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

Abstract

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.

The impact of the ovarian cycle on anxiety, allopregnanolone, and corticotropin releasing hormone changes after motherhood in female rats and women

“…These experiments demonstrate that reproductive experience may mitigate cyclic-related changes in anxiety in female rats and women; effects that persist long after the hormonal surges of pregnancy and lactation have diminished. Replicating previous findings [ 9 , 10 ], nulliparous rats showed heightened anxiety-like behavior during metestrus compared to proestrus on the EPM, and a trend in the same direction on the LDB (effect sizes ranging from medium to large). In contrast, no estrous effects were observed on the OFT.…”

“…In addition, compared to nulliparous rats, primiparous rats during the postpartum period are resistant to some effects of fluoxetine (an SSRI) and 8-OH-DPAT (a serotonergic agonist) [ 73 , 74 ]. Finally, recent reviews have outlined individual difference factors that may contribute to mixed results on menstrual cycle effects on anxiety in humans (e.g., individual differences in hormonal sensitivity or health anxiety; [ 7 – 9 ]). The current results suggest that reproductive status may be another individual difference factor contributing to mixed results across studies that could be accounted for in future studies.…”

“…Sex differences in the prevalence and burden of anxiety disorders typically emerge after puberty, suggesting that the menstrual cycle, and ensuing fluctuations in the ovarian steroids estradiol and progesterone, may contribute to the development and maintenance of anxiety disorders in women [ 3 – 6 ]. In addition, the menstrual cycle modulates the severity and expression of anxiety symptoms in a subset of hormonally sensitive healthy and anxious women, such that symptoms increase during menstrual phases of declining or low estradiol and progesterone levels (i.e., mid- to late-luteal phase and early-follicular phase, respectively) [ 7 – 9 ]. Conceptually consistent results occur across the rat estrous cycle, whereby anxiety-like behavior increases during estrous phases of low estradiol and progesterone (metestrus or diestrus) relative to those of high estradiol and progesterone (proestrus) [ 9 , 10 ].…”

“…In addition, the menstrual cycle modulates the severity and expression of anxiety symptoms in a subset of hormonally sensitive healthy and anxious women, such that symptoms increase during menstrual phases of declining or low estradiol and progesterone levels (i.e., mid- to late-luteal phase and early-follicular phase, respectively) [ 7 – 9 ]. Conceptually consistent results occur across the rat estrous cycle, whereby anxiety-like behavior increases during estrous phases of low estradiol and progesterone (metestrus or diestrus) relative to those of high estradiol and progesterone (proestrus) [ 9 , 10 ]. Administration of estradiol or progesterone and its metabolite allopregnanolone (a neurosteroid that acts as a positive allosteric modulator of the GABA A receptor) reduces anxiety-like behavior in ovariectomized rats (chronically low estradiol and progesterone) and intact rats during diestrus [ 11 – 13 ].…”

Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress

“…To avoid the possible effects of sex hormones on pain perception and emotion, experiments were performed only on male rats in the present study 59,60 . However, the single‐sex experimental design perhaps limits the observation of female subjects.…”