Abstract
Stress is a primary risk factor for several neuropsychiatric disorders. Evidence from preclinical models and clinical studies of depression have revealed an array of structural and functional maladaptive changes, whereby adverse environmental factors shape the brain. These changes, observed from the molecular and transcriptional levels through to large-scale brain networks, to the behaviours reveal a complex matrix of interrelated pathophysiological processes that differ between sexes, providing insight into the potential underpinnings of the sex bias of neuropsychiatric disorders. Although many preclinical studies use chronic stress protocols, long-term changes are also induced by acute exposure to traumatic stress, opening a path to identify determinants of resilient versus susceptible responses to both acute and chronic stress. Epigenetic regulation of gene expression has emerged as a key player underlying the persistent impact of stress on the brain. Indeed, histone modification, DNA methylation and microRNAs are closely involved in many aspects of the stress response and reveal the glutamate system as a key player. The success of ketamine has stimulated a whole line of research and development on drugs directly or indirectly targeting glutamate function. However, the challenge of translating the emerging understanding of stress pathophysiology into effective clinical treatments remains a major challenge.
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Acknowledgements
The authors dedicate this article to the memory of B. McEwen and R. Duman, two colleagues and friends who contributed with their thorough and passionate work to many of the findings illustrated here and to the development of knowledge on stress and mental illness. M.P. is indebted to former and present members of his group, in particular L. Musazzi, A. Mallei, A. Ieraci, G. Treccani and P. Tornese, for some of the works illustrated here. Z.Y. is grateful to her laboratory members who have worked on stress-related projects, past collaboration with B. McEwen and US National Institutes of Health (NIH) support (MH085774, MH108842, MH126443). G.S. is extremely appreciative of the mentorship of R. Duman and B. McEwen and the collaborations with M. Banasr. The authors thank A. Raiti for preparation of Fig. 1.
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G.S. has served as a consultant for Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics Biohaven Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Clexio, Denovo Biopharma, Engrail Therapeutics, EMA Wellness, Epiodyne, Intra-Cellular Therapies, Janssen, Lundbeck, Merck & Co., Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Taisho Pharmaceuticals, Valeant, Vistagen Therapeutics, and XW Labs over the past 36 months; has received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex, Servier and Usona over the past 36 months; holds equity in BioHaven Pharmaceuticals; and is a co-inventor on US Patent 8,778,979 held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on 20 August, 2018 by Yale University Office of Cooperative Research. Z.Y. has no competing interests. M.P. has received research contracts from Rodin Therapeutics (now Alkermes) in the last 36 months; and has received research contracts from Merck, GlaxoSmithKline, Servier, Sigma-Tau, Fidia and Abbott.
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Sanacora, G., Yan, Z. & Popoli, M. The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders. Nat Rev Neurosci 23, 86–103 (2022). https://doi.org/10.1038/s41583-021-00540-x
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DOI: https://doi.org/10.1038/s41583-021-00540-x
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