Altered exploratory behaviour and increased food intake in the spiny mouse before menstruation: a unique pre-clinical model for examining premenstrual syndrome

STUDY QUESTION: Does the newly discovered menstruating spiny mouse exhibit behavioural and metabolic changes in correlation with premenstrual phases of the menstrual cycle? SUMMARY ANSWER: This is the first report of cycle variability in the exploratory and interactive behaviour, and food consumption in menstruating spiny mice, and demonstrates that physiological changes are also dependent on within-subject variation. WHAT IS KNOWN ALREADY: Premenstrual syndrome (PMS) is a prominent cyclic disorder that affects millions of women worldwide. More than 70% of women endure symptoms of impending menstruation, such as bloating, abdominal cramping and nausea to some degree. Consequently, ~8% of women experience recurrent physical and emotional symptoms which are extreme enough to disrupt daily life and seek intervention. Due to a lack of an appropriate animal model, the mechanisms underlying PMS are poorly understood, and subsequently, effective treatments are limited. STUDY DESIGN, SIZE, DURATION: This study analyses the changes in behavioural responses to the investigator during vaginal lavage (n = 14), exploratory behaviour (n = 11) and metabolism (n = 20) across the menstrual cycle in the spiny mouse (Acomys cahirinus). PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed vaginal lavages on virgin spiny mice (6-8 months of age) and subjected each cohort of females to repeated measures for vaginal lavage, exploratory behaviour and metabolism. Stages of the menstrual cycle were designated as early follicular, late follicular, early luteal, late luteal, early menstrual and late menstrual, with the late luteal and early menstrual phases considered as premenstrual phases and analysed using generalized estimating equations. For vaginal lavage, the behavioural responses to researcher handling were scored on an increasing scale of severity during the lavage process (e.g. restraint, frequency of vocalizations, total handling time). For exploratory behaviour, exploration, memory and sociability were assessed through subjection to Open Field (OF), Novel Object Recognition (NORT), Social Novelty (SN) and Elevated Plus Maze (EPM) tests. For metabolism, physiological changes were measured over a 24-h period in metabolic cages. Results are mean ± SD with statistical significance set to P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Qualitative behavioural assessment showed that compared to early follicular controls, during premenstrual phases, cycling females had significantly increased probability of: manifesting difficulties during restraint (4×, P < 0.01), vocalizing (8×, P < 0.01) and exhibiting isolation in the cage (40×, P = 0.041). We saw significant increases in handling time during the premenstrual phase in cycling females (76 ± 16 s) compared to controls (55 ± 7 s, P < 0.001). For exploratory behaviour, cycling females in their early menstrual phase travelled significantly less distance in the outer zone of the OF arena (13.3 ± 9.0 m) than females in their early luteal phase (22.3 ± 9.9 m, P = 0.038) and at significantly reduced velocities (40.2 ± 10.5 mm/s and 78.8 ± 31.0 mm/s, respectively, P = 0.006). These females also had fewer entries into the EPM open arms during the same phases (9.6 ± 6.1 and versus 20.0 ± 7.2, respectively, P = 0.030) and travelled less distance (3.2 ± 2.8 m versus 7.0 ± 5.5 m, respectively, P = 0.026). No differences were observed in NORT or SN across the cycle. In the metabolism studies, spiny mice demonstrated a significant increase in food consumption (percentage of body weight) during the early follicular and late luteal phases (3.9 ± 2.4% and 3.8 ± 2.1%, respectively) compared to the late follicular phase (2.3 ± 2.6%, P = 0.015). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This is an observational study to determine fundamental changes in behaviour and metabolism in a novel species, and as such, lacks commercially available laboratory reagents and protocols specific to the spiny mouse. WIDER IMPLICATIONS OF THE FINDINGS: The timing of these behavioural and physiological changes suggests that spiny mice exhibit symptoms analogous to PMS in higher order primates, thus providing a pre-clinical model for testing novel interventions to alleviate premenstrual symptoms and overcoming many limitations associated with this research area. STUDY FUNDING/COMPETING INTEREST(S): N.B. is supported by a Research Training Program stipend through Monash University. J.E. is supported by a Fellowship awarded by the Peter Fielding Foundation. The Hudson Institute of Medical Research is supported by the Victorian Government Operational Research Infrastructure Support. The authors declare no conflicts of interest.