Cortical Slow Waves and Reduced Cholinergic Arousal in Mouse Model of Focal Limbic Seizures with Impaired Behavior
Abstract number :
1.189
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2022
Submission ID :
2204059
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:23 AM
Authors :
Jiayang Liu, PhD – Yale School of Medicine; Lim-Anna Sieu, PhD – Yale School of Medicine; Shobhit Singla, MD, PhD – Yale School of Medicine; Zheng Xinyuan, BS – Yale School of Medicine; Abdelrahman Sharafeldin, BS – Yale School of Medicine; Ganesh Chandrasekaran, BS – University of Pennsylvania; Marcus Valcarce-Aspegren, MD – Yale School of Medicine; Ava Niknahad, BS – John Hopkins school of medicine; Ivory Fu, BS – Yale School of Medicine; Natnael Doilicho, MD – Yale School of Medicine; Abhijeet Gummadavelli, MD – Yale School of Medicine; Cian McCafferty, PhD – University College Cork; Richard Crouse, PhD – Yale School of Medicine; Quentin Perrenoud, PhD – Yale School of Medicine; Marina Picciotto, PhD – Yale School of Medicine; Jessica Cardin, PhD – Yale School of Medicine; Hal Blumenfeld, MD, PhD – Yale School of Medicine
Rationale: Temporal lobe epilepsy (TLE) is often associated with loss of consciousness. In humans, temporal lobe seizures with neocortical slow waves on EEG, similar to the non-REM sleep state, is positively correlated with loss of consciousness. Studies in a rat model showed that subcortical arousal is reduced during focal limbic seizures coupled with cortical slow waves, including decreased brainstem and basal forebrain cholinergic activity. A mouse model of focal temporal lobe seizures would have many advantages: the ease of performing awake, head-fixed experiments to better probe the effect on behavior, and the vast genetic and molecular tools available to better understand underlying circuit and network mechanisms of loss of consciousness. Therefore, we developed an awake-behaving, head-fixed mouse model of temporal lobe seizures.
Methods: Mice were water-restricted and trained to lick a drop of water from a spout in response to a sound (0-50kHz, 12ms) every 10-15s while head-fixed on a freely moving running wheel. Local field potential recordings were performed via implanted bipolar electrodes in the right and left dorsal hippocampus and in the right orbitofrontal cortex (OFC). Focal limbic seizures were induced by a unilateral 2s, 60 Hz hippocampal stimulus via the implanted bipolar electrode. To examine cortical neuronal firing activity, multiunit activity (MUA) recordings were performed in left OFC via a tungsten electrode. To study cholinergic input to OFC during seizures, a genetically encoded fluorescent acetylcholine indicator was expressed in the left OFC via viral injection. Signals were detected via an implanted optic fiber into OFC.
Results: Electrical stimulation in hippocampus induced focal limbic seizures with 5-40s duration in mice and repeatable for several weeks (n= 26 animals). Responses to sound and running speed were reduced during seizures and recovered postictally (p < 0.01, n= 26 animals). Responses to sound were sometimes normal during seizures, suggesting that like in humans, induction of focal temporal lobe seizures in the mouse model do not always affect consciousness. Furthermore, impaired behavioral responses were correlated with increased amplitude of cortical slow waves (p < 0.01, n= 26 animals); and cortical slow waves followed an Up and Down state firing pattern on MUA recordings (n= 11 animals). In addition, cholinergic input to the cortex decreased during seizures (p < 0.01, n= 7 animals), with larger decreases associated with impaired behavior.
Neurophysiology