Abstract
Exposure to chronic stress can have broad effects on health ranging from increased predisposition for neuropsychiatric disorders to deregulation of immune responses. The chronic unpredictable stress (CUS) protocol has been widely used to study the impact of stress exposure in several animal models and consists in the random, intermittent, and unpredictable exposure to a variety of stressors during several weeks. CUS has consistently been shown to induce behavioral and immunological alterations typical of the chronic stress-response. Unfortunately C57BL/6 mice, one of the most widely used mouse strains, due to the great variety of genetically modified lines, seem to be resistant to the commonly used 4-week-long CUS protocol. The definition of an alternative CUS protocol allowing the use of C57BL/6 mice in chronic stress experiments is a need. Here, we show that by extending the CUS protocol to 8 weeks is possible to induce a chronic stress-response in C57BL/6 mice, as revealed by abrogated body weight gain, increased adrenals weight, and an overactive hypothalamic–pituitary–adrenal axis with increased levels of serum corticosterone. Moreover, we also observed stress-associated behavioral alterations, including the potentiation of anxious-like and depressive-like behaviors and a reduction of exploratory behavior, as well as subtle stress-related changes in the cell population of the thymus and of the spleen. The present protocol for C57BL/6 mice consistently triggers the spectrum of CUS-induced changes observed in rats and, thus, will be highly useful to researchers that need to use this particular mouse strain as an animal model of neuropsychiatric disorders and/or immune deregulation related to CUS.
Highlights
Stressful life events can be triggering factors of numerous neuropsychiatric disorders namely anxiety, depression, and dementia [1], and many of these are accompanied by immune dysfunction [2]
CHRONIC UNPREDICTABLE STRESS PARADIGM One group of C57BL/6 animals was exposed to 4 weeks of chronic unpredictable stress (CUS) and compared to a control group that was subjected to gentle handling, twice a week, for the same period
In the group submitted to the 4-week protocol of CUS, both time [F [4,72] = 23.85; p < 0.0001] and exposure to CUS [F [1,18] = 11.94; p = 0.003] had a significant impact on body weight (Figure 1A)
Summary
Stressful life events can be triggering factors of numerous neuropsychiatric disorders namely anxiety, depression, and dementia [1], and many of these are accompanied by immune dysfunction [2]. In contrast with chronic stress, the acute stress-response is a beneficial event since it is an alarm reaction that prepares the body to a possible threat. This response is characterized by the secretion of stress mediators, such as glucocorticoids and epinephrine, which allows the stability of body function by adaptation to the stressor [4]. When this response persists in time, it might render the system unable to cope with the stressor, leading to chronic-stress-associated illness. It is generally accepted that chronic-stress-associated changes in the immune system alter the vulnerability to infectious disease and auto-immunity [18]
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