Partner separation and sex contribute to anxiety-like behavior, but partner separation alone amplifies hippocampal inflammation following immune challenge.

Social bond disruption is increasingly recognized as a potent psychosocial stressor with widespread implications for mental and physical health. The monogamous California mouse (Peromyscus californicus), which forms enduring pair bonds and exhibits distress upon separation, provides a translational model for understanding the neuroimmune consequences of social loss. We hypothesized that partner separation would sensitize neuroimmune responses to systemic inflammation. Adult male and female mice were assigned to one of three housing conditions: naive (isolate-housed), partner (pair-housed for 20 days), or separated (pair-housed for 10 days followed by 10 days of isolation). Mice underwent partner preference assessment, open field testing, and were injected with saline or lipopolysaccharide (LPS; 1 mg/kg), followed by tissue collection. Partnered mice developed selective partner preferences, and both sex and partner status independently influenced anxiety-like behavior: males exhibited fewer unsupported rears than females, and separated mice showed fewer unsupported rears than partnered mice. Partner separation also led to greater weight loss in males. LPS administration produced robust neuroimmune activation, including elevated central pro-inflammatory cytokine expression, increased circulating corticosterone, splenomegaly, and changes in microglial morphology. Notably, partner separation amplified LPS-induced hippocampalTnfmRNA expression, indicating that social disruption sensitizes central inflammatory responses to immune challenge in a region-specific manner. These findings highlight the neuroimmune impact of partner separation and demonstrate that social context critically shapes the brain's inflammatory response to systemic immune activation. This work contributes to a growing understanding of how social loss influences immune dysregulation and may help inform strategies for mitigating the health effects of loneliness and isolation.