While stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying such resilience are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations that differ along several behavioral and physiological domains. By a combination of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability or insusceptibility. We show that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain's reward circuits in actively maintaining an emotional homeostasis.

Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.About one in six individuals in the United States will succumb to clinical depression during their lifetime 1 . Core symptoms include depressed mood, anhedonia (reduced ability to experience pleasure from natural rewards), irritability, difficulties in concentrating, and abnormalities in appetite and sleep ('neurovegetative symptoms') 2 . In addition to mortality associated with suicide, depressed patients are more likely to develop coronary artery disease and type 2 diabetes 3 . Depression also complicates the prognosis of a host of other chronic medical conditions 4,5 . The chronic, festering nature of depression contributes substantially to the global burden of disease and disability.Despite the prevalence of depression and its considerable impact, knowledge about its pathophysiology is rudimentary compared with knowledge of other common chronic and potentially fatal multifactorial conditions, such as type 2 diabetes (Table 1). There are several explanations for this discrepancy. First and foremost, observing pathological changes within the brain remains markedly more difficult than for all other organs. Available techniques to document the aberrant function of brain circuits depend on either post-mortem studies, which have numerous limitations, or neuroimaging techniques, which rely on detecting changes in neuronal activity by using indirect markers of activation 6 . Although these approaches have provided important insights into candidate brain regions, simple increases or decreases in regional brain activity are probably insufficient to explain the complex array of symptoms caused by depression. Several animal models have also informed knowledge of the neural Correspondence should be addressed to E.J.N. (E-mail: eric.nestler@mssm.edu). Author Information Reprints and permissions information is available at www.nature.com/reprintsThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at www.nature.com/nature. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript circuitry of depression, but there are important challenges to how information gained from these models should be interpreted (Box 1).Second, most depression occurs idiopathically,...

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.

Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood. bipolar disorder ͉ circadian rhythms ͉ dopamine