Many social factors and various aversive situations may induce affective disorders, like depression and anxiety-related disorders, suggesting complex relationships among stressful situations and the onset of clinical depression. The unpredictable chronic mild stress (UCMS) protocol is a valid, reliable, and sensitive model for the study of depressive disorders in rodents. It includes a sequence of mild socio-environmental stressors, thus replicating several depression-related behavioral and physiological impairments [1]. In the present study we investigated the impact of a six weeks UCMS paradigm (random pattern of mild stressors twice a day) on the development of a depressive and/or anxious phenotype in CD1 mice of both sexes. To assess the anxiety-like behavior, we used the Elevated Plus Maze (EPM) and the Open Field (OF) tests. The Two-Way ANOVA for mice activity on EPM revealed a significant gender-treatment interaction [p<0.01] for the time spent in open arms. The Bonferroni’s test indicated a significant [p<0.05] sex difference in control groups, being males less anxious than females (males spend more time in the open arms). Exposure to UCMS had an anxiolitic effect on females [p<0.05] but not on males. The Two-Way ANOVA for the open arm entries, showed also a significant gender-treatment interaction [p<0.05], but the Bonferroni’s test revealed only a significant difference [p<0.05] between female and male controls; this significant difference disappeared in UCMS-treated animals. For the OF test, the Two-way ANOVA indicated a significant gender-treatment interaction [p<0.05] for the time spent in the center of the arena. The Bonferroni’s test reveled no differences in control groups, whereas, the exposure to UCMS induced an anxiolitic effect in females only [p<0.05]. The Two-way ANOVA for the total distance travelled in the central zone, did not show any significant effect for treatment or interaction, whereas the effect of gender indicated a tendency to statistical significance [p=0.078]. The Bonferroni’s test indicated only a significant [p<0.05] sex difference in UCMS groups, being females less anxious than males (females travelled more distance than males in the center). To estimate the depressive profile we evaluated the time that the animal spent in immobile posture (floating) during a five min trial (Forced Swimming Test): Two-way ANOVA revealed a signicant effect of gender [p<0.05] meanwhile the interaction gender-treatment did not reach statistical significance [p=0.059]. The Bonferroni’s test showed only a significant difference [p<0.01] between female and male controls. For the hedonic behavior, we performed the sucrose preference test (SPT) calculating the consumption of 2% sucrose solution and water. For the sucrose consumption, the Two-way ANOVA, indicated only a tendency to statistical significance of gender-treatment interaction [p=0.086] and treatment [p=0.062], while Bonferroni’s test indicated a significant decrease in UCMS males compared to control males [p<0.05]. For water consumption, the Two-way ANOVA revealed a significant effect of treatment [p<0.01], and a tendency for gender effect [p=0.052]; the Bonferroni’s test showed a significant decrease in UCMS males compared to controls [p<0.05]. We also considered the total liquid ingested (2% sucrose solution and water), in this case the Two-way ANOVA indicated a significant effect of treatment [p<0.01], and the Bonferroni’ test showed a significant decrease of liquid ingestion [p<0.01] in stressed males compared to controls. In summary, these data show that the treatment causes a reduction in the fluids intake (sucrose, water and total), in particular in males, suggesting that UCMS may induce a less anhedonic state. In conclusion, these data indicate that the UCMS treatment is a good model to test the sexually dimorphic onset of affective disorders. We are currently investigating changes in the vasopressin system after UCMS exposure in the parvocellular sexually dimorphic circuits and in the future we will analyze also other circuits involved on the control of anxiety behavior (i.e. nNOS system) and on regulation of stress response (i.e serotonin system). This research was supported by Compagnia di San Paolo (Progetto Neuroscienze) – Torino (Italy) and Fondazione Cavalieri-Ottolenghi, Orbassano (Italy)
Sexually dimorphic effects of unpredictable chronic mild stress (UCMS) in a murine model of depression and anxiety
FOGLIO, BENEDETTA;PANZICA, Giancarlo
2013-01-01
Abstract
Many social factors and various aversive situations may induce affective disorders, like depression and anxiety-related disorders, suggesting complex relationships among stressful situations and the onset of clinical depression. The unpredictable chronic mild stress (UCMS) protocol is a valid, reliable, and sensitive model for the study of depressive disorders in rodents. It includes a sequence of mild socio-environmental stressors, thus replicating several depression-related behavioral and physiological impairments [1]. In the present study we investigated the impact of a six weeks UCMS paradigm (random pattern of mild stressors twice a day) on the development of a depressive and/or anxious phenotype in CD1 mice of both sexes. To assess the anxiety-like behavior, we used the Elevated Plus Maze (EPM) and the Open Field (OF) tests. The Two-Way ANOVA for mice activity on EPM revealed a significant gender-treatment interaction [p<0.01] for the time spent in open arms. The Bonferroni’s test indicated a significant [p<0.05] sex difference in control groups, being males less anxious than females (males spend more time in the open arms). Exposure to UCMS had an anxiolitic effect on females [p<0.05] but not on males. The Two-Way ANOVA for the open arm entries, showed also a significant gender-treatment interaction [p<0.05], but the Bonferroni’s test revealed only a significant difference [p<0.05] between female and male controls; this significant difference disappeared in UCMS-treated animals. For the OF test, the Two-way ANOVA indicated a significant gender-treatment interaction [p<0.05] for the time spent in the center of the arena. The Bonferroni’s test reveled no differences in control groups, whereas, the exposure to UCMS induced an anxiolitic effect in females only [p<0.05]. The Two-way ANOVA for the total distance travelled in the central zone, did not show any significant effect for treatment or interaction, whereas the effect of gender indicated a tendency to statistical significance [p=0.078]. The Bonferroni’s test indicated only a significant [p<0.05] sex difference in UCMS groups, being females less anxious than males (females travelled more distance than males in the center). To estimate the depressive profile we evaluated the time that the animal spent in immobile posture (floating) during a five min trial (Forced Swimming Test): Two-way ANOVA revealed a signicant effect of gender [p<0.05] meanwhile the interaction gender-treatment did not reach statistical significance [p=0.059]. The Bonferroni’s test showed only a significant difference [p<0.01] between female and male controls. For the hedonic behavior, we performed the sucrose preference test (SPT) calculating the consumption of 2% sucrose solution and water. For the sucrose consumption, the Two-way ANOVA, indicated only a tendency to statistical significance of gender-treatment interaction [p=0.086] and treatment [p=0.062], while Bonferroni’s test indicated a significant decrease in UCMS males compared to control males [p<0.05]. For water consumption, the Two-way ANOVA revealed a significant effect of treatment [p<0.01], and a tendency for gender effect [p=0.052]; the Bonferroni’s test showed a significant decrease in UCMS males compared to controls [p<0.05]. We also considered the total liquid ingested (2% sucrose solution and water), in this case the Two-way ANOVA indicated a significant effect of treatment [p<0.01], and the Bonferroni’ test showed a significant decrease of liquid ingestion [p<0.01] in stressed males compared to controls. In summary, these data show that the treatment causes a reduction in the fluids intake (sucrose, water and total), in particular in males, suggesting that UCMS may induce a less anhedonic state. In conclusion, these data indicate that the UCMS treatment is a good model to test the sexually dimorphic onset of affective disorders. We are currently investigating changes in the vasopressin system after UCMS exposure in the parvocellular sexually dimorphic circuits and in the future we will analyze also other circuits involved on the control of anxiety behavior (i.e. nNOS system) and on regulation of stress response (i.e serotonin system). This research was supported by Compagnia di San Paolo (Progetto Neuroscienze) – Torino (Italy) and Fondazione Cavalieri-Ottolenghi, Orbassano (Italy)
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