Major depressive disorder is a common mental illness that affects over 280 million people worldwide each year (Mansouri et al., 2023). Depression has serious negative impacts on individual health and societal development. The low emotion, anhedonia, irritability, fatigue, appetite and sleep disturbances caused by depression significantly affect patients' work and life, leading to a huge economic burden and even suicide (Mansouri et al., 2023).

Mouse models of depression are important model organisms for exploring the pathological mechanisms of depression and developing targeted therapeutic drugs (Gururajan et al., 2019). The common rodent models of depression include chronic restraint stress (CRS) model (Luo et al., 2023), chronic social defeat stress (CSDS) model (Bordes et al., 2023), chronic unpredictable mild stress (CUMS) model (Zhang et al., 2022), lipopolysaccharide (LPS)-induced depression model, etc (Zhang et al., 2020). However, these models have certain limitations. For instance, the CRS model is a relatively simple and less provocative depression model that partially simulates psychological stress states with a higher degree of similarity to human depression (Mao et al., 2022). However, the CRS model can easily develop adaptation, leading to a reduction or disappearance of depressive-like behaviors (Hao et al., 2019). Malondialdehyde (MDA) is an oxidative stress-related substance closely associated with depression, and previous studies reported that within 14 days of CRS, MDA levels continuously increased. However, on the first day after modeling, MDA levels decreased from 154.5% to 36.4%, and then recovered to normal level on the second day (Seo et al., 2012). In addition, the modeling period typically takes two weeks or even longer time. On the other hand, the LPS-induced depression model could activate the natural immune system, promote the release of various inflammatory factors, and finally produce depressive-like behaviors such as reduced locomotor activity and lack of pleasure (Li et al., 2021). However, the LPS-induced depression model mainly focuses on the role of neuroinflammation and ignores other factors that may contribute to depression, such as social stress and genetic factors. Therefore, choosing any single depression model is obviously limited for the related studies, since no single model could completely simulate the pathological mechanism of human depression.

The purpose of this study was to establish a new combined depression model, namely intraperitoneal injection of LPS combined with CRS. We evaluated the differences of depressive-like behaviors in this combined depression model among three different strains of mice.