Cover Story：Objective The unclear mechanism of depression occurrence and the undesired clinical efficacy of drugs are the difficult problems all over the world. Previous studies have found that gaseous formaldehyde (FA) exposure or intraperitoneal injection of FA can directly induce depression-like behaviors in mice. Whether endogenous FA leads to depression is unclear. This study was to explore whether lipopolysaccharide (LPS) induces depression-like behaviors in mice by stimulating endogenous FA generation, and to observe whether non-invasive physical therapy——630 nm red light irradiation can activate FA dehydrogenase and degrade FA, thereby attenuate depression-like behaviors in mice.Methods Male adult C57BL/6J mice were randomly divided into: (1) control group, intraperitoneal injection of phosphate buffered saline (PBS); (2) depression model group, intraperitoneal injection of LPS at a concentration gradient; (3) red light intervention group, these mice were intraperitoneally injected with LPS and treated with 630 nm red light irradiation. The depression-like behaviors of mice were evaluated by open field test, sucrose preference test, tail suspension test and forced swimming test. The concentration and distribution of FA in brain tissue of mice were detected by FA fluorescence (Na-FA, specific FA fluorescent probe) quantitative method and whole brain FA fluorescence imaging. The concentrations of IL-1β, TNF-α, IL-6 and semicarbazide-sensitive amine oxidase (SSAO) were detected by ELISA.Results One hour after acute injection of LPS, FA accumulated rapidly in the whole brain, especially in the midbrain. With the increase of IL-1β and TNF-α content; 24-hour depression-like behaviors, for example, open field total movement distance, central area movement time (distance) decreased significantly; the total immobility time of tail suspension test and forced swimming test were increased. However, 630 nm red light treatment significantly attenuated LPS-induced depression-like behavior in mice accompanied by a decrease in midbrain inflammatory factors IL-1β and TNF-α.Conclusion The accumulation of FA in the midbrain is an initiating factor for depression, stimulating a large release of inflammatory factors and leading to depression-like behaviors. However, red light irradiation can scavenge FA and reduce neuroinflammation. It is a promising new strategy for non-invasive treatment of depression.