ReviewDefeat stress in rodents: From behavior to molecules
Introduction
Social defeat can be defined as losing a confrontation between conspecific individuals (Hollis and Kabbaj, 2014). In humans, social defeat has been connected with subjective feelings of being placed in a subordinate or outsider position (Selten and Cantor-Graae, 2005, Selten and Cantor-Graae, 2007, Selten et al., 2013). It has been proposed that social defeat stress plays a central role in the pathogenesis of different psychiatric disorders including psychotic disorders, depression and addiction (Berton et al., 2006, Selten and Cantor-Graae, 2005, Selten and Cantor-Graae, 2007, Selten et al., 2013). A range of studies have been employed to discover the neurobiological impact of social defeat exposures as well as the bio-psycho-social factors moderating the response to social defeat exposure. The subjective nature of the experience of social defeat in humans challenges research on the impact and consequences of social defeat. Studies on humans have therefore mainly focused on different proxy-measures of social defeat exposures, while experimental animal studies have mostly focused on behavioral signs of being in a subordinate or an outsider position after a socially stressful exposure. In the past decades, several animal models of social defeat stress have been developed. Most of these models make use of the natural and predictable behavior of male rodents to defend their territory against intruders, such that a stronger resident–animal defeats an intruder–animal. In the present manuscript, we aim to review the current state of the literature on social defeat stress in rodents. First, we describe the general principles of the social defeat stress paradigms used to date, and compare different experimental settings for studying social defeat stress in rodents focusing predominantly on the resident–intruder paradigm. Second, we describe the range of behavioral changes observed in defeated animals as well as alterations in metabolic and physiological parameters. Third, we give an overview of the alterations at the molecular biological as well as the cellular level, with special attention to alterations in distinct neural circuits and neuroendocrine signaling. Fourth, we critically reflect on the translational aspects of the model, and discuss current considerations, challenges and future perspectives.
Section snippets
Principles of acute and chronic social defeat stress paradigms
Initial investigation of territorial behavior in rodents inspired the idea of using a resident–intruder confrontation as an animal model of psychiatric disorders. It has been shown that adult male rodents have a strong motivation to defend their territory against unfamiliar males (Olivier and Mos, 1992). The classical resident–intruder paradigm has been developed on the basis of one or more dyadic agonistic encounters between male conspecifics. The unfamiliar intruder in the territory of an
Social defeat and behavior
In general, defeated animals show signs of lower wellbeing, reflected by core symptoms of disturbed social behavior, increased anhedonia, and more anxiety- and depressive-like behavior. In the following paragraphs, behavioral changes induced by acute and chronic social defeat stress are discussed. A detailed overview is given in Table 2.
Biological changes after social defeat
Although psychological and physiological stressors both activate the same central biological stress pathways, evidence exists that organisms respond differentially to different types of stressors (Dayas et al., 2001). The next chapter will focus on the biological responses after the psychosocial stress of social defeat, as summarized in Table 3.
Changes in neurotransmitter systems
A growing number of studies have started to define the brain circuits that mediate distinct aspects of mood and emotion under normal circumstances and in various pathological conditions. In the following sections, we review how those regions interact to mediate distinct emotional behaviors that are related to social defeat.
Differential susceptibility to social defeat stress
Krishnan et al. (2007) proposed to segregate social defeat exposed mice into two groups, i.e. susceptible or unsusceptible mice, based on their social behavior in the social avoidance test. Social interaction behavior, expressed as the social interaction ratio, was scored as the time the mouse spends in the interaction zone when the target is present, divided by the time the mouse spends in the interaction zone when the target is absent. An interaction ratio of 100 was set as a cut-off: mice
Challenges of the social defeat paradigm
The social defeat paradigm is based on physical interaction between a dominant resident and a submissive intruder. However, this paradigm has mostly been described in male rodents, because of methodological challenges in designing appropriate animal paradigms for female animals (e.g. females show much less aggressive behavior). In the human population, however, females have higher ratings of fear, irritability and unhappiness to psychosocial stress as compared to men, while men show a larger
Translation to human psychopathology
An ideal animal model for affective disorders would have identical causes, symptomatology and treatment efficacies as seen in human pathology. However, a number of symptoms associated with mood disorders, such as feelings of worthlessness, sadness and guilt, are impossible to measure in animals. Moreover, evolution has led to development of a complex cerebral cortex in humans, giving us feelings of self-esteem and the ability to perceive the future, psychological concepts that are critically
Conclusion
It has been widely described that stress is a strong risk factor for mental health and behavioral disturbances, especially in individuals that are genetically or environmentally predisposed. Exposure to acute or chronic stress has been used for decades to investigate neurobiological mechanisms underlying stress-related behavioral signs and stress-related symptoms of psychiatric disorders. Social defeat can be applied acute, intermittently chronic or chronic, using the resident–intruder paradigm
Acknowledgements
B.P.F. Rutten has received funds via a VENI Award from the Netherlands Organisation for Scientific Research (NWO, grant number 916.11.086). The European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909 [Project EU-GEI]).
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