Systemic Inflammation Triggers Sex-Specific Social Proximity Changes in Mice

Major depressive disorder is increasingly recognized as a systemic condition where peripheral inflammatory processes significantly contribute to central nervous system pathophysiology [1]. Pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha can alter neurotransmitter metabolism and activate the kynurenine pathway, a metabolic route that converts tryptophan into neuroactive metabolites linked to depressive symptoms [2, 3]. While the cytokine hypothesis suggests that immune activation drives the motivational and cognitive deficits seen in clinical depression, the specific impact on social behavior remains complex [4, 5]. Current research into the microbiota-gut-brain axis further underscores how immune signaling molecules, including lipopolysaccharides (endotoxins that trigger systemic inflammatory responses), serve as critical regulators of host behavior and homeostasis [6, 7, 8]. A new study using C57BL/6J mice now provides evidence that lipopolysaccharide-induced inflammation produces divergent social behavioral outcomes depending on biological sex, specifically increasing social contact and reducing social distance in males while having no such effect in females [9].