Activity-based anorexia alters innate and adaptive immune response dynamics inducing late microglia activation in the ventral hippocampus of adolescent rats.

Anorexia Nervosa (AN) is a life-threatening psychiatric disorder characterized by severe emaciation whose root- based molecular mechanisms are unknown and treatments elusive. Our hypothesis is that a dysregulation of the immune system induced by loss of body weight and hyperactivity may act as a fil rouge establishing a dysfunctional neuro-immune-metabolic axis potentially critical in AN long- lasting maintenance. Using the activity-based anorexia (ABA) rat model, which consists of exposing adolescent female rats to the combination of food restriction and wheel exercise, we found reduced circulating CD45+cells, and a shift in the percentage of B cells and granulocytes in the pool of total immune cells in the bone marrow, suggesting that the acute ABA condition induced a shift from adaptive towards innate immunity, which persisted even after body- weight recovery. Moreover, acute AN induced hippocampal neuroinflammation in ABA rats increasing Tnf-alpha expression both in its ventral and dorsal subregions. This pro-inflammatory effect did not trigger microglia activation in the acute phase, since Cd11b, Iba1, and Cd68 mRNA levels were unaltered. Interestingly, after recovery, only ventral hippocampus microglial cells shifted towards an active state increasing Cd11b, Iba1, and Cd68 expression. These results prompt us to speculate that ABA-induced alterations in the medullary skewing of innate immune arm may cause severe endurable central dysfunctions throughout the activation of a microglial response in ventral hippocampus, known to be critical in vulnerable phenotypes. This may represents a potential central mechanism behind the increased risk, recurrence, and severity of infections in patients and the reiteration of AN maladaptive behaviors.