigm and evaluate cortical acetylcholine dynamics during task performance using fiber photometry to characterize arousal state changes at the neurotransmitter level. Aim 2 will utilize in vivo single unit recordings to identify cortical neurons associated with SWD-disrupted behaviors and characterize distinct firing patterns underlying consciousness impairment. Experiments from Aim 1 will provide the first characterization of chemical mediators of impaired arousal in absence epilepsy, particularly within the auditory primary and association cortex processing network. By correlating single-neuron activity with behavioral impairment severity and establishing morphological identity through juxtacellular labeling, Aim 2 will reveal which specific cortical cell types and firing dynamics underlie consciousness disruption during absence seizures. These findings will advance our fundamental understanding of the neural mechanisms underlying consciousness and arousal, with direct implications for developing targeted interventions for childhood absence epilepsy. The mechanistic insights gained may also inform therapeutic approaches for other neurological conditions affecting consciousness and cognitive function in pediatric populations. This project is well-positioned for success through the integration of strong mentorship, technical expertise from key collaborators, comprehensive training opportunities, and state-of-the-art research facilities.