Figure 1 Stress has different effects on anxiety- and depression-like behavioural phenotypes in female and male rats. (A) Schematic timeline and experimental paradigm. (B–E) Comparisons of behavioural effects of unpredictable maternal separation (UMS) in female and male rats, which were affected differently. (B) Distance moved in the open field test (OFT). There was a main effect of sex on distance moved (F1,43 = 59.86, p < 0.0001). Among control rats, males showed a decreased distance moved relative to females (post hoc test, p < 0.001). (C) Duration in central zone in the OFT (2-way analysis of variance [ANOVA], interaction: F1,43 = 7.202, p = 0.0103; effect of UMS: F1,43 = 3.694, p = 0.0612; effect of sex: F1,43 = 0.004930, p = 0.9443). Among male rats, time in central zone was significantly decreased (post hoc test, p = 0.0232) after UMS, and no detectable behavioural effect of UMS was observed in females in the OFT (post hoc test, p = 0.9320). From left to right in the figure panel: n = 15, n = 13, n = 10 and n = 9 rats). (D) Open arm ratio in the elevated plus maze (EPM) test (2-way ANOVA, interaction: F1,33 = 0.008304, p = 0.92793; effect of UMS: F1,33 = 21.46, p < 0.0001; effect of sex: F1,33 = 19.85, p < 0.0001). Although time spent in open arms was significantly decreased both in females (post hoc test, p = 0.0164) and males (post hoc test, p = 0.0096), the decrease was more pronounced in males. Additionally, among control rats, males showed a decreased open arm ratio relative to females (post hoc test, p = 0.0184). From left to right in the figure panel: n = 9, n = 9, n = 10 and n = 9 rats. (E) Sucrose consumption in the sucrose preference test (SPT) (2-way ANOVA, interaction: F1,41 = 1.458, p = 0.2342; effect of UMS: F1,41 = 11.39, p = 0.0016; effect of sex: F1,41 = 3.571, p = 0.0659). Among male rats, preference for sucrose was significantly decreased (post hoc test, p = 0.0192). From left to right in the figure panel: n = 12, n = 13, n = 11 and n = 9 rats. (F–I) Comparisons of behavioural effects of adult restraint stress (RS) in female and male rats. (F) distance moved in the OFT. There was a main effect of sex on distance moved (F1,35 = 26.65, p < 0.0001). Among control rats, males showed a decreased distance moved relative to females (post hoc test, p = 0.036). (G) Duration in central zone in the OFT (2-way ANOVA, interaction: F1,35 = 8.419, p = 0.0064; effect of RS: F1,35 = 5.529, p = 0.0245; effect of sex: F1,35 = 15.66, p = 0.0004). In males, RS decreased the duration in the central zone in the OFT (post hoc test, p = 0.0033). Notably, females did not show an elevated anxiety phenotype after exposure to RS (post hoc test, p = 0.9805). From left to right in the figure panel: n = 8, n = 10, n = 9 and n = 10 rats. (H) Open arm ratio in the EPM (2-way ANOVA, interaction: F1,33 = 4.579, p = 0.0399; effect of RS: F1,33 = 4.617, p = 0.0391; effect of sex: F1,33 = 38.59, p < 0.0001). Male rats showed a decreased open arm ratio in the EPM (post hoc test, p = 0.0210) after RS. Notably, females did not show an elevated anxiety phenotype after exposure to RS (post hoc test, p > 0.9999). Additionally, among control rats, males showed a decreased open arm ratio relative to females (post hoc test, p = 0.0305). From left to right in the figure panel: n = 9, n = 9, n = 10 and n = 10 rats. (I) Sucrose consumption in the SPT (2-way ANOVA, interaction: F1,34 = 2.118, p = 0.1548; effect of RS: F1,34 = 0.00, p = 0.9972; effect of sex: F1,34 = 2.048, p = 0.1615). There was no difference in sucrose preference in male (post hoc test, p = 0.7159) and female (post hoc test, p = 0.7501) rats. From left to right in the figure panel: n = 9, n = 9, n = 10 and n = 10 rats. Ctrl = control; mPFC = medial prefrontal cortex; PND = postnatal day. *p < 0.05, **p < 0.01, ***p < 0.001.