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      Social stress models in depression research: what do they tell us?

      Cell and Tissue Research
      Animals, Behavior, Animal, Depression, psychology, Disease Models, Animal, Humans, Mice, Rats, Stress, Psychological

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          Abstract

          Interest has recently surged in the use of social stress models, especially social defeat. Such interest lies both in the recognition that stressors of social origin play a major role in human psychopathologies and in the acknowledgement that natural and hence ethologically-based stress models have important translational value. The use of the most recent technology has allowed the recognition of the mechanisms through which social defeat might have enduring psychoneuroendocrine effects, especially social avoidance and anhedonia, two behaviours relevant to human depression. In view of the sensitivity of these behavioural outcomes to repeated antidepressant treatments, the social defeat model has been proposed as a possible animal model of depression. The present survey is aimed at examining the limits of such an interpretation and focuses on methodological aspects and on the relevance of social defeat to the study of anxiety-related pathologies.

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          Most cited references86

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          Animal models of neuropsychiatric disorders.

          Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.
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            Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.

            Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
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              Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action.

              To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.
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                Author and article information

                Journal
                23532563
                10.1007/s00441-013-1606-x

                Chemistry
                Animals,Behavior, Animal,Depression,psychology,Disease Models, Animal,Humans,Mice,Rats,Stress, Psychological

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