Slow and fast cortical cholinergic arousal is reduced in a mouse model of focal seizures with impaired consciousness
Lim-Anna Sieu,
Shobhit Singla,
Jiayang Liu,
Xinyuan Zheng,
Abdelrahman Sharafeldin,
Ganesh Chandrasekaran,
Marcus Valcarce-Aspegren,
Ava Niknahad,
Ivory Fu,
Natnael Doilicho,
Abhijeet Gummadavelli,
Cian McCafferty,
Richard B. Crouse,
Quentin Perrenoud,
Marina R. Picciotto,
Jessica A. Cardin,
Hal Blumenfeld
Affiliations
Lim-Anna Sieu
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Shobhit Singla
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Jiayang Liu
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Xinyuan Zheng
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Abdelrahman Sharafeldin
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Ganesh Chandrasekaran
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Marcus Valcarce-Aspegren
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Ava Niknahad
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Ivory Fu
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Natnael Doilicho
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Abhijeet Gummadavelli
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA
Cian McCafferty
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Anatomy and Neuroscience Program, University College Cork, Cork, Ireland
Richard B. Crouse
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA
Quentin Perrenoud
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA
Marina R. Picciotto
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA
Jessica A. Cardin
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA
Hal Blumenfeld
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA; Corresponding author
Summary: Patients with focal temporal lobe seizures often experience loss of consciousness associated with cortical slow waves, like those in deep sleep. Previous work in rat models suggests that decreased subcortical arousal causes depressed cortical function during focal seizures. However, these studies were performed under light anesthesia, making it impossible to correlate conscious behavior with physiology. We show in an awake mouse model that electrically induced focal seizures in the hippocampus cause impaired behavioral responses to auditory stimuli, cortical slow waves, and reduced mean cortical high-frequency activity. Behavioral responses are related to cortical cholinergic release at two different timescales. Slow state-related decreases in acetylcholine correlate with overall impaired behavior during seizures. Fast phasic acetylcholine release is related to variable spared or impaired behavioral responses with each auditory stimulus. These findings establish a strong relationship between decreased cortical arousal and impaired consciousness in focal seizures, which may help guide future treatment.
