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.
Highlights
We report that the infusion of carbachol (1 mM) or nicotine (100 mM) into prefrontal cortex decreased the latency to onset of wake state and increased the latency to onset of rapid eye movement (REM) sleep
The injection sites for the carbachol (1 mM) and nicotine (10 and 100 mM) cohorts were localized to prefrontal cortex (Figure 1)
Statistical comparison showed that as compared to the saline infusion, carbachol into prefrontal cortex significantly decreased the latency to the onset of wake state [mean ± standard error of the mean (SEM): 95.0 ± 28.5 s (21.8–168.2) for saline vs. 10.0 ± 10.0 s (−15.7 – 35.7) for carbachol, p = 0.03, t(5) = 3.1] (Figure 2A)
Summary
Studies over the past century have demonstrated that increase in cortical acetylcholine (ACh) is accompanied by electroencephalographic activation and behavioral arousal while decrease in cortical ACh correlates with slow wave sleep (SWS) and anesthetic-induced unconsciousness (Celesia and Jasper, 1966; Phillis, 1968; Jasper and Tessier, 1971; Marrosu et al, 1995; Kikuchi et al, 1998; Shichino et al, 1998; Lydic and Baghdoyan, 2005; Pal et al, 2016). In a recent study from our laboratory, we demonstrated that reverse dialysis delivery of carbachol, a mixed cholinergic agonist, into rat prefrontal cortex reversed the traits of anesthesia and restored a wake-like state despite the presence of clinically relevant levels of sevoflurane anesthesia (Pal et al, 2018). The carbachol-induced wake-like state was accompanied by an increase in prefrontal ACh levels (Pal et al, 2018) These studies provide compelling evidence in support of a role for prefrontal cortex in arousal, and for cholinergic modulation of behavioral arousal and electroencephalographic activation, evidence for a direct role of prefrontal cholinergic mechanisms in modulating spontaneous sleep-wake states is lacking. In this study, we tested the hypothesis that infusion of cholinergic agonists – carbachol and nicotine – into prefrontal cortex of rats during SWS will (i) produce behavioral arousal, (ii) increase wakefulness, and (iii) suppress sleep states. Infusion of 1 mM carbachol into prefrontal cortex increased wakefulness and decreased SWS whereas infusion of 10 or 100 mM nicotine did not produce any statistically significant effect on sleep-wake states
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
