Activity-Based Anorexia impairs HPA axis activity in the brain and the stress-coping response 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. However, its involvement in AN maladaptive behavior is still unclear. Our aim was to investigate the impact of AN history in adolescence on stress-related mechanisms in amygdala and ventral Hippocampus (vHip), brain areas that modulate HPA axis response, and on anxiety-like behavior in adulthood. Thus, adolescent female rats were exposed to Activity-Based Anorexia (ABA) model (i.e. combination of food restriction and wheel access) from post-natal day[P]38 till P42. Animals were sacrificed at P42, at the establishment of the AN phenotype, or at P49, after a 7-day recovery period, for molecular analyses. At P63, another cohort of rats 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) and altered transcription of GR-responsive genes (Sgk1, Gilz) in both amygdala and vHip. At P49, ABA animals showed reduced corticosterone levels, persistent reduction of GR levels in amygdala, restored GR levels in vHip and downregulated GR-responsive genes transcription in both regions. At P63, ARS blunted the response, in terms of time spent in the open arms, in the EPM of ABA group. Overall, we observed a long-lasting unbalance of the central GR-related mechanisms induced by the ABA paradigm 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.