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The sinking platform test: a novel paradigm to measure persistence in animal models

Abstract

Persistence is the propensity to maintain goal-directed actions despite adversities. While this temperamental trait is crucial to mitigate depression risk, its neurobiological foundations remain elusive. Developing behavioral tasks to capture persistence in animal models is crucial for understanding its molecular underpinnings. Here, we introduce the Sinking Platform Test (SPT), a novel high-throughput paradigm to measure persistence. Mice were trained to exit a water-filled tank by ascending onto a platform above water level. Throughout the training, mice were also occasionally exposed to “failure trials,” during which an operator would submerge a platform right after the mouse climbed onto it, requiring the mouse to reach and ascend a newly introduced platform. Following training, mice were subjected to a 5-min test exclusively consisting of failure trials. Male and female mice exhibited comparable persistence, measured by the number of climbed platforms during the test. Furthermore, this index was increased by chronic administration of fluoxetine or imipramine; conversely, it was reduced by acute and chronic haloperidol. Notably, six weeks of social isolation reduced SPT performance, and this effect was rescued by imipramine treatment over the last two weeks. A 4-week regimen of voluntary wheel running also improved persistence in socially isolated mice. Finally, comparing transcriptomic profiles of the prefrontal cortex of mice with high and low SPT performance revealed significant enrichment of immediate-early genes known to shape susceptibility for chronic stress. These findings highlight the potential of SPT as a promising method to uncover the biological mechanisms of persistence and evaluate novel interventions to enhance this response.

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Fig. 1: Description of the apparatus and procedures for the Sinking Platform Test.
Fig. 2: Sex differences in the SPT.
Fig. 3: Effects of acute and chronic antidepressant treatment on persistence in the SPT.
Fig. 4: Effects of chronic imipramine (IMI) treatment and voluntary exercise on SPT performance deficits induced by social isolation (SI) in mice.
Fig. 5: Distinct transcriptional signature in the prefrontal cortex reflects SPT performance differences.

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Acknowledgements

We thank William O Wright IV, Hunter Strathman, Karen Odeh, Easton vanLuik, Conor Craig, Yingduo Yang, and Amanda Wall for their technical assistance with animal testing. We thank Dr. Caterina Branca for her precious editorial assistance and suggestions.

Funding

This study was partially supported by the NIH grants R01 MH104603 and R56 MH130006 (to MB).

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Authors and Affiliations

Authors

Contributions

Gabriele Floris: Behavioral and pharmacological investigation, Conceptualization of Experimental design,  Formal analysis, Writing – original draft, Writing – review & editing. Sean C Godar: Behavioral and pharmacological investigation; Conceptualization of Methodology. Giulia Braccagni: Behavioral and pharmacological investigation. Ignazio S Piras: Bioinformatic analysis; Writing – review & editing. Alicia Ravens: Behavioral investigation. Mary T Zanda: Formal analysis. Matthew J Huentelman: Bioinformatic analysis. Writing – review & editing. Marco Bortolato: Conceptualization and Development of Methodology and Experimental design, Data curation, Writing – original draft, Writing – review & editing, Funding acquisition.

Corresponding author

Correspondence to Marco Bortolato.

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Competing interests

MB consults for Asarina Pharmaceuticals and receives research funding from Asarina and Lundbeck Pharmaceuticals. The other authors declare no conflict of interest.

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Floris, G., Godar, S.C., Braccagni, G. et al. The sinking platform test: a novel paradigm to measure persistence in animal models. Neuropsychopharmacol. 49, 1373–1382 (2024). https://doi.org/10.1038/s41386-024-01827-0

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