title: Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility.
abstract: Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two subpopulations of mice: susceptible mice that show mood-related abnormalities compared with resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress-sensitive marker of individual differences to stress-induced mood disorders. Indeed, genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MRs), decrease resilience to stress via downregulation of mGlu2 receptors. We also provide a mechanistic link between MRs and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.
authors.affiliation: 1] Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA [2] Department Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Nasca
authors.affiliation: The Rockefeller University, Center for Clinical and Translational Science, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Bigio
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zelli
authors.affiliation: 1] Department Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy [2] Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: McEwen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005518:Food Preferences / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D046353:Immobility Response, Tonic / Q000187:drug effects; D007206:Individuality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015735:Mifepristone; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
chemical_list: D005938:Glucocorticoids; D018094:Receptors, Metabotropic Glutamate; D018161:Receptors, Mineralocorticoid; D013549:Sweetening Agents; C108822:metabotropic glutamate receptor 2; D015735:Mifepristone; D018698:Glutamic Acid; D013395:Sucrose