Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology

Moran Furman, Qiong Zhan, Cian McCafferty, Benjamin A Lerner, Joshua E Motelow, Jin Meng, Chanthia Ma, Gordon F Buchanan, Ilana B Witten, Karl Deisseroth, Jessica A Cardin, Hal Blumenfeld

Focal temporal lobe seizures often cause impaired cortical function and loss of consciousness. Recent work suggests that the mechanism for depressed cortical function during focal seizures may depend on decreased subcortical cholinergic arousal, which leads to a sleep-like state of cortical slow-wave activity. To test this hypothesis, we sought to directly activate subcortical cholinergic neurons during focal limbic seizures to determine the effects on cortical function. Here we used an optogenetic approach to selectively stimulate cholinergic brainstem neurons in the pedunculopontine tegmental nucleus during focal limbic seizures induced in a lightly anesthetized rat model. We found an increase in cortical gamma activity and a decrease in delta activity in response to cholinergic stimulation. These findings support the mechanistic role of reduced subcortical cholinergic arousal in causing cortical dysfunction during seizures. Through further work, electrical or optogenetic stimulation of subcortical arousal networks may ultimately lead to new treatments aimed at preventing cortical dysfunction during seizures.