Sex-dependent modulation of social distance by lipopolysaccharide-induced inflammation in mice

Depression is a major psychiatric disorder, and accumulating evidence indicates that inflammatory processes contribute to its pathophysiology. Peripheral administration of lipopolysaccharide (LPS) reliably induces systemic inflammation and is widely used to model inflammation-related depression and sickness behavior. However, despite the strong association between social behavior and depressive states, the impact of LPS-induced inflammation on social interactions remains insufficiently understood. Here, we investigated how acute inflammatory responses influence social and non-social behaviors in C57BL/6 J mice following intraperitoneal LPS administration. Immunological analyses using ELISA and flow cytometry revealed marked increases in circulating IL-1β, IL-6, and TNF-α, accompanied by reductions in T cells, B cells, neutrophils, and monocytes. Baseline levels of B cells, neutrophils, and monocytes differed between sexes. Behavioral assessments demonstrated that LPS-treated male mice exhibited increased social contact and reduced social distance in both familiar and unfamiliar dyads, whereas these effects were absent in female pairs. In contrast, LPS induced comparable reductions in body weight, locomotor activity, and fecal output in the open-field test, as well as decreased sucrose preference and overall licking counts in the sucrose preference task, in both sexes. These findings indicate that LPS-induced inflammation modulates social behavior in a sex-dependent manner. Notably, the enhanced social contact observed in male dyads cannot be attributed to weight loss, hypoactivity, altered orofacial movements, or reduced reward sensitivity, as these physiological and motivational impairments were similarly present in both sexes. This study highlights distinct social behavioral consequences of inflammatory activation and advances our understanding of immune-behavior interactions.