Activity-Based Anorexia alters genomic glucocorticoid signaling in the amygdala and induces cognitive and emotional impairments in adolescent female rats

Background Anorexia Nervosa (AN) is a psychiatric disorder affecting mainly adolescent females, characterized by dietary restriction and compulsive exercise, reinforced by emotional instability. AN patients show high cortisol plasma levels, index of a hyperactivated Hypothalamic-Pituitary-Adrenal (HPA) axis, suggesting its role in AN maladaptive behaviors. Thus, we investigated the impact of AN history on stress-related mechanisms in a stress-responsive brain area (amygdala) by means of the Activity-Based Anorexia (ABA) model, which combines food restriction and physical activity, and on cognitive and emotional behaviors. Methods At post-natal day[P]38 adolescent female rats were exposed to food restriction (food access 2 h/day) and wheel access (22h/day) till P42, the acute phase. Half of the animals underwent a bodyweight recovery period until P49. At both timepoints, molecular analysis were performed in the amygdala through Western Blot and RT-PCR. Spatial memory and anxiety-like behavior were assessed at P42 and/or P49 through the spatial order object recognition (SOOR) and elevated plus maze (EPM) test, respectively. Results At P42, ABA rats showed enhanced corticosterone plasma levels, increased nuclear shuttling of the glucocorticoid receptor (GR) and transcription of GR-responsive genes, as Sgk1 and Gilz. All these effects were downregulated below control levels after recovery. In parallel, ABA rats showed long-lasting spatial memory impairment and a tendency toward anxiolytic-like behaviors at P49. Conclusion These data suggest a long-lasting impairment of GR system in amygdala that might sustain, at least in part, the increased vulnerability of AN patients to psychiatric comorbidities and to relapse.