THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AS A NEUROENDOCRINE VULNERABILITY SIGNATURE IN THE DEVELOPMENTAL ACTIVITY-BASED ANOREXIA RAT MODEL

Restrictive dieting and hyperactive behaviors of patients with Anorexia Nervosa (AN) lead to cognitive deficits and emotional susceptibility which may sustain the low rate of recovery and high relapse. The hypercortisolemic state of patients points to the Hypothalamic-Pituitary-Adrenal (HPA) axis, the neuroendocrine stress response system, as driver of AN. We thus investigated the modulation of glucocorticoids, molecular mediators of HPA axis response, their synthesis in the adrenal glands and their signaling in the hippocampus, a stress-responsive brain region, in adolescent female rats exposed to the Activity-Based Anorexia (ABA) model of AN. At the acute phase, induced by the combination of food restriction and exercise and defined by 25% of weight loss and hyperactivity, ABA rats show hypercorticosteronemia, sustained by increased protein and gene expression of MC2R, SRB1, Cyp11a1 and 3b-HSD, regulators of corticosterone synthesis, in the adrenal glands. In the hippocampus, ABA rats display altered glucocorticoid genomic signaling, with reduced cytosolic glucocorticoid receptor (GR) expression and increased Sgk1 and Gilz mRNA levels, and non-genomic pathway, with reduced membrane-bound GR expression. These effects are paralleled by cognitive deficits detected with the Spatial Order Object Recognition (SOOR) test. After a 7-day weight recovery period, ABA rats show reduced corticosterone plasma levels and markers of its synthesis in the adrenals, restored hippocampal glucocorticoid genomic signaling, while persistent reduced non-genomic signaling and cognitive deficits. These data support the hypothesis that AN is characterized by a maladaptive response of the HPA axis that persists from the acute phase through weight recovery, thus contributing to vulnerability.