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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 SR9009 Alters Sleep ArchitectureEffect of SR9009 administered at ZT6 (analysis of data from Figure 3A) 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 4: Administration of SR9009 Alters Sleep ArchitectureEffect of SR9009 administered at ZT6 (analysis of data from Figure 3A) 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: In order to further assess the specificity of this effect for REV-ERB agonists, we examined the effects of a distinct synthetic REV-ERB agonist, SR9009, on sleep architecture under L:D conditions. As shown in Fig. 3A, the effect of SR9009 was very similar to SR9011 with induction of wakefulness and suppression of SWS and REM sleep followed by a recovery period during the subsequent dark period. Latency to enter SWS and REM sleep was also extended following SR9009 injection (Fig. 3B). Similar to SR9011 treated mice, mice treated with SR9009 returned to normal patterns of wakefulness/sleep 12h after administration. Assessment of sleep architecture revealed a similar profile to that observed with administration of SR9011. After administration of SR9009 at ZT6 there was a general increase in episodes of SWS with a decrease in episode duration (Fig. 4A & 4B). The only distinction between SR9011 and SR9009 is a short delay in the increased SWS episode number where the number of episodes is actually decreased for one time point. REM sleep is also similarly affected with REM sleep episodes and episode duration suppressed following administration of SR9009 (Fig. 4C & 4D). The effect on sleep recovery was also observed after SR9009 treatment where the number of episodes of SWS and REM sleep were elevated after transition to the dark period (Fig. 4A and 4C). No effect on EEG power was observed (Supplementary Figure 1B).


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 SR9009 Alters Sleep ArchitectureEffect of SR9009 administered at ZT6 (analysis of data from Figure 3A) 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 4: Administration of SR9009 Alters Sleep ArchitectureEffect of SR9009 administered at ZT6 (analysis of data from Figure 3A) 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: In order to further assess the specificity of this effect for REV-ERB agonists, we examined the effects of a distinct synthetic REV-ERB agonist, SR9009, on sleep architecture under L:D conditions. As shown in Fig. 3A, the effect of SR9009 was very similar to SR9011 with induction of wakefulness and suppression of SWS and REM sleep followed by a recovery period during the subsequent dark period. Latency to enter SWS and REM sleep was also extended following SR9009 injection (Fig. 3B). Similar to SR9011 treated mice, mice treated with SR9009 returned to normal patterns of wakefulness/sleep 12h after administration. Assessment of sleep architecture revealed a similar profile to that observed with administration of SR9011. After administration of SR9009 at ZT6 there was a general increase in episodes of SWS with a decrease in episode duration (Fig. 4A & 4B). The only distinction between SR9011 and SR9009 is a short delay in the increased SWS episode number where the number of episodes is actually decreased for one time point. REM sleep is also similarly affected with REM sleep episodes and episode duration suppressed following administration of SR9009 (Fig. 4C & 4D). The effect on sleep recovery was also observed after SR9009 treatment where the number of episodes of SWS and REM sleep were elevated after transition to the dark period (Fig. 4A and 4C). No effect on EEG power was observed (Supplementary Figure 1B).

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