The pathophysiology of major depressive disorders is not completely understood. In this issue of Journal of Neurochemistry, Ni and colleagues investigate the role of cyclic adenosine monophosphate response element-binding protein (CREB)-dependent signaling in the hippocampus on depressive-like behaviors. This editorial highlights the key findings reported by Ni et al., (2018) and how they demonstrated the importance of CREB-regulated transcription cofactor 1 in LPS-induced neuroinflammation and depressive-like behaviors. (Figure presented.).