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Advancing preclinical chronic stress models to promote therapeutic discovery for human stress disorders

Neuropsychopharmacology volume 49, pages 215–226 (2024)Cite this article

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Abstract

There is an urgent need to develop more effective treatments for stress-related illnesses, which include depression, post-traumatic stress disorder, and anxiety. We view animal models as playing an essential role in this effort, but to date, such approaches have generally not succeeded in developing therapeutics with new mechanisms of action. This is partly due to the complexity of the brain and its disorders, but also to inherent difficulties in modeling human disorders in rodents and to the incorrect use of animal models: namely, trying to recapitulate a human syndrome in a rodent which is likely not possible as opposed to using animals to understand underlying mechanisms and evaluating potential therapeutic paths. Recent transcriptomic research has established the ability of several different chronic stress procedures in rodents to recapitulate large portions of the molecular pathology seen in postmortem brain tissue of individuals with depression. These findings provide crucial validation for the clear relevance of rodent stress models to better understand the pathophysiology of human stress disorders and help guide therapeutic discovery. In this review, we first discuss the current limitations of preclinical chronic stress models as well as traditional behavioral phenotyping approaches. We then explore opportunities to dramatically enhance the translational use of rodent stress models through the application of new experimental technologies. The goal of this review is to promote the synthesis of these novel approaches in rodents with human cell-based approaches and ultimately with early-phase proof-of-concept studies in humans to develop more effective treatments for human stress disorders.

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Fig. 1: Research efforts aimed at the discovery of novel treatments for human stress disorders.
Fig. 2: Current approaches for therapeutic discovery in preclinical chronic stress models.

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Acknowledgements

We would like to thank Jill Gregory for graphic design and illustrations.

Funding

National Institutes of Health grants R01MH051399 and R01MH129306 (EJN); Hope for Depression Research Foundation (EJN), and the Brain & Behavior Research Foundation (EMP).

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  1. Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Trevonn M. Gyles, Eric J. Nestler & Eric M. Parise

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TMG wrote this article. EMP and EJN reviewed and edited this article.

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Gyles, T.M., Nestler, E.J. & Parise, E.M. Advancing preclinical chronic stress models to promote therapeutic discovery for human stress disorders. Neuropsychopharmacol. 49, 215–226 (2024). https://doi.org/10.1038/s41386-023-01625-0

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