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

Abstract

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.

Regional and global connectivity disturbances in focal epilepsy, related neurocognitive sequelae, and potential mechanistic underpinnings

“…69 Furthermore, ictal neocortical inhibition during focal seizures is associated with aberrant activity in subcortical structures important for cortical activation, such as the thalamus and brainstem reticular activation system, 70,71 and activation of thalamic and brainstem reticular targets during seizures may mitigate this cortical suppression. 72,73 These human and animal studies support the "network inhibition hypothesis" of neocortical deactivation during focal consciousness-impairing seizures, and it is possible that recurrent network inhibition during seizures leads to long-term connectivity reorganization. As summarized in Figure 5, a small consciousness-sparing focal seizure (or simple-partial seizure, using previous terminology) in MTLE may remain confined to the mesial temporal lobe and not impair global cerebral function (Fig.…”

“…This suppressed neocortical activity during focal seizures in rodents is starkly contrasted with cortical excitation during secondarily generalized seizures, which is instead associated with increases in neuronal activity, cerebral blood flow, and fMRI signals . Furthermore, ictal neocortical inhibition during focal seizures is associated with aberrant activity in subcortical structures important for cortical activation, such as the thalamus and brainstem reticular activation system, and activation of thalamic and brainstem reticular targets during seizures may mitigate this cortical suppression …”

Optogenetic activation of superior colliculus neurons suppresses seizures originating in diverse brain networks

“…These projections are anatomically and neurochemically well-suited to attenuate seizures, as application of cholinergic agonists to thalamus and the nucleus reticularis pontis oralis (NPRO) both attenuate seizures (Danober et al, 1995; Peterson, 1993). In addition, the PPN has recently been examined in the context of loss of consciousness during focal limbic seizures; partial limbic seizures suppress neuronal firing within the PPN (Motelow et al, 2015), while optogenetic stimulation of these neurons during limbic seizures normalizes cortical slowing seen with focal hippocampal seizures (Furman et al, 2015). These data are consistent with a role for PPN in regulating seizure phenotypes.…”

Neural Circuitry of Wakefulness and Sleep

“…These neurons fire fastest during wake, especially active wake and REM sleep (Boucetta et al, 2014), and electrical stimulation of the PPT region induces fast EEG activity, in part through cholinergic excitation of thalamocortical neurons (Steriade et al, 1991). Selective chemogenetic activation of PPT cholinergic neurons strongly suppresses slow EEG activity during NREM sleep (Kroeger et al, in press), and photostimulation of these cells reduces slow wave activity during seizures (Furman et al, 2015). Thus, much like BF cholinergic neurons, PPT/LDT cholinergic neurons can suppress slow cortical activity, but it remains unknown whether they promote wake itself.…”