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24-hour-restraint stress induces long-term depressive-like phenotypes in mice

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ABSTRACT

There is an increasing risk of mental disorders, such as acute stress disorder (ASD), post-traumatic stress disorder (PTSD) and depression among survivors who were trapped in rubble during earthquake. Such long-term impaction of a single acute restraint stress has not been extensively explored. In this study, we subjected mice to 24-hour-restraint to simulate the trapping episode, and investigated the acute (2 days after the restraint) and long-term (35 days after the restraint) impacts. Surprisingly, we found that the mice displayed depression-like behaviors, decreased glucose uptake in brain and reduced adult hippocampal neurogenesis 35 days after the restraint. Differential expression profiling based on microarrays suggested that genes and pathways related to depression and other mental disorders were differentially expressed in both PFC and hippocampus. Furthermore, the depression-like phenotypes induced by 24-hour-restraint could be reversed by fluoxetine, a type of antidepressant drug. These findings demonstrated that a single severe stressful event could produce long-term depressive-like phenotypes. Moreover, the 24-hour-restraint stress mice could also be used for further studies on mood disorders.

No MeSH data available.


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Fluoxetine treatment reverses the depressive-like phenotypes induced by 24-hour-restraint.(A) Experiment design in order to test the effect of fluoxetine (flx) treatment. (B) The sucrose consumption in the sucrose preference test. (2-way ANOVA, stress × durg: p < 0.01, drug: p = 0.03; stress: p < 0.01, N = C:23, R:28, flx-C:28, flx-R:28). (C) The struggling time before the first abandon in the forced swim test (2-way ANOVA, stress×durg: p = 0.2271; drug: p = 0.092; stress: p < 0.01; N = C:30, R:30, flx-C:29, flx-R:30). (D) The total time of immobility in the forced swim test (2-way ANOVA, stress×durg: p < 0.01; drug: p = 0.095; stress: p < 0.05, N = C:30, R:30, flx-C:29, flx-R:30). (E) The percentage of freezing in the fear condition test (2-way ANOVA, stress × durg: p = 0.25; drug: p < 0.001; stress: p < 0.01, N = C:30, R:30, flx-C:29, flx-R:27). (F) The number of Brdu+ cells (2-way ANOVA, stress × durg: p = 0.62; drug: p < 0.01; stress: p = 0.09, N = C:4, R:4, flx-C:3, flx-R:3). (G,H) Changes of ATP concentration level in the PFC (G) (2-way ANOVA, stress × durg: p = 0.945; drug: p < 0.05; stress: p = 0.436, N = 5 for each group) and hippocampus (H) (2-way ANOVA, stress × durg: p < 0.01; drug: p = 0.25; stress: p = 0.73, N = 5 for each group). The asterisks in the figures showed the significant interactions of subgroups detected by post-hoc tests (Tukey Honest Significant Differences): *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± SEM.
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f5: Fluoxetine treatment reverses the depressive-like phenotypes induced by 24-hour-restraint.(A) Experiment design in order to test the effect of fluoxetine (flx) treatment. (B) The sucrose consumption in the sucrose preference test. (2-way ANOVA, stress × durg: p < 0.01, drug: p = 0.03; stress: p < 0.01, N = C:23, R:28, flx-C:28, flx-R:28). (C) The struggling time before the first abandon in the forced swim test (2-way ANOVA, stress×durg: p = 0.2271; drug: p = 0.092; stress: p < 0.01; N = C:30, R:30, flx-C:29, flx-R:30). (D) The total time of immobility in the forced swim test (2-way ANOVA, stress×durg: p < 0.01; drug: p = 0.095; stress: p < 0.05, N = C:30, R:30, flx-C:29, flx-R:30). (E) The percentage of freezing in the fear condition test (2-way ANOVA, stress × durg: p = 0.25; drug: p < 0.001; stress: p < 0.01, N = C:30, R:30, flx-C:29, flx-R:27). (F) The number of Brdu+ cells (2-way ANOVA, stress × durg: p = 0.62; drug: p < 0.01; stress: p = 0.09, N = C:4, R:4, flx-C:3, flx-R:3). (G,H) Changes of ATP concentration level in the PFC (G) (2-way ANOVA, stress × durg: p = 0.945; drug: p < 0.05; stress: p = 0.436, N = 5 for each group) and hippocampus (H) (2-way ANOVA, stress × durg: p < 0.01; drug: p = 0.25; stress: p = 0.73, N = 5 for each group). The asterisks in the figures showed the significant interactions of subgroups detected by post-hoc tests (Tukey Honest Significant Differences): *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± SEM.

Mentions: The 24-hour restraint mice showed depressive-like behaviors and we wondered if these behaviors could be reversed with antidepressant. Fluoxetine (flx) is a classical serotonin selective reuptake inhibitor (SSRI) antidepressant and is widely used for therapy of depression35. It is also effective in the treatment of PTSD36. We administrated fluoxetine to mice for 5 weeks (Fig. 5A) since 2 days after the restraint and conducted similar behavioral tests mentioned above. Firstly, the sucrose preference of the restraint mice treated with fluoxetine was significantly enhanced (Fig. 5B). Secondly, the latency to first immobility and duration of immobility in the forced swim test were also increased in the restraint mice treated with fluoxetine (Fig. 5C,D). Thirdly, the decreased freezing time in restraint mice was also reversed by fluoxetine treatment (Fig. 5E). In addition, after five weeks fluoxetine treatment, increased generation of new granule neurons were found in DG of the restraint mice (Fig. 5F), similar to findings of previous researches that chronic fluoxetine treatment could increase neurogenesis in adult hippocampus37. We further inspected the ATP abundance in the brain, as previous research suggested low ATP abundance in the brain was associated with depressive-like behaviors38. Notably, we found the concentration of ATP was decreased in PFC (student t-test, p < 0.05) and hippocampus (student t-test, p < 0.05) in the restraint mice compared to controls and this decrease could be reversed with fluoxetine treatment (Fig. 5G,H). In summary, the depression-like phenotypes induced by 24-hour-restraint could be reversed by chronic fluoxetine treatment.


24-hour-restraint stress induces long-term depressive-like phenotypes in mice
Fluoxetine treatment reverses the depressive-like phenotypes induced by 24-hour-restraint.(A) Experiment design in order to test the effect of fluoxetine (flx) treatment. (B) The sucrose consumption in the sucrose preference test. (2-way ANOVA, stress × durg: p < 0.01, drug: p = 0.03; stress: p < 0.01, N = C:23, R:28, flx-C:28, flx-R:28). (C) The struggling time before the first abandon in the forced swim test (2-way ANOVA, stress×durg: p = 0.2271; drug: p = 0.092; stress: p < 0.01; N = C:30, R:30, flx-C:29, flx-R:30). (D) The total time of immobility in the forced swim test (2-way ANOVA, stress×durg: p < 0.01; drug: p = 0.095; stress: p < 0.05, N = C:30, R:30, flx-C:29, flx-R:30). (E) The percentage of freezing in the fear condition test (2-way ANOVA, stress × durg: p = 0.25; drug: p < 0.001; stress: p < 0.01, N = C:30, R:30, flx-C:29, flx-R:27). (F) The number of Brdu+ cells (2-way ANOVA, stress × durg: p = 0.62; drug: p < 0.01; stress: p = 0.09, N = C:4, R:4, flx-C:3, flx-R:3). (G,H) Changes of ATP concentration level in the PFC (G) (2-way ANOVA, stress × durg: p = 0.945; drug: p < 0.05; stress: p = 0.436, N = 5 for each group) and hippocampus (H) (2-way ANOVA, stress × durg: p < 0.01; drug: p = 0.25; stress: p = 0.73, N = 5 for each group). The asterisks in the figures showed the significant interactions of subgroups detected by post-hoc tests (Tukey Honest Significant Differences): *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± SEM.
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f5: Fluoxetine treatment reverses the depressive-like phenotypes induced by 24-hour-restraint.(A) Experiment design in order to test the effect of fluoxetine (flx) treatment. (B) The sucrose consumption in the sucrose preference test. (2-way ANOVA, stress × durg: p < 0.01, drug: p = 0.03; stress: p < 0.01, N = C:23, R:28, flx-C:28, flx-R:28). (C) The struggling time before the first abandon in the forced swim test (2-way ANOVA, stress×durg: p = 0.2271; drug: p = 0.092; stress: p < 0.01; N = C:30, R:30, flx-C:29, flx-R:30). (D) The total time of immobility in the forced swim test (2-way ANOVA, stress×durg: p < 0.01; drug: p = 0.095; stress: p < 0.05, N = C:30, R:30, flx-C:29, flx-R:30). (E) The percentage of freezing in the fear condition test (2-way ANOVA, stress × durg: p = 0.25; drug: p < 0.001; stress: p < 0.01, N = C:30, R:30, flx-C:29, flx-R:27). (F) The number of Brdu+ cells (2-way ANOVA, stress × durg: p = 0.62; drug: p < 0.01; stress: p = 0.09, N = C:4, R:4, flx-C:3, flx-R:3). (G,H) Changes of ATP concentration level in the PFC (G) (2-way ANOVA, stress × durg: p = 0.945; drug: p < 0.05; stress: p = 0.436, N = 5 for each group) and hippocampus (H) (2-way ANOVA, stress × durg: p < 0.01; drug: p = 0.25; stress: p = 0.73, N = 5 for each group). The asterisks in the figures showed the significant interactions of subgroups detected by post-hoc tests (Tukey Honest Significant Differences): *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± SEM.
Mentions: The 24-hour restraint mice showed depressive-like behaviors and we wondered if these behaviors could be reversed with antidepressant. Fluoxetine (flx) is a classical serotonin selective reuptake inhibitor (SSRI) antidepressant and is widely used for therapy of depression35. It is also effective in the treatment of PTSD36. We administrated fluoxetine to mice for 5 weeks (Fig. 5A) since 2 days after the restraint and conducted similar behavioral tests mentioned above. Firstly, the sucrose preference of the restraint mice treated with fluoxetine was significantly enhanced (Fig. 5B). Secondly, the latency to first immobility and duration of immobility in the forced swim test were also increased in the restraint mice treated with fluoxetine (Fig. 5C,D). Thirdly, the decreased freezing time in restraint mice was also reversed by fluoxetine treatment (Fig. 5E). In addition, after five weeks fluoxetine treatment, increased generation of new granule neurons were found in DG of the restraint mice (Fig. 5F), similar to findings of previous researches that chronic fluoxetine treatment could increase neurogenesis in adult hippocampus37. We further inspected the ATP abundance in the brain, as previous research suggested low ATP abundance in the brain was associated with depressive-like behaviors38. Notably, we found the concentration of ATP was decreased in PFC (student t-test, p < 0.05) and hippocampus (student t-test, p < 0.05) in the restraint mice compared to controls and this decrease could be reversed with fluoxetine treatment (Fig. 5G,H). In summary, the depression-like phenotypes induced by 24-hour-restraint could be reversed by chronic fluoxetine treatment.

View Article: PubMed Central - PubMed

ABSTRACT

There is an increasing risk of mental disorders, such as acute stress disorder (ASD), post-traumatic stress disorder (PTSD) and depression among survivors who were trapped in rubble during earthquake. Such long-term impaction of a single acute restraint stress has not been extensively explored. In this study, we subjected mice to 24-hour-restraint to simulate the trapping episode, and investigated the acute (2 days after the restraint) and long-term (35 days after the restraint) impacts. Surprisingly, we found that the mice displayed depression-like behaviors, decreased glucose uptake in brain and reduced adult hippocampal neurogenesis 35 days after the restraint. Differential expression profiling based on microarrays suggested that genes and pathways related to depression and other mental disorders were differentially expressed in both PFC and hippocampus. Furthermore, the depression-like phenotypes induced by 24-hour-restraint could be reversed by fluoxetine, a type of antidepressant drug. These findings demonstrated that a single severe stressful event could produce long-term depressive-like phenotypes. Moreover, the 24-hour-restraint stress mice could also be used for further studies on mood disorders.

No MeSH data available.


Related in: MedlinePlus