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Refinement of the stress-enhanced fear learning model of post-traumatic stress disorder: a behavioral and molecular analysis

Lab Animal volume 51, pages 293–300 (2022)Cite this article

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Abstract

Post-traumatic stress disorder (PTSD) is a debilitating mental health condition for which current treatments have long-term efficacy in 50% of patients. There is a clear need for better understanding of the mechanisms underlying PTSD and the development of new treatment approaches. Analog trauma procedures in animals, such as the stress-enhanced fear learning (SEFL) procedure, can be used to produce behavioral and neurobiological changes that have validity in modeling PTSD. However, by necessity, the modeling of PTSD in animals requires them to potentially experience pain and suffering. Consistent with the ‘3Rs’ (reduction, refinement and replacement) of animal research, this study aimed to determine whether the SEFL procedure can be refined to reduce potential animal pain and suffering while retaining the same behavioral and neurobiological changes. Here we showed that PTSD-relevant changes could be produced in both behavior and the brain of rats that were group- rather than single-housed and that received lower-magnitude electric shocks in the ‘trauma analog’ session. We also varied the number of shock exposures in the trauma analog session, finding SEFL-susceptible and SEFL-resilient populations at all levels of shock exposure, but with greater levels of shock increasing the proportion of rats showing the SEFL-susceptible phenotype. These data demonstrate that the SEFL procedure can be used as an animal analog of PTSD with reduced potential pain and suffering to the animals and that variations in the procedure could be used to generate specific proportions of SEFL-susceptible and SEFL-resilient animals in future studies.

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Fig. 1: The behavioral phenotype associated with SEFL could be observed in rat populations given different degrees of massed shock exposure.
Fig. 2: Expression of glutamate receptor subunits varied differentially depending on SEFL classification and the number of shocks experienced in context A.
Fig. 3: SEFL-resilient and SEFL-susceptible populations showed different correlations of glutamate receptor subunits.

Data availability

All data accompanying this publication are available at the University of Cambridge data repository (https://doi.org/10.17863/CAM.75449).

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Acknowledgements

This research was funded by the Department of Psychology, University of Cambridge. A.L.M. is the Ferreras-Willetts Fellow in Neuroscience at Downing College, University of Cambridge. The authors would like to thank G. Vousden for writing the MATLAB scripts that were used to quantify conditioned freezing.

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Authors and Affiliations

  1. Department of Psychology, University of Cambridge, Downing Site, Cambridge, UK

    Indra A. Van Assche, Mc Stephen Padilla, Olivia S. R. P. Stupart & Amy L. Milton

  2. Biomedical Sciences Group: Woman and Child, KU Leuven, Leuven, Belgium

    Indra A. Van Assche

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Contributions

A.L.M. conceived and designed the experiments and analysis. I.A.V.A. and A.L.M. collected the data and performed the analysis for the behavioral experiments. M.S.P., O.S.R.P.S. and A.L.M. collected the data and performed the analysis for the western blotting experiments. A.L.M. wrote the manuscript, and all authors edited and approved the manuscript.

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Correspondence to Amy L. Milton.

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Lab Animal thanks Julia Chester, Jennifer Quinn, Graziano Pinna and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Van Assche, I.A., Padilla, M.S., Stupart, O.S.R.P. et al. Refinement of the stress-enhanced fear learning model of post-traumatic stress disorder: a behavioral and molecular analysis. Lab Anim 51, 293–300 (2022). https://doi.org/10.1038/s41684-022-01054-4

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