Research Article: Greater Physiological and Behavioral Effects of Interrupted Stress Pattern Compared to Daily Restraint Stress in Rats

Date Published: July 11, 2014

Publisher: Public Library of Science

Author(s): Wei Zhang, Andrea Hetzel, Bijal Shah, Derek Atchley, Shannon R. Blume, Mallika A. Padival, J. Amiel Rosenkranz, Leonardo Barbosa Moraes Resstel.


Repeated stress can trigger a range of psychiatric disorders, including anxiety. The propensity to develop abnormal behaviors after repeated stress is related to the severity, frequency and number of stressors. However, the pattern of stress exposure may contribute to the impact of stress. In addition, the anxiogenic nature of repeated stress exposure can be moderated by the degree of coping that occurs, and can be reflected in homotypic habituation to the repeated stress. However, expectations are not clear when a pattern of stress presentation is utilized that diminishes habituation. The purpose of these experiments is to test whether interrupted stress exposure decreases homotypic habituation and leads to greater effects on anxiety-like behavior in adult male rats. We found that repeated interrupted restraint stress resulted in less overall homotypic habituation compared to repeated daily restraint stress. This was demonstrated by greater production of fecal boli and greater corticosterone response to restraint. Furthermore, interrupted restraint stress resulted in a lower body weight and greater adrenal gland weight than daily restraint stress, and greater anxiety-like behavior in the elevated plus maze. Control experiments demonstrated that these effects of the interrupted pattern could not be explained by differences in the total number of stress exposures, differences in the total number of days that the stress periods encompased, nor could it be explained as a result of only the stress exposures after an interruption from stress. These experiments demonstrate that the pattern of stress exposure is a significant determinant of the effects of repeated stress, and that interrupted stress exposure that decreases habituation can have larger effects than a greater number of daily stress exposures. Differences in the pattern of stress exposure are therefore an important factor to consider when predicting the severity of the effects of repeated stress on psychiatric disorders.

Partial Text

Repeated stress exacerbates depression and anxiety, and can trigger post-traumatic stress disorder. The effects of stress depend on a range of factors, and are believed to be proportional to the severity and frequency of the stress exposure [1]–[12]. However, the pattern of stress exposure may also play a role in its effects [13], [14]. Common patterns of stress exposure include 1) continuous over an extended period of time (chronic), 2) daily acute episodes over an extended period (daily), or 3) sporadic acute episodes over an extended period. Two types of sporadic exposures include intermitent, when the stressor is not a frequent occurrence over a given period of time, or interrupted, when the stressor occurs frequently over a given period of time with occassional interuptions. Stress exposure in humans is often in an interrupted pattern. A classic example is 5 day work-related stress interspersed with 2 day weekends. There have been few studies to test whether interrupted stressors exert the same effects on physical and behavioral manifestations of repeated stress.

All experiments were approved by the Institutional Animal Care and Use Committee of Rosalind Franklin University (protocol #11-47 and 13-10), and followed the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011). Efforts were made to minimize animal suffering and to reduce the number of animals used. At the end of the study, rats were euthanized by overdose of ketamine/xylazine followed by decapitation.

The response to repeated stressors over time is dependent upon an interplay between intensity of the stressor, pattern of stress presentation and habituation to the stress. In addition, the acute response to homotypic stress is strongly attenuated with repeated exposures (i.e. habituation), while the long-lasting outcomes of the effects of stress are enhanced with repeated exposures. It has been predicted that increased homotypic habituation to acute stress predicts greater cumulative effects on longer lasting outcomes. This study tested whether the stress exposure pattern exerted parallel modification of homotypic habituation and longer lasting outcomes. The acute response to repeated stressors was quantified by struggling behavior and fecal pellet production during restraint, and CORT release in response to the stressor. The net outcomes of repeated stress exposure were measured by adrenal gland weight, body weight and anxiety-like behavior in the EPM. This study found that an interrupted pattern of repeated stress can lead to a greater effect on all of the longer lasting outcomes, despite diminished effects on habituation compared to daily stress. This was observed even if the interrupted pattern included fewer total number of stress exposures. This provides direct evidence that the pattern of exposure significantly contributes to the effects of stress, and that the link between stress habituation and outcome does not follow the predictions described above.