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One of the big methodological breakthroughs in neurobiological resilience research was the development of what is currently THE animal model in the field: preserved social interaction (SI) after chronic social defeat (CSD) (Krishnan et al., 2007; Golden et al., 2011). During CSD, a test mouse is repeatedly placed over several consecutive days into the cages of far older and heavier mice selected for their aggressive behavior. Relative to control mice not subjected to CSD, the repeated attack and defeat that test mice experience in CSD leads to a long-lasting reduction of SI with other conspecifics, when the test mice are later placed into an arena where they can see, hear and smell the other mouse but cannot be attacked. This social avoidance has been interpreted as a stress-induced impairment of normal exploratory and appetitive behavior towards new social targets, analogous to symptoms of anhedonia and social withdrawal in depression (Berton et al., 2006). In many studies, social avoidance is also accompanied by other variants of anhedonic behavior, such as reduced sucrose preference (e.g., Krishnan et al., 2007; Dias-Ferreira et al., 2009; but see also Chou et al., 2014). The attractiveness of the model for resilience research stems from the observation that a subgroup of mice do not develop social avoidance after CSD. This has been interpreted as preservation of normal adaptive behavior despite stressor exposure (Krishnan et al., 2007; Golden et al., 2011; Russo et al., 2012) and has been likened to the human phenomenon of resilience, which many people now define as the observation of preserved mental health despite adversity.

The model has been the bases for a now innumerable number of publications in Cell, Nature, Science, Nature Neuroscience and other high-profile journals, and it is fair to say that it really only brought the field of resilience into the spotlight of modern neuroscience. Next to its two core features - the considerable inter-individual spread in SI after CSD and its high face (and also pharmacological) validity as a model of not getting depressed (see above) -, the model has further attractive aspects:  its remarkable robustness, its amenability to standardization, and the relative short experimental time it takes to produce stable behavioral outcomes – at least compared with the typical experimental durations needed in animal models of depression. It is those features that have allowed researchers to employ the model as something close to a “high throughput” test in combination with genetics, epigenetics, optogenetics, chemogenetics, and so forth.

This story might now have to be written a bit differently. In a recent paper, Ayash and colleagues (2020) raise an intriguing question. The mice used as social targets in the SI test are always from the same strain as the aggressor mice used during CSD. Hence, could the test mice simply be conditioned during CSD to fear other mice that look, sound and smell like the mice that attacked them during CSD? And if so, could that mean that social avoidance after CSD is not a depression-like stress-induced impairment of the brain systems mediating social exploration, but simply normal and adaptive defensive behavior to a likely source of threat?

Ayash et al. perform two critical experiments to test that hypothesis: in a first experiment, they give defeated mice the choice during the SI test to interact with a mouse from the aggressor strain or also with a mouse from another strain with a rather different phenotype. They call this alternative SI test the Modified Social Interaction Test. See the picture. In a second experiment, after CSD and a classical SI test, they repeatedly expose defeated mice to other mice from the aggressor strain in situations where no attack is possible, i.e., they perform a fear extinction training.

What they observe is pretty unambiguous and not hard to interpret: First, mice given a choice between the aggressor strain and a different strain interact normally with the mouse from the different strain (that is, like non-defeated controls). Hence, their capacity for social interaction is fully intact, which contradicts the idea of a stress-induced impairment. Second, socially avoidant mice repeatedly exposed to other mice from the aggressor strain without being attacked lose their social avoidance, another result not in line with the stress-induced depression hypothesis.

Both results, however, are congruent with CSD being a type of social fear conditioning or social trauma that makes a defeated mouse afraid of any mouse from the aggressors’ clan (conditioned fear reaction) but not of those from another clan (preserved threat-safety discrimination) and that can also be unlearned again given the right type of safety experience (preserved extinction). Should social avoidance after CSD then be considered pathological? And, conversely, are mice that do not develop social avoidance after CSD really resilient – or perhaps just stupid? And what does that mean for resilience research?

A key question for future methodological research on this model surely is the question of individual differences. Will all defeated mice show intact discrimination and extinction? Or will some mice show generalized and extinction-resistant fear (as is typically observed in PTSD and anxiety patients; Duits et al., 2015) and others perhaps no fear at all? What would be adaptive and resilient behavior in such a constellation? Interesting times ahead for resilience research. And maybe some more writing to do.

Raffael Kalisch

Ayash S, Schmitt U, Müller MB (2020) Chronic social defeat-induced social avoidance as a proxy of stress resilience in mice involves conditioned learning. J Psychiatr Res 120:64–71.

Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864.

Chou D, Huang C-C, Hsu K-S (2014) Brain-derived neurotrophic factor in the amygdala mediates susceptibility to fear conditioning. Exp Neurol 255:19–29.

Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, Costa RM, Sousa N (2009) Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325:621–625.

Duits P, Cath DC, Lissek S, Hox JJ, Hamm AO, Engelhard IM, van den Hout MA, Baas JMP (2015) Updated meta-analysis of classical fear conditioning in the anxiety disorders. Depress Anxiety 32:239–253.

Golden SA, Covington HE, Berton O, Russo SJ (2011) A standardized protocol for repeated social defeat stress in mice. Nat Protoc 6:1183–1191.

Krishnan V et al. (2007) Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions. Cell 131:391–404.

Russo SJ, Murrough JW, Han M-H, Charney DS, Nestler EJ (2012) Neurobiology of resilience. Nature Neuroscience 15:1475–1484.