Fig. 5. CB2R inhibition in combination with PE increases hippocampal BDNF levels and reverts behavioural, cellular, and molecular changes evoked by chronic stress.

a Chronic stress significantly increases CORT levels, and AM630 treatment in combination with PE elevates BDNF hippocampal levels (a1); animals with higher CORT levels display lower levels of BDNF, an effect prominent in chronically stressed animals (a2). b Principal component analysis (PCA) score plot showing the discrimination among different experimental conditions, with the cluster of animals treated with AM630 in combination with PE overlapping with the CTRL cluster; symbol size varies according to CORT levels, as illustrated. c Correlational heatmaps of behavioural, cellular, and molecular readouts reveal positive associations in CTRL animals (c1) and in uCMS animals treated with a combination of AM630 and PE (c5); while uCMS animals (c2) and those subjected to the PE regimen (c3) or treated with AM630 alone (c4) reveal negative correlations in assessed readouts. Data presented as mean ± SEM and circles represent individual data points (animals); heatmap gradients vary between -1 (purple; negative correlation) and 1 (yellow; positive correlation) [Student’s t test/Pearson r test: **p < 0.01, *p < 0.05 vs CTRL; Two-way ANOVA: ^#p < 0.05 vs uCMS; further statistical details in Table S4; correlational matrices: ****p < 0.0001, **p < 0.01, *p < 0.05 vs each parameter]. uCMS unpredictable chronic mild stress, AM630 CB2R inverse agonist, PE physical exercise.