Activity-based anorexia disrupts the hippocampal membrane-bound glucocorticoid receptor signaling and impairs structural plasticity and spatial memory

Anorexia Nervosa (AN) is a devastating psychiatric disorder marked by self-imposed food restriction and constant fear of gaining weight that, combined with excessive physical activity, results in massive weight loss. The etiology of AN, which predominantly affects adolescent females, is still under-researched. Evidence in anorexic patients suggests a hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, the system responsible for stress response. Our study aimed at investigating the stress-related mechanisms and structural changes induced by the anorexic phenotype in the hippocampus, a brain area involved in the negative feedback of the HPA axis. Thus, adolescent female rats were exposed to the combination of food restriction and wheel access, i.e., the activity-based anorexia (ABA) protocol, and sacrificed in the acute phase of the pathology (postnatal day [P]42) or after a 7-day recovery period (P49). ABA rats exhibited significant weight loss, increased wheel activity and food anticipatory activity, a measure of enhanced motivation for running. In ABA rats, corticosterone plasma levels were elevated at P42 while decreased at P49. Molecular analysis of the hippocampal crude membrane fraction revealed reduced glucocorticoid receptor levels as well as decreased markers of cytoskeletal stability, such as caldesmon, n-cadherin and neuroligin-1. These molecular changes were accompanied by structural impairments, including reduced spine density and mushroom-shaped active spines. ABA rats exhibited cognitive deficits in the spatial order object recognition (SOOR) test. These molecular, morphological, structural, and cognitive deficits persisted even after 7 days of recovery. Overall, our findings suggest that the AN induction alters the non-genomic response and induces a hippocampal reorganization that could explain the observed cognitive deficits, providing novel neurobiological basis for AN-induced long-lasting vulnerability. Sponsored by MIUR PRIN (grant number: P2022E4MLS)