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Inconvenient truths and the usefulness of identifying unknown unknowns

We studied how the sex of human experimenters affected mouse behaviors and brain functions under normal conditions and in the context of ketamine administration. Identifying such unknown unknowns was critical to understanding how, specifically and quantitatively, they affected experimental outcomes, which led to fresh insight into ketamine’s mechanism as an antidepressant drug.

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Fig. 1: Sex of the human experimenter modulates antidepressant effects of ketamine through the CRF system.


  1. Gould, T. D. & Riggs, L. M. Ketamine and future of rapid-acting antidepressants. Annu. Rev. Clin. Psychol. 17, 207–231 (2021). This review covers the history of antidepressant treatment advances, including the discovery of ketamine's antidepressant properties.

    Article  Google Scholar 

  2. Zanos, P. et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486 (2016). This paper replicates earlier findings of antidepressant-like actions of ketamine in mice and identifies bioactive properties of ketamine’s hydroxynorketamine metabolites.

    Article  CAS  Google Scholar 

  3. Sorge, R. E. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat. Methods 11, 629–632 (2014). This paper reports that stimuli related to male but not female experimenters induced a robust physiological stress response in rodents that resulted in stress-induced analgesia.

    Article  CAS  Google Scholar 

  4. Mogil, J. S. Laboratory environmental factors and pain behavior: the relevance of unknown unknowns to reproducibility and translation. Lab Anim. 46, 136–141 (2017). A commentary review article that argues that if replication and translation are to be improved, greater attention needs to be focused on the laboratory environment.

    Article  Google Scholar 

  5. Butler-Struben, H. M., Kentner, A. C. & Trainor, B. C. What’s wrong with my experiment?: The impact of hidden variables on neuropsychopharmacology research. Neuropsychopharmacology 47, 1285–1291 (2022). A review article that describes under-appreciated environmental factors that can have a major impact on results.

    Article  Google Scholar 

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This is a summary of: Georgiou, P. et al. Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor. Nat. Neurosci. (2022).

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Inconvenient truths and the usefulness of identifying unknown unknowns. Nat Neurosci 25, 1122–1123 (2022).

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