Authors :
Presenting Author: Jiayang Liu, PhD – Yale University
Vivian Doan, BS – Yale University
Jessica Cardin, PhD – Yale University
Hal Blumenfeld, MD, PhD – Yale University
Rationale:
Loss of consciousness is often experienced by patients with focal and generalized seizures and this impaired consciousness persists into the post-ictal period. During focal limbic seizures, impaired arousal is linked to suppression of subcortical arousal systems, including brainstem serotonergic (5-HT) pathways. Dysfunction in these circuits also contributes to post-ictal unresponsiveness, altered cardiorespiratory function, and increased risk of morbidity and mortality. Awake rodent model studies in our lab show that during focal seizures, slow waves in the orbitofrontal cortex (OFC) and reduced cholinergic arousal due to direct inhibition and indirect deexcitation from basal forebrain in mice; Decreased multi-unit activity in the locus coeruleus (LC) during focal seizures in mice; Reduced single-unit activity in the medullary raphe during focal and generalized seizures in rats.
Based on these findings, we hypothesize that in the OFC, not only acetylcholine (Ach) but also serotonin (5-HT) levels decrease due to serotonergic output from the medullary raphe during both focal and generalized seizures. These reductions all contribute to depressed cortical arousal.
Methods:
We use the awake mouse model in which focal and generalized seizures can be induced by electrically stimulating the hippocampus. We record local field potential (LFP) from the hippocampus and the OFC while monitoring running and licking behaviors. We record the change of levels of 5-HT in the OFC using fiber photometry in two experimental scenarios: 1. focal temporal lobe seizures; 2. generalized seizures.Results:
1. During focal-induced seizures, we observed slow wave activity in the OFC and arrested running and licking behavior that quickly returned to normal licking and running (< 30s after seizure offset). 2. 5HT levels in OFC decreased during focal seizures. During generalized seizures, we found poly-spike and wave ictal activity in the OFC, and the 5-HT level (5 seizures) showed a bigger and longer decrease during and after seizures than those observed in focal seizures. In addition, in generalized seizures, the animals showed extended impaired running and licking ( >30s after seizure offset).Conclusions:
Our results show during focal and generalized seizures, 5-HT is suppressed, which we hypothesize may contribute to decreased cortical arousal. Further work will include cell-type specific GCaMP measure of serotonergic neuronal activity in the brain stem and sensing of other neurotransmitters in the OFC in the same experimental scenarios. We aim to uncover the mechanisms responsible for impaired consciousness during ictal and postictal periods in focal and generalized seizures and potentially leading to the development of innovative treatments.Funding:
NIH R01 NS066974