Experimenter sex modulates mouse biobehavioural and pharmacological responses

Abstract

Differential rodent responses to the sex of human experimenters could have far reaching consequences in preclinical studies. Here, we show that the sex of human experimenters affects mouse behaviours and responses to the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. We found that mice manifest aversion to human male odours, preference to female odours, and increased susceptibility to stress when handled by male experimenters. This male induced aversion and stress susceptibility is mediated by the activation of brain corticotropin-releasing factor (CRF) neurons projecting from the entorhinal cortrex to hippocampal area CA1. We further establish that exposure to male scent prior to ketamine administration activates CRF neurons projecting from the entorhinal cortex to hippocampus, and that CRF is necessary and sufficient for the in vivo and in vitro actions of ketamine. Further understanding of the specific and quantitative contributions of the sex of human experimenters to different experimental outcomes in rodents may lead not only to reduced heterogeneity between studies, but also increased capability to uncover novel biological mechanisms.

Sex differences in Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and experimental autoimmune neuritis

“…It will also be necessary to report the age of the animal, given that sex differences change over time-becoming more apparent with puberty and showing differences in older age. It has also been found that, in some experiments, the sex of the researcher can influence the results of the study (317,318), so this should also be recorded.…”

Erasure of Biologically Meaningful Signal by Unsupervised scRNAseq Batch-correction Methods

“…One illustration of this is a recent discovery that the sex of the experimenter alters the metabolic pathway of ketamine in isogenic mice. This was ultimately traced back to the scent of human males compared the scent of human females 57 . Additionally, there are many other sources of within-subject environmental variation impacting cell states, such as time since feeding, circadian rhythm patterns, and so on – none of which can be completely controlled.…”

Effects of biological sex and pregnancy in experimental autoimmune encephalomyelitis: It’s complicated

“…It may even be that the sex of the experimenter can affect outcomes. Whilst this has not been systematically investigated in EAE, as far as we are aware, there are several reports that rodents of both sexes are more stressed when the person doing the experiments on them is male, and that this can lead to differences in behavioral assays of pain and stress (142,143). This could potentially add another layer of complexity to investigation of the effects of biological sex on the pathophysiology of EAE.…”