Paradoxical enhancement of fear expression and extinction deficits in mice resilient to social defeat

Abstract

The exposure to stress has been associated with increased depressive and anxiety symptoms, yet not all individuals respond negatively to the experience of stress. Recent rodent social defeat models demonstrate similar individual differences in response to social stress. In particular, mice subjected to chronic social defeat have been characterized as being either "susceptible" or "resilient" by the level of social interaction following social defeat. Susceptibility is associated with lasting social avoidance as well as increased anxiety-like behavior, and depressive-like symptoms. Resilient animals, however, do not show social avoidance or increased depressive-like symptoms, but retain increased anxiety-like behavior. Thus, it is unclear what "resilience" as measured by social interaction represents in terms of an overall behavioral and physiological phenotype. Here, we use an acute social defeat procedure, which produces distinct behavioral phenotypes in social interaction with no apparent changes in anxiety-like behavior. Susceptible mice display lasting social avoidance, whereas resilient mice display normal social interaction. Susceptible mice also displayed deficits in fear extinction retention but had normal within-session extinction. Paradoxically, resilience was associated with enhanced fear expression, and severe deficits in fear extinction and extinction retention beyond that observed in susceptible mice. These effects in resilient mice were only apparent after the experience of social stress and were not due to impaired behavioral flexibility. These data suggest that mechanisms controlling resilience to acute social defeat as characterized by social interaction leave animals vulnerable to maladaptive fear behavior.

Indomethacin counteracts the effects of chronic social defeat stress on emotional but not recognition memory in mice

“…Similar to non-stressed mice, resilient animals remained in the interaction zone for a longer period when the target was present than when it was absent; however, susceptible subjects remained in the interaction zone for less time and spent longer periods in the corner zones when there was social stimuli. These data are consistent with previous studies [8, 37, 53] in which the social defeat stress paradigm induced two phenotypic responses during a subsequent social interaction test: resilient mice did not display a decrease in social interaction after social defeat, in a similar way to the non-stressed group, whereas susceptible mice were characterized by prolonged social avoidance, even though all animals had an identical genetic background and all had been exposed to similar conditions of social defeat stress. Therefore, resilient animals displayed a similar behavioral pattern to that of non-stressed mice.…”

Sex differences in PTSD resilience and susceptibility: Challenges for animal models of fear learning

“…The relationship of resilient vs. susceptible phenotypes to learned fear behavior has recently begun to be studied, but a clear picture has not yet emerged: Chou et al. (2014) found that susceptible mice exhibited greater freezing during fear conditioning compared to a resilient population, while Meduri et al. (2013) previously reported that resilient animals expressed higher and longer-sustained fear levels.…”

Two weeks of predatory stress induces anxiety-like behavior with co-morbid depressive-like behavior in adult male mice

“…A commonly used chronic stress paradigm is chronic mild unpredictable stress, which has both face validity in producing symptoms and predictive validity for response to antidepressants in rats [13]; however, the effects of this paradigm in mice have been less consistent [6,7]. Social defeat is another commonly used stress paradigm in rats [11], but a percentage of mice are resistant to the negative effects of chronic social defeat [14–16]. An alternative chronic stress paradigm is the use of predatory stress, which is more potent than exposure to chronic mild unpredictable stress in mice [17].…”