Sleep-Wake and Epilepsy Interactions in a Mouse Model of Temporal Lobe Epileps

PI: Pedersen R21 - 2020年6月

PI: Pedersen R21 – June, 2020 PROJECT SUMMARY/ABSTRACT Epilepsy affects more than three million people in the US alone, with most reporting a relationship between seizures and sleep-wake patterns, and about one million having sleep disorders. Furthermore, many of the comorbidities of epilepsy, such as mood disorder, attentional and executive difficulties, memory dysfunction, and psychosis, are worsened by disrupted sleep. Despite this long-appreciated and robust relationship between sleep-wake and epilepsy, little is known about the underlying mechanisms of this interaction. The long-term objective of this work is to understand better key large-scale brain circuits, namely those that control sleep-wake and how they influence seizure frequency and severity. The overall hypothesis is that careful manipulations of component cell groups of sleep-wake circuits can be used to treat epilepsy and seizures, potentially including some comorbidities of epilepsy. We hypothesize, also based on preliminary findings, that the intra-amygdala kainic acid model of medial temporal lobe epilepsy in mice will show sleep disruptions that are similar to those of people with epilepsy. We further hypothesize that circuit-based manipulations of sleep-wake control circuits will have predictable effects on seizures, with increases in sleep reducing seizures and decreased sleep further worsening epilepsy. We examine these hypotheses in two Specific Aims using a novel purpose-build head plate that permits rapid implantation of microinjection cannula, screw, neck muscle, and depth electrodes in mice. The first Aim examines the mutual influence of sleep-wake and seizures in the mouse intra-amygdala kainic acid model of temporal lobe epilepsy. Preliminary data shows dramatic sleep disruption of sleep in mice with seizures and that seizures are associated with slow-wave sleep and rare in rapid eye movement sleep. The second Aim includes two experiments: One examines the effect of chemogenetically increasing sleep, by activating inhibitory neurons of the parafacial zone of the brainstem; the other activates a vital component of the hypothalamic arousal network, the supramammillary nucleus, that drives wake without sleep rebound. We anticipate that seizures will be reduced by increased sleep and worsened by prolonged wakefulness, respectively. This work Aims to provide a new line of research targeting other sleep-wake nuclei, a new avenue for epilepsy research that focuses on large-scale modulatory circuits and brings together sleep-wake and epilepsy research. We hope that this work will improve our understanding of brain function and help develop novel approaches to the treatment of epilepsy. 1