Sex differences in Chronobiology: evidence and urgency mounts to reduce a harmful bias
Researchers at the University of Bristol are uncovering sex differences in the behaviour and infradian rhythms of mice, bringing to light the importance of considering sex in chronobiology research.
Studying the activity of mice can be tedious work; watching endless hours of footage, waiting for moments of movement and eating, one might draw parallels to the work of a reality-TV producer. As the hours pass, even the most attentive eye might develop bias and so the latest studies have come up with a solution. By training AI to recognise specific activity, researchers can greatly reduce bias; the AI does not get tired, the AI does not have expectations, and the AI is able to stay completely focussed. Using this, and a whole host of other tools, Dr Pi-shan Chang and her colleagues at the University of Bristol are investigating the infradian rhythms of mice.
Sex differences in the periodogram of locomotor activity
Initial analysis of 5, 10 and 14 day durations show strong cycles of feeding, drinking, and locomotor activity. For chronobiologists this is makes perfect sense – biological rhythms affect the behaviour and physiology of virtually all organisms. Most notably however, there is a very distinct difference between the cycles exhibited by males compared to females. Sex differences in circadian rhythms have been observed in a number of models including humans, rodents and even flies. This research demonstrates that differences in rhythmic behaviour extend beyond 24 hours. Evidence continues to grow and the importance of considering sex as a variable in chronobiological research is becoming increasingly clear.
Whilst the inclusion of the sexes in chronobiology research conducted on humans is fortunately fairly even, the picture for animal studies is less clear. Only recently have journals implemented sex-reporting requirements as part of a push to improve transparency – but these do not include the requirement to actually study females. For now, most physiological and pharmacological research relies on male mice. This bias has persisted despite decades of advocacy, and whilst there are a number of perfectly valid reasons to prefer the use of male models, if 80% of studies in a given field are only conducted on males, one has to question whether its discoveries are at all applicable to females.
In an age promising to be the golden dawn of precision medicine, it is baffling that the sex bias is still so prominent. We’re facing the exciting prospect of being able to tailor treatments to specific individuals, so why does the present reality of prescribing still see half the population suffering through the adverse side effects of medications that were tested solely on male physiologies? Precision must be inclusive, and that inclusion has to begin at the fundamental-research level, not in phase 5 of clinical trials.
As more and more chronobiologists push for the consideration of circadian variables in animal experiments, it is becoming ever more important that sex differences are acknowledged and actively studied. Labs like Dr Chang’s are pioneering this, paving the way to better models, and, one day, better medical outcomes.
Who is involved in this research?
Lorena Rosen
17 March 2025