In contrast to the vast literature on stress effects on the brain relatively little is known about the molecular mechanisms of resilience the ability of some individuals to escape Ko-143 the deleterious effects of stress. the standard antidepressant fluoxetine to reverse behavioral pathology induced by interpersonal defeat. ΔFosB generates these effects through the induction of the GluR2 AMPA glutamate receptor subunit which decreases the responsiveness of nucleus accumbens neurons to Ko-143 glutamate and through additional synaptic proteins. Collectively these findings establish a novel molecular pathway underlying both resilience and antidepressant action. INTRODUCTION People subjected to severe stress show widely differing reactions with some able to conquer crisis while others develop severe psychopathology such as major depression or post-traumatic stress disorder (PTSD). The ability to cope with nerve-racking situations i.e. resilience depends on the development of adequate behavioral and mental adaptations to chronic stress1 2 Psychological constructs that promote resilience include commitment persistence optimism and self-esteem as well as the capacity to modulate emotions and develop adaptive interpersonal behavior. These characteristics implicate Ko-143 the brain’s incentive circuitry which appears to be a critical determinant for the emergence of pathological vs. resilient phenotypes3 4 Neurobiological correlates of vulnerability or resistance to stress have 2 been identified in humans but the extent to which they are the cause or consequence of susceptibility remains unknown5. Among current rodent models of depressive disorder and PTSD chronic social defeat stress is an ethologically valid approach which induces long-term physiological6-8 and behavioral9-11 alterations including social avoidance anhedonia and anxiety-like symptoms involving activation of several neural circuits and neurochemical systems12-15. The normalization of social avoidance by chronic but not acute antidepressant treatment makes it a valuable model for examining aspects of depressive disorder and PTSD in humans11 16 A significant proportion (~30%) of chronically defeated mice avoid most of the unfavorable behavioral sequelae of defeat10 thereby allowing for experimental investigations of resiliency. While the induction of several proteins within the nucleus accumbens (NAc) a key brain reward region has been shown to be important for the expression of depressive-like behaviors after defeat10 11 17 18 much less is known about the molecular basis of resiliency mediated by this brain region. Here we addressed this question by focusing on ΔFosB a Fos family transcription factor induced in NAc by drugs of abuse natural rewards and several types of stress19-21. RESULTS ΔFosB in NAc promotes resilience to social defeat stress C57BL/6J male mice were subjected to ten consecutives days of social defeat10 11 and then separated into susceptible and resilient populations based on a measure of social avoidance (Fig. 1a) which correlates with several other depressive-like behaviors10. We found an increase in ΔFosB Rabbit polyclonal to ARHGDIA. measured by immunohistochemistry in NAc after chronic social defeat (Fig. 1b c) with resilient mice showing the greatest induction of ΔFosB in both core and shell NAc subregions (Fig. 1b c). Moreover we observed a strong (p<0.01) correlation between levels of ΔFosB and social conversation (r = 0.80 NAc shell; r = 0.85 NAc core; r = 0.86 whole NAc) suggesting that the degree of ΔFosB induction in NAc may be a critical determinant of whether an animal shows a susceptible vs. resilient phenotype. Western blot analysis of NAc dissections made up of core and shell subregions confirmed ΔFosB induction in resilient mice only (see Supplementary Fig. 1). Physique 1 ΔFosB induction in NAc by social defeat mediates resilience To test the functional consequences of ΔFosB induction we used bitransgenic mice that inducibly overexpress ΔFosB specifically in the adult NAc and Ko-143 dorsal striatum22. These mice showed a reduced propensity to develop social avoidance after four or ten days of social defeat (Fig. 1d) thereby suggesting that ΔFosB exerts a protective action against social stress. Conversely we used bitransgenic mice that inducibly overexpress ΔcJun a transcriptionally inactive truncated cJun mutant that antagonizes ΔFosB activity23 24 In contrast to mice overexpressing ΔFosB mice overexpressing ΔcJun are more susceptible to chronic social defeat than control littermates and show maximal avoidance behavior following 4 days of defeat (Fig. 1e). The ΔcJun mice also exhibited increased immobility in a one day forced swim test as well as reduced sucrose preference both interpreted as.