The rules leading to the emergence of a social organization and the role of social ranking on normal and pathological behaviors remain elusive. Here we show that groups of four genetically identical male mice rapidly form enduring social ranking determined by precedence test and the sharing of beneficial resources. Highest ranked individuals are more anxious, more social and display increased spatial working memory. Whereas differences in anxiety between individuals appear after rank attainment, the higher sociability of top-ranked mice preexist. These behavioral differences correlate with physiological change. The highest ranked mice display indeed lower bursting activity of VTA dopamine neurons. The same animals are less responsive to preclinical models of stress behavioral disorders involving changes of dopamine system. They display lower locomotor sensitization to cocaine and are more resilient to repeated social defeat. The ablation of stress-elicited glucocorticoid receptor gene in dopaminoceptive neurons that affects the same pathological models, upwards the ranking status of mutant individuals. Altogether, these results support a role for social ranking in patterning interindividual VTA dopaminergic activity, behavioral responses and susceptibility to stressrelated psychopathologies.

Enduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

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Stress exposure is a cardinal risk factor for most psychiatric diseases. Preclinical and clinical studies point to changes in gene expression involving epigenetic modifications within mesocorticolimbic brain circuits. Brahma (BRM) and Brahma-Related-Gene-1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that repeated social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.