Commonly-used rodent tests of anxiety-like behavior lack predictive validity for human sex differences

Börchers, Stina; Krieger, Jean‐Philippe; Asker, Mohammed; Maric, Ivana; Skibicka, Karolina P.

doi:10.1016/j.psyneuen.2022.105733

Cited by 27 publications

(21 citation statements)

References 73 publications

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“…These effects are highly robust across various rat strains, testing paradigms, lighting conditions and experimental designs and have not diminished over time, with several recent studies reporting similar results [51-65, 66•, 67•, 68, 69•]. A minority report null effects [70][71][72][73][74][75]. The analogous findings cross-species suggest that changes in anxiety coincident with cycling hormones are likely linked to an evolutionarily conserved mechanism in female rats and women.…”

Section: Oestrous Fluctuations In Anxiety-like Behaviour In Female Ratsmentioning

confidence: 70%

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

Pestana

Islam

Eyk

et al. 2022

Curr Psychiatry Rep

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Purpose of Review Anxiety symptoms increase during the peri-menstrual phase of the menstrual cycle in people with anxiety disorders. Whether this reflects a heightened variant of normal menstrual-related changes in psychological states experienced by healthy (i.e. non-anxious) people is unknown. Moreover, menstrual-related change in anxiety symptoms is a poorly understood phenomenon, highlighting a need for pre-clinical models to aid mechanistic discovery. Here, we review recent evidence for menstrual effects on anxiety-like features in healthy humans as a counterpart to recent reviews that have focused on clinically anxious populations. We appraise the utility of rodent models to identify mechanisms of menstrual effects on anxiety and offer suggestions to harmonise methodological practices across species to advance knowledge in this field. Recent Findings Consistent with reports in clinical populations, some evidence indicates anxiety symptoms increase during the peri-menstrual period in healthy people, although null results have been reported, and these effects are heterogeneous across studies and individuals. Studies in rats show robust increases in anxiety during analogous phases of the oestrous cycle. Summary Studies in female rats are useful to identify the evolutionarily conserved biological mechanisms of menstrual-related changes in anxiety. Future experimental approaches in rats should model the heterogeneity observed in human studies to increase alignment across species and advance understanding of the individual factors that increase the propensity to experience menstrual-related changes in anxiety.

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Section: Oestrous Fluctuations In Anxiety-like Behaviour In Female Ratsmentioning

confidence: 70%

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

Pestana

Islam

Eyk

et al. 2022

Curr Psychiatry Rep

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“…First, we show that in our anxiety-related behavioral data and gene expression results for Htr2b, a gene implicated in these behaviors, we can find sex differences only if we account for the estrous cycle stage. This is important because it was suggested that the old tests that were developed for males, such as the elevated plus maze, may not be applicable to females as they cannot re-create increased female risk for anxiety disorders reported in humans [23,41]. What we demonstrate, though, is that proper classification of females will show the same trend that we see in humans, which is that low-estrogenic female mice (diestrus) show higher anxiety indices than highestrogenic females (proestrus) and males, thus recreating the fact that sex hormone withdrawal in humans is a trigger for increased anxiety and depression symptoms [8,9] or other reproduction-related disorders such as PMDD [10], postpartum depression [11,12], and perimenopausal depression [8,14].…”

Section: The Estrous Cycle Tracking Is a Stressor And May Represent A...mentioning

confidence: 99%

Why the estrous cycle matters for neuroscience

2022

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Background Ovarian hormone fluctuations over the rodent estrous cycle and the human menstrual cycle are known to significantly impact brain physiology and disease risk, yet this variable is largely ignored in preclinical neuroscience research, clinical studies, and psychiatric practice. Methods To assess the importance of the estrous cycle information for the analysis of sex differences in neuroscience research, we re-analyzed our previously published data with or without the estrous cycle information, giving a side-by-side comparison of the analyses of behavior, brain structure, gene expression, and 3D genome organization in female and male mice. We also examined and compared the variance of female and male groups across all neurobehavioral measures. Results We show that accounting for the estrous cycle significantly increases the resolution of the neuroscience studies and allows for: (a) identification of masked sex differences; (b) mechanistic insight(s) into the identified sex differences, across different neurobehavioral outcomes, from behavior to molecular phenotypes. We confirm previous findings that female data from either mixed- or staged-female groups are, on average, not more variable than that of males. However, we show that female variability is not, at all, predictive of whether the estrous cycle plays an important role in regulating the outcome of interest. Conclusions We argue that “bringing back” the estrous cycle variable to the main stage is important in order to enhance the resolution and quality of the data, to advance the health of women and other menstruators, and to make research more gender-inclusive. We strongly encourage the neuroscience community to incorporate the estrous cycle information in their study design and data analysis, whenever possible, and we debunk some myths that tend to de-emphasize the importance and discourage the inclusion of this critically important biological variable. Highlights Ovarian hormone fluctuation impacts brain physiology and is a major psychiatric risk factor, yet this variable has been overlooked in neuroscience research and psychiatric practice. From rodent behavior to gene regulation, accounting for the estrous cycle increases the resolution of the neuroscience data, allowing identification and mechanistic insight(s) into sex differences. Female variability does not equal (and is not predictive of) the estrous cycle effect and should not be used as a proxy for the effects of ovarian hormones on the outcome of interest. Neuroscience researchers are advised to incorporate the estrous cycle information in their studies to foster more equitable, female- and gender-inclusive research. Studies of the ovarian cycle are especially important for improving women’s mental health.

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“…Differences in human anxiety are not consistently replicated in rodent models (Donner and Lowry, 2013;Scholl et al, 2019). Most tests for anxiety-like behavior were developed >20 years ago and were validated in male rodents only (Donner and Lowry, 2013;Börchers et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Anxiety-like behaviors in mice unmasked: Revealing sex differences in anxiety using a novel light-heat conflict test

Lee

Greenough

Oancea

et al. 2022

Preprint

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Anxiety and chronic pain afflict hundreds of millions worldwide. Both anxiety and pain are more prevalent in females (vs. males). Unfortunately, robust sex differences in human anxiety are not recapitulated in rodent tests, and results from rodent pain studies frequently fail to translate clinically. Therefore, there is a need to develop tests that reflect the differential salience of anxiety or pain-related stimuli between the sexes. Accordingly, here we introduce the Thermal Increments Dark-Light (TIDAL) conflict test. The TIDAL test places an anxiety-relevant stimulus (dark vs. illuminated chamber) in conflict with a heat-related stimulus (incrementally heated vs. isothermic chamber); mice freely explore the dark-heating and illuminated-isothermic chambers. Here, we aim to determine whether the TIDAL conflict test reveals in mice underappreciated sex differences in anxiety and/or heat sensitivity. We establish in three distinct experiments that females on the TIDAL conflict test persist substantially longer on the dark-heated plate, suggesting that females (vs. males) exhibit elevated anxiety-like behavior. Mice more strongly prefer the dark plate on the TIDAL conflict test compared to control thermal place preference with both chambers illuminated. We also reveal that mice exposed to TIDAL for a second session exhibit signs of learning. Therefore, our new TIDAL conflict test reliably unmasks the relative salience of anxiety (vs. heat sensitivity): mice that are female exhibit robust anxiety-like behaviors not consistently observed in classical tests. Future studies should incorporate TIDAL and other conflict tests to better understand rodent behavior and to identify mechanisms underlying anxiety and pain.

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Commonly-used rodent tests of anxiety-like behavior lack predictive validity for human sex differences

Cited by 27 publications

References 73 publications

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

What Pre-clinical Rat Models Can Tell Us About Anxiety Across the Menstrual Cycle in Healthy and Clinically Anxious Humans

Why the estrous cycle matters for neuroscience

Anxiety-like behaviors in mice unmasked: Revealing sex differences in anxiety using a novel light-heat conflict test

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