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Acute sleep disruption reduces fear memories in male and female mice

Neuropsychopharmacology (2024)Cite this article

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Abstract

Sleep problems are a prominent feature of mental health conditions including post-traumatic stress disorder (PTSD). Despite its potential importance, the role of sleep in the development of and/or recovery from trauma-related illnesses is not understood. Interestingly, there are reports that sleep disruption immediately after a traumatic experience can reduce fear memories, an effect that could be utilized therapeutically in humans. While the mechanisms of this effect are not completely understood, one possible explanation for these findings is that immediate sleep disruption interferes with consolidation of fear memories, rendering them weaker and more sensitive to intervention. Here, we allowed fear-conditioned mice to sleep immediately after fear conditioning during a time frame (18 h) that includes and extends beyond periods typically associated with memory consolidation before subjecting them to 6-h of sleep disruption. Mice exposed to this delayed regimen showed dramatic reductions in fear during tests conducted immediately after sleep disruption, as well as 24 h later. This sleep disruption regimen also increased levels of mRNA encoding brain-derived neurotrophic factor (BDNF), a molecule implicated in neuroplasticity, in the basolateral amygdala (BLA), a brain area implicated in fear and its extinction. These findings raise the possibility that the effects of our delayed sleep disruption regimen are not due to disruption of memory consolidation, but instead are caused by BDNF-mediated neuroadaptations within the BLA that actively suppress expression of fear. Treatments that safely reduce expression of fear memories would have considerable therapeutic potential in the treatment of conditions triggered by trauma.

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Fig. 1: Plasma CORT after sleep disruption.
Fig. 2: Effects of “delayed” sleep disruption on fear responses in male and female mice.
Fig. 3: Fear memory is consolidated prior to sleep disruption.
Fig. 4: Effects of gentle stimulation-induced sleep disruption on expression of mRNA encoding BDNF across numerous brain regions in male and female mice.

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Acknowledgements

Graphic experimental timelines in Figs. 2A and 3A were created with BioRender.com. We thank David Potter for his expert technical assistance in molecular analyses.

Funding

P50MH115874 (to WAC/KJR), R01MH063266 (to WAC), and a Rappaport Mental Health Research Scholar Award (to ARF).

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Authors and Affiliations

  1. Department of Psychiatry, Basic Neuroscience Division, McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Allison R. Foilb, Elisa M. Taylor-Yeremeeva, Brett D. Schmidt, Kerry J. Ressler & William A. Carlezon Jr.

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Contributions

ARF, KJR, and WAC designed the studies; ARF, EMTY, and BDS conducted the experiments; ARF and WAC performed the statistical analyses; ARF and WAC wrote early drafts of the manuscript; and all authors provided editing and approval of the final version.

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Correspondence to William A. Carlezon Jr..

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Competing interests

WAC and KJR are members of the NPP editorial board. WAC is a consultant for Psy Therapeutics and has sponsored research agreements with Cerevel Therapeutics and Delix Therapeutics. KJR has performed scientific consultation for Bioxcel, Bionomics, Acer, Takeda, and Jazz Pharma; serves on Scientific Advisory Boards for Sage and the Brain Research Foundation, and he has received sponsored research support from Takeda, Brainsway, and Alto Neuroscience. ARF, EMTY, and BDS report no competing interests.

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Foilb, A.R., Taylor-Yeremeeva, E.M., Schmidt, B.D. et al. Acute sleep disruption reduces fear memories in male and female mice. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01978-0

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