Highlights • The neuroprotective effects of resveratrol in vitro or in vivo were investigated. • The increases of PDE4D in the hippocampus led to depression- and anxiety-like behavior. •  PDE4D-mediated cAMP signaling may play an important role in resveratrol’s protective effects in stressed mice. Abstract Resveratrol is a natural non-flavonoid polyphenol found in red wine, which has numerous pharmacological properties including anti-stress and antidepressant-like abilities. […]