Figure 5. REV-ERB Regulates Anxiety-Like Behavior.

SR9011 displays anxiolytic activity in a range of behavioral assays. A, Results from the open field assay demonstrating that mice administered SR9011 spend a significantly greater amount of time in the center field during the first 5 minutes after placing the animals in the apparatus than mice treated with vehicle. B, SR9011 treated mice display equivalent locomotor activity as vehicle treated mice in the open field assay. Results from elevated plus maze demonstrates that SR9011 treated mice spend a greater percentage of time exploring the open quadrants (C) and exhibit a greater frequency of open arm entries (D) than vehicle treated mice. Results from the novel object (neophobia) assay demonstrating that SR9011 treated mice spend more time near the novel object (E) and travel more distance near the novel object (F) than vehicle treated mice. Results from the light–dark box assay demonstrating that mice treated with SR9011 spend considerably more time in the light box than vehicle treated mice (G) while displaying no difference in the total number of transitions between the boxes (H). Results for the social interaction assay indicating that mice treated with SR9011 display greater social interaction with a novel mouse than mice treated with vehicle (I). Results from the marble burying assay demonstrate that SR9011 treated mice bury fewer marbles than vehicle treated mice (J). and this effect is dose-responsive (K). L, Rev-erbβ^−/− mice display more anxiety in the marble burying assay consistent with data indicating that activation of REV-ERB leads to anxiolytic activity. M, The REV-ERB agonist, SR9011, does not display anxiolytic activity in Rev-erbβ null mice. Rev-erbβ null mice were treated with SR9011 in an identical manner as described in L and subjected the marble burying assay to examine the potential anxiolytic activity of SR9011. Consistent with the actions of SR9011, a distinct REV-ERB agonist, SR9009, also reduces anxiety-like behavior in the open field assay (N) the light-dark transition assay (O and P) and the marble burying assay (Q). Values are mean ± SEM, n=12 mice per group for all experiments except the marble burying test where n=8. With the exception of panel K differences between treatment groups (vehicle vs. SR) were assessed by a two-tailed t test (Student’s) with significance *P < 0.05. In panel K, differences between groups were assessed using one-way ANOVA followed by Tukey’s post hoc test with significance *P<0.05.