A Comparison of Isolation Stress and Unpredictable Chronic Mild Stress for the Establishment of Mouse Models of Depressive Disorder

Abstract

This study aimed to help to understand the influence of stress on depression, which reflects the social environments of especially solitary life and the increasing prevalence of depressive disorders. To determine the distinguishable features of two-representative animal models of stress-induced depressive disorder, we compared isolation stress (IS) and unpredictable chronic mild stress (UCMS). After 4-week of stress, both models showed significant depressive- and anxiety-like behaviors in an open field test (OFT; p < 0.01 for IS, p < 0.01 for UCMS), forced swimming test (FST; p < 0.01 for IS, p < 0.01 for UCMS), and tail suspension test (TST; p < 0.01 for IS, p < 0.05 for UCMS) along with alterations in serum corticosterone levels, serotonin activity in the dorsal raphe nuclei (DRN) and microglial activity in the dentate gyrus of the hippocampus (p < 0.05 for both parameters). In a comparison of the two stress models, IS strongly induced depressive and anxiety features, as indicated by all parameters: behavior test scores (p < 0.05 for OFT, FST, and TST), serum corticosterone levels (p < 0.05), immunohistological alterations for serotonin activity (p < 0.05) and microglial activity (p = 0.072). Our results indicate the suitability of IS for the development of animal models of depressive disorders and may reveal the medical impact of social isolation environment in modern society.

Effect of chronic restraint stress and western‐diet feeding on colonic regulatory gene expression in mice

“…The current study did note a generalized hyperactivity in the open‐field arena in CRS‐exposed mice, which is supported by similar studies utilizing mild stressors 91,96 . Despite this, entries into the center square, which is associated with exploratory behavior, were unaltered by CRS in either dietary group, which contrasts our previous work and others using restraint and social isolation stressors 24,97,98 . In our previous work, we demonstrated that after 9 weeks of feeding, a 3‐week CRS intervention (30min per day) induced synergistic effects on cardiometabolic parameters resulting in elevated insulin levels and worsened myocardial tolerance to ischemic/reperfusion injury.…”

Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice

“…Such G x E interactions seen in these behaviors may suggest that environmental factors (adolescent social isolation) influence similar regions/ pathways of the brain as genetic risk factors (Kpna1 deletion), where the cumulative effects from both factors cause increased levels of impairment. Administration of social isolation stress has been shown to alter performance in FS along with increases in serum corticosterone levels and hippocampal microglial activation [66]. Similar increases in serum corticosterone levels have been found in mice with decreased IA performance after social isolation [67].…”

Using Mice to Model Human Disease: Understanding the Roles of Baseline Housing-Induced and Experimentally Imposed Stresses in Animal Welfare and Experimental Reproducibility

“…The first is restraint stress in which a mouse is placed in a 50 mL conical tube for several hours at a time for several days in a row [80,108]. The second is the chronic unpredictable model of stress (CUMS) in which animals are subjected to several different stressors, including wet bedding, sleep deprivation, foot-shock, cage tilting, water and food deprivation, confinement, continuous illumination, cold stress, and/or forced swim on a random basis [99,109,110]. The CUMS model is thought to be representative of the stressors faced by humans in everyday life and is often used in depression models to study the therapeutic efficacy of candidate anti-depressants; however, a recent study comparing the CUMS to IS found that social isolation is a stronger inducer of depression-like behavior and is more relevant to the role of isolation in stress-induced depression in people [110].…”

“…The second is the chronic unpredictable model of stress (CUMS) in which animals are subjected to several different stressors, including wet bedding, sleep deprivation, foot-shock, cage tilting, water and food deprivation, confinement, continuous illumination, cold stress, and/or forced swim on a random basis [99,109,110]. The CUMS model is thought to be representative of the stressors faced by humans in everyday life and is often used in depression models to study the therapeutic efficacy of candidate anti-depressants; however, a recent study comparing the CUMS to IS found that social isolation is a stronger inducer of depression-like behavior and is more relevant to the role of isolation in stress-induced depression in people [110]. Other models have been developed based on inducing fear, but are not widely used, including exposure of mice to recordings of mice screaming [111], housing adjacent to cats [112], predator odors [113], or chronic social defeat stress (CSDS) in which stranger/aggressor mice are introduced into the cage [101,114].…”

“…As with many of the stressinducing strategies and assessments, there is variability in reliability and Liu et al have published a Nature Protocol to improve the reproducibility of results obtained with this test [131]. Other tests which are frequently used are the forced swim test, in which the time it takes for a mouse to "give up" and float is a measure of depression, as well as the tail suspension test which measures immobility (depressive behavior) and activity [100,110]. Overall, the stressors are imposed to generate models of psychiatric conditions and then the efficacy of therapeutic approaches is measured by discerning their ability to counteract these behaviors as evaluated by the various behavioral tests.…”