Lipocalin-2 is dispensable in inflammation-induced sickness and depression-like behavior.

RATIONALE: While the relationship between inflammation and depression is well-established, the molecular mechanisms mediating this relationship remain unclear. RNA sequencing analysis comparing brains of vehicle- and lipopolysaccharide-treated mice revealed LCN2 among the most dysregulated genes. As LCN2 is known to be an important regulator of the immune response to bacterial infection, we investigated its role in the behavioral response to lipopolysaccharide. OBJECTIVE: To explore the role of LCN2 in modulating behavior following lipopolysaccharide administration using wild type (WT) and lcn2-/- mice. METHODS: Using a within-subjects design, mice were treated with 0.33 mg/kg liposaccharide (LPS) and vehicle. Primary outcome measures included body weight, food consumption, voluntary wheel running, sucrose preference, and the tail suspension test. To evaluate the inflammatory response, 1 week later, mice were re-administered either vehicle or LPS and terminated at 6 h. RESULTS: While lcn2-/- mice had increased baseline food consumption and body weight, they showed a pattern of reduced food consumption and weight loss similar to WT mice in response to LPS. WT and lcn2-/- mice both recovered voluntary activity on the fourth day following LPS. LPS induced equivalent reductions in sucrose preference and TST immobility in the WT and lcn2-/- mice. Finally, there were no significant effects of genotype on inflammatory markers. CONCLUSIONS: Our data demonstrate that lcn2 is dispensable for sterile inflammation-induced sickness and depression-like behavior. Specifically, lcn2-/- mice displayed sickness and immobility in the tail suspension test comparable to that of WT mice both in terms of intensity and duration.

Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase.

Despite years of research, our understanding of the mechanisms by which inflammation induces depression is still limited. As clinical data points to a strong association between depression and motivational alterations, we sought to (1) characterize the motivational changes that are associated with inflammation in mice, and (2) determine if they depend on inflammation-induced activation of indoleamine 2,3 dioxygenase-1 (IDO1). Lipopolysaccharide (LPS)-treated or spared nerve injured (SNI) wild type (WT) and Ido1-/- mice underwent behavioral tests of antidepressant activity (e.g., forced swim test) and motivated behavior, including assessment of (1) reward expectancy using a food-related anticipatory activity task, (2) willingness to work for reward using a progressive ratio schedule of food reinforcement, (3) effort allocation using a concurrent choice task, and (4) ability to associate environmental cues with reward using conditioned place preference. LPS- and SNI-induced deficits in behavioral tests of antidepressant activity in WT but not Ido1-/- mice. Further, LPS decreased food related-anticipatory activity, reduced performance in the progressive ratio task, and shifted effort toward the preferred reward in the concurrent choice task. These effects were observed in both WT and Ido1-/- mice. Finally, SNI mice developed a conditioned place preference based on relief from pain in an IDO1-independent manner. These findings demonstrate that the motivational effects of inflammation do not require IDO1. Further, they indicate that the motivational component of inflammation-induced depression is mechanistically distinct from that measured by behavioral tests of antidepressant activity.