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Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour.

Banerjee S, Wang Y, Solt LA, Griffett K, Kazantzis M, Amador A, El-Gendy BM, Huitron-Resendiz S, Roberts AJ, Shin Y, Kamenecka TM, Burris TP - Nat Commun (2014)

Bottom Line: REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep.Interestingly, REV-ERB agonists also reduce anxiety-like behaviour.These data are consistent with increased anxiety-like behaviour of REV-ERBβ- mice, in which REV-ERB agonists have no effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.

ABSTRACT
Synthetic drug-like molecules that directly modulate the activity of key clock proteins offer the potential to directly modulate the endogenous circadian rhythm and treat diseases associated with clock dysfunction. Here we demonstrate that synthetic ligands targeting a key component of the mammalian clock, the nuclear receptors REV-ERBα and β, regulate sleep architecture and emotional behaviour in mice. REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behaviour. These data are consistent with increased anxiety-like behaviour of REV-ERBβ- mice, in which REV-ERB agonists have no effect. These results indicate that pharmacological targeting of REV-ERB may lead to the development of novel therapeutics to treat sleep disorders and anxiety.

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Related in: MedlinePlus

Administration of SR9011 Alters Sleep ArchitectureEffect of SR9011 administered at ZT6 (analysis of data from Figure 1A) on SWS (number of episodes (A) and episode duration (B)) and on REM sleep (number of episodes (C) and episode duration (D)). potential differences between treatments were assessed by repeated measure two-way ANOVA followed by Bonferroni post hoc test with significance *P < 0.05
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Figure 2: Administration of SR9011 Alters Sleep ArchitectureEffect of SR9011 administered at ZT6 (analysis of data from Figure 1A) on SWS (number of episodes (A) and episode duration (B)) and on REM sleep (number of episodes (C) and episode duration (D)). potential differences between treatments were assessed by repeated measure two-way ANOVA followed by Bonferroni post hoc test with significance *P < 0.05

Mentions: The “master” circadian clock located in the suprachiasmatic nucleus of the hypothalamus plays an essential role in regulation of sleep16 and given this close relationship, we sought to investigate the effect of pharmacological activation of REV-ERB on patterns of sleep and wakefulness. Although we observed alterations in circadian wheel running activity previously9, the effect on sleep was not clear. In order to investigate this we administered a REV-ERB agonist, SR9011, to mice and examined the effect on sleep and wakefulness by electroencephalogram (EEG). As illustrated in Fig. 1A, mice displayed a normal nocturnal profile with low wakefulness and high slow wave sleep (SWS) and paradoxical sleep – rapid eye movement (REM) sleep during the daytime (zeitgeiber time 0 (ZT0) to ZT12). Mice were administered SR9011 (100 mg kg−1, i.p.) or vehicle at ZT6 when Reverb expression is at its peak9. SR9011 treated mice displayed a large increase in wakefulness that was maintained for 2h post injection (Fig. 1A top panel). As expected this corresponded to a decrease in SWS and REM sleep during the same time period (Fig. 1A bottom panels). Latency to enter SWS and REM sleep after administration of SR9011 was increased as illustrated in Fig. 1B. At the onset of the dark period (ZT12) vehicle treated mice displayed a normal, rapid increase in wakefulness (and decrease in SWS and REM sleep) while this effect was delayed in SR9011-treated mice (Fig. 1A). A normal pattern of sleep was observed after this recovery period approximately 12h after the initial injection. Analysis of sleep architecture after the single injection of SR9011 at ZT6 revealed effects on both SWS and REM sleep architecture (Fig. 2). Following injection of SR9011 the number of episodes of SWS increased while their duration was shortened (Fig. 2A & 2B). REM sleep was also affected and was more impressive with REM sleep episodes and duration being nearly completely suppressed for 3 hours following administration of SR9011 (Fig. 2C & 2D). The sleep recovery period that was observed following transition to dark was also observed in the sleep architecture. Episodes of SWS were increased in SR9011 treated mice from ZT13-15 while SWS duration remained constant (Fig. 2A & 2B). Episodes of REM sleep were also elevated after transition to dark with SR9011 treatment (Fig. 2C). No effect of SR9011 treatment was observed on EEG power (Supplementary Fig. 1A).


Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour.

Banerjee S, Wang Y, Solt LA, Griffett K, Kazantzis M, Amador A, El-Gendy BM, Huitron-Resendiz S, Roberts AJ, Shin Y, Kamenecka TM, Burris TP - Nat Commun (2014)

Administration of SR9011 Alters Sleep ArchitectureEffect of SR9011 administered at ZT6 (analysis of data from Figure 1A) on SWS (number of episodes (A) and episode duration (B)) and on REM sleep (number of episodes (C) and episode duration (D)). potential differences between treatments were assessed by repeated measure two-way ANOVA followed by Bonferroni post hoc test with significance *P < 0.05
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495958&req=5

Figure 2: Administration of SR9011 Alters Sleep ArchitectureEffect of SR9011 administered at ZT6 (analysis of data from Figure 1A) on SWS (number of episodes (A) and episode duration (B)) and on REM sleep (number of episodes (C) and episode duration (D)). potential differences between treatments were assessed by repeated measure two-way ANOVA followed by Bonferroni post hoc test with significance *P < 0.05
Mentions: The “master” circadian clock located in the suprachiasmatic nucleus of the hypothalamus plays an essential role in regulation of sleep16 and given this close relationship, we sought to investigate the effect of pharmacological activation of REV-ERB on patterns of sleep and wakefulness. Although we observed alterations in circadian wheel running activity previously9, the effect on sleep was not clear. In order to investigate this we administered a REV-ERB agonist, SR9011, to mice and examined the effect on sleep and wakefulness by electroencephalogram (EEG). As illustrated in Fig. 1A, mice displayed a normal nocturnal profile with low wakefulness and high slow wave sleep (SWS) and paradoxical sleep – rapid eye movement (REM) sleep during the daytime (zeitgeiber time 0 (ZT0) to ZT12). Mice were administered SR9011 (100 mg kg−1, i.p.) or vehicle at ZT6 when Reverb expression is at its peak9. SR9011 treated mice displayed a large increase in wakefulness that was maintained for 2h post injection (Fig. 1A top panel). As expected this corresponded to a decrease in SWS and REM sleep during the same time period (Fig. 1A bottom panels). Latency to enter SWS and REM sleep after administration of SR9011 was increased as illustrated in Fig. 1B. At the onset of the dark period (ZT12) vehicle treated mice displayed a normal, rapid increase in wakefulness (and decrease in SWS and REM sleep) while this effect was delayed in SR9011-treated mice (Fig. 1A). A normal pattern of sleep was observed after this recovery period approximately 12h after the initial injection. Analysis of sleep architecture after the single injection of SR9011 at ZT6 revealed effects on both SWS and REM sleep architecture (Fig. 2). Following injection of SR9011 the number of episodes of SWS increased while their duration was shortened (Fig. 2A & 2B). REM sleep was also affected and was more impressive with REM sleep episodes and duration being nearly completely suppressed for 3 hours following administration of SR9011 (Fig. 2C & 2D). The sleep recovery period that was observed following transition to dark was also observed in the sleep architecture. Episodes of SWS were increased in SR9011 treated mice from ZT13-15 while SWS duration remained constant (Fig. 2A & 2B). Episodes of REM sleep were also elevated after transition to dark with SR9011 treatment (Fig. 2C). No effect of SR9011 treatment was observed on EEG power (Supplementary Fig. 1A).

Bottom Line: REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep.Interestingly, REV-ERB agonists also reduce anxiety-like behaviour.These data are consistent with increased anxiety-like behaviour of REV-ERBβ- mice, in which REV-ERB agonists have no effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.

ABSTRACT
Synthetic drug-like molecules that directly modulate the activity of key clock proteins offer the potential to directly modulate the endogenous circadian rhythm and treat diseases associated with clock dysfunction. Here we demonstrate that synthetic ligands targeting a key component of the mammalian clock, the nuclear receptors REV-ERBα and β, regulate sleep architecture and emotional behaviour in mice. REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behaviour. These data are consistent with increased anxiety-like behaviour of REV-ERBβ- mice, in which REV-ERB agonists have no effect. These results indicate that pharmacological targeting of REV-ERB may lead to the development of novel therapeutics to treat sleep disorders and anxiety.

Show MeSH
Related in: MedlinePlus