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


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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.


          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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          Most cited references86

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          The use of the elevated plus maze as an assay of anxiety-related behavior in rodents.

          The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethological parameters (i.e., rears, head dips and stretched-attend postures) can also be observed. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our laboratory, rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent.
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            Why are women so vulnerable to anxiety, trauma-related and stress-related disorders? The potential role of sex hormones.

            Increased prevalence, severity, and burden of anxiety, trauma-related and stress-related disorders in women compared with men has been well documented. Evidence from a variety of fields has emerged suggesting that sex hormones, particularly oestradiol and progesterone, play a significant part in generation of these sex differences. In this Series paper, we aim to integrate the literature reporting on the effects of sex hormones on biological, behavioural, and cognitive pathways, to propose two broad mechanisms by which oestradiol and progesterone influence sex differences in anxiety disorders: augmentation of vulnerability factors associated with anxiety disorder development; and facilitation of the maintenance of anxious symptoms post-development. The implications for future research, along with novel approaches to psychological and pharmacological treatment of anxiety disorders, are also considered.
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              Strategies and methods for research on sex differences in brain and behavior.

              Female and male brains differ. Differences begin early during development due to a combination of genetic and hormonal events and continue throughout the lifespan of an individual. Although researchers from a myriad of disciplines are beginning to appreciate the importance of considering sex differences in the design and interpretation of their studies, this is an area that is full of potential pitfalls. A female's reproductive status and ovarian cycle have to be taken into account when studying sex differences in health and disease susceptibility, in the pharmacological effects of drugs, and in the study of brain and behavior. To investigate sex differences in brain and behavior there is a logical series of questions that should be answered in a comprehensive investigation of any trait. First, it is important to determine that there is a sex difference in the trait in intact males and females, taking into consideration the reproductive cycle of the female. Then, one must consider whether the sex difference is attributable to the actions of gonadal steroids at the time of testing and/or is sexually differentiated permanently by the action of gonadal steroids during development. To answer these questions requires knowledge of how to assess and/or manipulate the hormonal condition of the subjects in the experiment appropriately. This article describes methods and procedures to assist scientists new to the field in designing and conducting experiments to investigate sex differences in research involving both laboratory animals and humans.

                Author and article information

                Curr Psychiatry Rep
                Curr Psychiatry Rep
                Current Psychiatry Reports
                Springer US (New York )
                18 October 2022
                18 October 2022
                : 24
                : 11
                : 697-707
                GRID grid.1005.4, ISNI 0000 0004 4902 0432, School of Psychology, , The University of New South Wales Australia, ; Sydney, NSW Australia
                Author information
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                : 19 September 2022
                Funded by: FundRef http://dx.doi.org/10.13039/501100000923, Australian Research Council;
                Award ID: DP220101339
                Award Recipient :
                Funded by: University of New South Wales
                Reproductive Psychiatry and Women's Health (L Hantsoo and S Nagle-Yang, Section Editors)
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2022

                Clinical Psychology & Psychiatry
                menstrual cycle,oestrous cycle,anxiety,unlearned fear,sex hormones


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