Carbachol and Nicotine in Prefrontal Cortex Have Differential Effects on Sleep-Wake States

Abstract

The role of the brainstem cholinergic system in the regulation of sleep-wake states has been studied extensively but relatively little is known about the role of cholinergic mechanisms in prefrontal cortex in the regulation of sleep-wake states. In a recent study, we showed that prefrontal cholinergic stimulation in anesthetized rat can reverse the traits associated with anesthesia and restore a wake-like state, thereby providing evidence for a causal role for prefrontal cholinergic mechanisms in modulating level of arousal. However, the effect of increase in prefrontal cholinergic tone on spontaneous sleep-wake states has yet to be demonstrated. Therefore, in this study, we tested the hypothesis that delivery of cholinergic agonists – carbachol or nicotine – into prefrontal cortex of rat during slow wave sleep (SWS) would produce behavioral arousal and increase the time spent in wake state. We show that unilateral microinjection (200 nL) of carbachol (1 mM) or nicotine (100 mM) into prefrontal cortex during SWS decreased the latency to the onset of wake state (p = 0.03 for carbachol, p = 0.03 for nicotine) and increased the latency to the onset of rapid eye movement sleep (p = 0.008 for carbachol, p = 0.006 for nicotine). Although the infusion of 1 mM carbachol increased the time spent in wake state (p = 0.01) and decreased the time spent in SWS (p = 0.01), infusion of 10 or 100 mM nicotine did not produce any statistically significant change in sleep-wake architecture. These data demonstrate a differential role of prefrontal cholinergic receptors in modulating spontaneous sleep-wake states.

Inactivation of Prefrontal Cortex Delays Emergence From Sevoflurane Anesthesia

“…In contrast, cholinergic stimulation of parietal cortex in sevoflurane-anesthetized rats failed to produce behavioral arousal (Pal et al, 2018). We also demonstrated that infusion of carbachol into prefrontal cortex during slow-wave sleep reduced the latency to the onset of wakefulness and increased the time spent in wakefulness (Parkar et al, 2020). These studies suggest a causal role for prefrontal cortex in behavioral arousal.…”

“…in wake state (Parkar et al, 2020). A rat study focused on thalamocortical synchronization during anesthesia demonstrated similar neural dynamics between rat and human prefrontal cortex and posited a role for prefrontal cortex in emergence from anesthesia (Flores et al, 2017).…”

“…Therefore, we used anesthetic state transitions as a model system to systematically compare the effect of pharmacologic inactivation of (1) prefrontal cortex, and (2) two subregions within parietal cortex-somatosensory barrel field (S1BF) and medial/lateral parietal association cortex (M/LPtA)on behavioral arousal. Based on our recent studies (Pal et al, 2018;Parkar et al, 2020), we hypothesized that inactivation of prefrontal, but not parietal, cortex would facilitate anesthetic induction and delay the emergence from sevoflurane anesthesia. To test the hypothesis, we implemented a loss-of-function approach using tetrodotoxin (TTX)-mediated inactivation of prefrontal or parietal cortices prior to sevoflurane anesthesia and measured the time to loss and return of righting reflexsurrogates for, respectively, loss and return of consciousness in rodents.…”

Is the insula linked to sleep? A systematic review and narrative synthesis

“…Given the importance of sleep to the body, sleep mechanisms have been intensively investigated. Sleep has been shown to involve many regions and nuclei in the brain, including subcortical nuclei such as the hypothalamus, brainstem, and basal forebrain, as well as the prefrontal cortex, motor cortex, anterior cingulate cortex (ACC), and primary visual cortex [ 13 , 14 , 15 , 16 , 17 , 18 ]. However, these findings have raised new questions, such as why so many nuclei as well as the cerebral cortex are involved in the maintenance of sleep or wakefulness while the detailed mechanisms underlying sleep and wakefulness are incompletely understood.…”

Inactivation of Prefrontal Cortex Attenuates Behavioral Arousal Induced by Stimulation of Basal Forebrain During Sevoflurane Anesthesia

“… 1 Similarly, cholinergic stimulation of PFC during slow-wave sleep decreases the latency to wakefulness and increases the time spent in wakefulness. 2 Conversely, tetrodotoxin (TTX)-mediated inactivation of PFC, but not parietal cortex, delays emergence from sevoflurane anesthesia. 3 Notably, reversal of general anesthesia after carbachol delivery into PFC was associated with an increase in local acetylcholine levels, 1 which is consistent with a wide array of studies demonstrating high cortical acetylcholine levels in association with cortical activation and wakefulness.…”