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Failure to replicate results between (or within) laboratories can be due to inadequate control of unidentified experimental variables. The sex of human experimenters is rarely seen as a biological variable that can influence the results of experiments. However, rodents' ability to distinguish between the sexes of human experimenters can have measurable effects on their behavior and/or biological responses.
As a result, the Todd D. Gould team recently published their latest research in the journal Nature Neuroscience, "Experimenters' sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor". The effect of the sex of the experimenters on stress-induced maladaptive behaviors was studied, and how odors in male and female experimenters affected the biological behavioral response of rodents to drug antidepressant treatment. They found that the sex of human experimenters affected the behavior of mice and the response to the administration of the fast-acting antidepressant ketamine and its biologically active metabolites. Mice showed an aversion to the male experimenter's odor, a preference for the female experimenter's odor, and an increased susceptibility to stress when the male experimenters handled it.
Human experimenters regulate behavioral responses to odor regulation
The sex of human experimenters is recorded based on self-identification, and this article uses the term "sex" to refer to the classification of such reports. Amphoteric mice consistently show a preference for female scented swabs (Figure 1a). This preference may be odor-driven, as it is not observed in mice that lose their sense of smell with intranasal treatment with zinc sulfate (Figure 1b). In addition, when choosing between a swab dipped in water and a swab with human male or female skin exposed, the mice showed aversion to male swabs, while they showed a preference for female swabs (Figure 1c). Similarly, in the real-time location preference paradigm, mice exhibited avoidance of T-shirts worn by male experimenters, while they showed a preference for T-shirts worn by female experimenters (Figure 1d).
The authors then found that mice spent less time in the maze arm containing male experimenter exposure swabs (Figures 1e, f). No difference was observed in the time spent between the maze arm containing the control and the female experimenter swab (Figures 1e, f). Odor in male experimenters induced endopathy (Figures 1g, h), however, after exposure to odors in female experimenters, neither local preference nor disgust was observed (Figures 1g, h). In the sucrose splash test, the authors observed that when exposed to swabs from male experimenters, mice showed reduced self-care (Figure 1j), a necessary manifestation of increased stress. These findings suggest that the sex of human experimenters may influence rodent behavior and experiments that measure behavioral outcomes.
Figure 1.Mice exhibit different behavioral responses after exposure to male and female experimenter odors
The sex of the human experimenter affects how antidepressants and EEG respond to KET
The authors found that in five pairs of different experimenters, KET injected by men, the experimenters reduced quiescent time in male CD1 mice tested 1 h after treatment (Figure 2a). In addition, KET administered by men reversed CSDS-induced sucrose preference deficiencies in male C57BL/6J mice (Figure 2b). When CD1 and CFW mice were given KET by male experimenters, they also significantly reduced escape defects induced by unavoidable shock 24 h after treatment (Figure 2c). Regardless of the test dose, (2R, 6R)-HNK had no effect on immobility when administered to female subjects (Figure 2f). Finally, KET adds qEEG power in the 30-120-Hz range (Figure 2h-k); However, this effect of KET was greater when male experimenters were given KET (Figure 2h-k).
Figure 2. Identification of MPRA functional regulation variants
CRF mediates the effects of experimenter sex
Female experimenters who administered CRF in the intraceranial compartment (ICV) resulted in a decrease in the rest time of FST after 24 h (Figure 3a) prior to KET administration( Figure 3b) and (Figure 3b) and (2R, 6R)-HNK treated mice (Figure 3c) with less escape failure in the learned helplessness paradigm. In addition, the treatment reduced mouse aversion to male experimenter skin swabs (Figures 3g, h) and eliminated the KET-induced increase in cortical oscillations of 30-120-Hz (Figure 3i-l).
Figure 3. CRF-mediated antidepressant response to KET
Conclusion
Exposure to the scent of male and female experimenters induces different behavioral responses and alters the mice's response to antidepressant-related doses of KET. In addition, the mice's aversion to human male odor is due to the activation of CRF-expressing neurons projected from EC to CA1, and this pathway is the basis for the mice's different behavioral responses to male and female experimenters. The authors' study highlights the relevance of the sex of human experimenters to the reproducibility and interpretation of results within and between laboratories. The stress response triggered by male experimenters leads to the desired results (antidepressant effect of KET); In other studies, female experimenters were more likely to get the desired results. Controlling these factors and understanding how they specifically and quantitatively affect different experimental outcomes can not only reduce heterogeneity between studies, but also, equally important, discover new biological mechanisms to advance scientific knowledge and drug discovery.
Original link:
https://doi.org/10.1038/s41593-022-01146-x
bibliography
Georgiou, P., Zanos, P., Mou, TC.M. et al. Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor. Nat Neurosci 25, 1191–1200 (2022). https://doi.org/10.1038/s41593-022-01146-x
Compiled by Ayden (Brainnews Creative Team)
Reviewer: Simon (Brainnews Editorial Board)