According to above mentioned unknowns, the present study used the A/J mice, which have successfully been used to develop lung cancer animal model for tobacco smoke carcinogenesis [56], to explore (1) whether CUMS and smoke combination can promote the development of lung cancer; (2) whether a synergistic effect between CUMS and smoke exposure can deteriorate depression-like symptoms and neuropathology; (3) whether the synergistic effects are through common factors, such as excessive corticosterone, inflammation and neurotrophin dysfunction. The gene discussed is BDNF; the disease is major depressive disorder.