Activity-Based Anorexia affects glucocorticoid-dependent mechanisms in the brain and impairs stress-coping behaviors in female rats

Anorexia Nervosa (AN) is a psychiatric disorder characterized by dietary restriction and compulsive exercise, reinforced by emotional instability, that a=ects mainly adolescent girls. AN patients show high cortisol plasma levels, index of a hyperactivated Hypothalamic- Pituitary-Adrenal (HPA) axis, suggesting its role in AN. Thus, we investigated the impact of AN history in adolescence on stress-related mechanisms in amygdala and ventral Hippocampus (vHip), brain areas that complementarily modulate HPA axis response. Moreover, we explored the presence of emotional impairments in adulthood. To this end, adolescent female rats were exposed to Activity-Based Anorexia (ABA) model, which combines food restriction (food access 2h/day) and physical activity (wheel access 22h/day) from post-natal day[P]38 till P42, at the establishment of the AN phenotype. Half of the animals underwent a bodyweight recovery period until P49. Molecular analyses were performed in amygdala and vHip at both timepoints. Another cohort of rats underwent recovery till P63, was exposed to 1h of acute restraint stress (ARS) and tested for anxiety-like behaviors through the elevated plus maze (EPM) test. At P42, ABA rats showed enhanced corticosterone plasma levels, reduced cytosolic and nuclear glucocorticoid receptor (GR) in amygdala and vHip, and altered transcription of GR- responsive genes (Sgk1, Gilz) in both regions. After recovery (P49), ABA animals showed reduced corticosterone plasma levels, persistent reduction of GR levels in amygdala, restored GR levels in vHip and downregulated GR-responsive genes transcription in both regions. In adulthood (P63), ARS blunted the response in terms of time spent in the open arms of the EPM of the ABA group. Overall, we observed a long-lasting unbalance of the central GR-related mechanisms that might contribute to an impaired ability to cope with a challenging stimulus in adulthood. These data may represent a potential mechanism underpinning comorbid mental disorders and the long-term individual susceptibility, observed in AN patients.