Stress and Brain Plasticity

Any kind of stressor can leave a lasting imprint on the brain, reshaping its plasticity via dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in ways that may fuel the onset and progression of psychiatric disorders. Anorexia nervosa (AN) is a severe psychiatric condition mainly affecting adolescent female, strongly influenced by various stressors and indeed characterized by a hyperactivated HPA axis. However, AN still lacks a clear understanding of the neuroplastic molecular mechanisms, hampering the development of e#ective therapeutic strategies. We investigated the impact of AN history on stress-related structural and functional neuroplastic mechanisms in the hippocampus, a brain region highly sensitive to glucocorticoids, in the gold standard animal model of AN, the activity-based anorexia (ABA). The AN phenotype enhanced corticosterone plasma levels and led to long-lasting changes in the glucocorticoid system. In parallel, ABA rats show structural synaptic alterations of the dendritic spine morphology and an impairment in the hippocampal-dependent spatial memory domain. Moreover, the acute AN phenotype induced hippocampal neuroinflammation and boosted Glucocorticoid receptor (GR) translocation in the ventral hippocampus of ABA rats, which, in turn, evoked microglial hyperactivation after recovery. Interestingly, mifepristone, a non-selective GR antagonist, blunted ABA rats’ hyperactivity, a core symptom of the disease, and restored, at least partially, the molecular signatures induced by the AN phenotype. Our findings indicate that ABA induction, a highly stressful condition, orchestrates hippocampal maladaptive structural and functional plasticity, contributing to cognitive deficits, providing a putative mechanism that could be targeted in AN patients.