Central neuroimmune activity and depressive-like behavior in response to repeated maternal separation and injection...

Disruption of attachment relations in early life is linked to greater vulnerability to depressive illness at later ages. Evidence suggests this process involves stress-induced activation of central inflammatory factors, though the specific mediators and processes involved are not known. We used a guinea pig model in which effects of maternal separation appear more clearly due to absence of the attachment figure than is the case for other laboratory rodents. Separation in a novel environment on two consecutive days evoked a depressive-like behavioral response that sensitized during a final test 9 days later. At this time, prior separation blunted the response of prostaglandin synthesizing enzymes (COX-2 and mPGES) and chemokines (CXCL-1 and MCP-1) 120 min following injection with lipopolysaccharide and isolation in a novel cage. The blunted response was not associated with a greater plasma cortisol elevation. In addition, injection of saline just prior to isolation at the oldest age elicited small, but significant, elevations in several signaling molecules, particularly at 30 min. These results demonstrate lasting central inflammatory consequences of our separation procedure. However, contrary to expectations, sensitization of depressive-like behavior was not associated with an increase in expression of neuroimmune mediators to inflammatory challenge. Together with earlier findings, the results suggest a multi-step process in which inflammatory response to an initial separation affects downstream mediators to sensitize depressive-like behavior.