Reviewer #1's Review

“The article by Böer et al. describes that chronic social stress treatment results in increased transcription levels driven by a CRE promoter sequence in several mouse brain regions such as hippocampus, cerebellum, pons and colliculi. The authors also show that this stress-induced effect is blocked with the concomitant administration of the antidepressant imipramine to the stressed animals. The approach they use to obtain these results is the generation of a transgenic mouse line carrying a reporter gene (luciferase enzime) under the control of a CRE promoter sequence from the somatostatin gene. Hence, they are able to measure luciferase expression in the transgenic mouse brain, which reflects the activation of the transcription factor CREB.

Several other groups have explored before brain expression levels of CREB and its activated form phospho-CREB after chronic stress and antidepressant treatment. Although some of the works are contradictory regarding the direction of the change observed (up or down regulation), the general conclusion is that this transcription factor is very likely to be involved in the stress/antidepressant response. Now, the study of Böer and co-workers adds evidence that implies CREB functionality in these processes. I believe that the results provided in this manuscript are attractive in light of the field's profound interest about stress-induced effects in the brain. In my opinion, the manuscript is easy to understand and the experiments they have done are of high quality.

Still, I have some questions about their work:
1. Given that they describe for the first time this CRE-Luciferase transgenic line, it would be nice to see whether there is no misexpression of the reporter gene, for example by showing that levels of luciferase in different parts of the brain (Fig. 2) correlate with phospho-CREB levels; or that there is a good co-localization between luciferase and phospho-CREB proteins in the brain.

2. While they show luciferase activity measurements in distinct brain regions, they analyze phospho-CREB levels in whole brain homogenates. I think that it would be more appropriate to investigate both parameters in the same brain areas in order to draw a conclusion out of the two results.

3. They find several parts of the brain where CREB transcriptional activity is enhanced by stress treatment. It would be interesting that the authors investigate or discuss the potential targets of this CREB-induced transcription in the different brain regions, as well as the biological significance of this regulation according to the brain area.”

n.b. These are the more general comments made by the referee when reviewing this paper. The published version was revised in light of these comments. Specific points addressed during revision of the paper are not shown.