Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions

Department of Psychiatry, The University of Texas Southwestern Medical Center (UTSWMC), 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
Cell (Impact Factor: 33.12). 11/2007; 131(2):391-404. DOI: 10.1016/j.cell.2007.09.018
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Olivier Berton, Aug 25, 2015
  • Source
    • "For example, the responses to stress vary substantially among individuals, including animals and humans. Some may exhibit resilience, whereas others may exhibit MDDlike vulnerability after the same stress exposure (Krishnan et al., 2007). In addition, the effectiveness of antidepressants in treating MDD varies among individuals (Trivedi et al., 2006), while the predominant clinical manifestations, severity, or courses differ markedly among individuals (Rush, 2007), which has prompted physicians to subtype this disorder (Harald and Gordon, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stress is a major factor in the development of major depressive disorder (MDD), but few studies have assessed individual risk based on pre-stress behavioral and cognitive traits. To address this issue, we employed appetitive instrumental lever pressing with a progressive ratio (PR) schedule to assess these traits in experimentally naïve Sprague-Dawley rats. Based on four distinct traits that were identified by hierarchical cluster analysis, the animals were classified into the corresponding four subgroups (Low Motivation, Quick Learner, Slow Learner, and Hypermotivation), and exposed to chronic unpredictable stress (CUS) before monitoring their post-stress responses for 4 weeks. The four subgroups represented the following distinct behavioral phenotypes after CUS: the Low Motivation subgroup demonstrated weight loss and a late-developing paradoxical enhancement in PR performance that may be related to inappropriate decision-making in human MDD. The Quick Learner subgroup exhibited a transient loss of motivation and the habituation of serum corticosterone (CORT) response to repeated stress. The Slow Learner subgroup displayed resistance to demotivation and a suppressed CORT response to acute stress. Finally, the Hypermotivation subgroup exhibited resistance to weight loss, habituated CORT response to an acute stress, and a long-lasting amotivation. Overall, we identified causal relationships between pre-stress traits in the performance of the instrumental training and post-stress phenotypes in each subgroup. In addition, many of the CUS-induced phenotypes in rats corresponded to or had putative relationships with representative symptoms in human MDD. We concluded that the consequences of stress may be predictable before stress exposure by determining the pre-stress behavioral or cognitive traits of each individual in rats.
    Frontiers in Behavioral Neuroscience 05/2015; 9(119):1-13. DOI:10.3389/fnbeh.2015.00119 · 4.16 Impact Factor
  • Source
    • "Multiple animal models of depressiondincluding chronic unpredictable stress, chronic social defeat stress, and early life stressdrecapitulate neuroendocrine abnormalities found in patients, including blunted glucocorticoid oscillations , elevated glucocorticoid activity, and disrupted circadian troughs (Willner, 1997; Meaney, 2001; Krishnan et al., 2007; Nestler and Hyman, 2010). In at least one study, blunted circadian cycling was linked specifically to stress susceptibility: circadian rhythm amplitudes were blunted only in mice that exhibited a vulnerable behavioral phenotype in response to chronic social defeat stress, relative to resilient mice that did not develop depression-like symptoms (Krishnan et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stress-especially chronic, uncontrollable stress-is an important risk factor for many neuropsychiatric disorders. The underlying mechanisms are complex and multifactorial, but they involve correlated changes in structural and functional measures of neuronal connectivity within cortical microcircuits and across neuroanatomically distributed brain networks. Here, we review evidence from animal models and human neuroimaging studies implicating stress-associated changes in functional connectivity in the pathogenesis of PTSD, depression, and other neuropsychiatric conditions. Changes in fMRI measures of corticocortical connectivity across distributed networks may be caused by specific structural alterations that have been observed in the prefrontal cortex, hippocampus, and other vulnerable brain regions. These effects are mediated in part by glucocorticoids, which are released from the adrenal gland in response to a stressor and also oscillate in synchrony with diurnal rhythms. Recent work indicates that circadian glucocorticoid oscillations act to balance synapse formation and pruning after learning and during development, and chronic stress disrupts this balance. We conclude by considering how disrupted glucocorticoid oscillations may contribute to the pathophysiology of depression and PTSD in vulnerable individuals, and how circadian rhythm disturbances may affect non-psychiatric populations, including frequent travelers, shift workers, and patients undergoing treatment for autoimmune disorders.
    01/2015; 1:174-183. DOI:10.1016/j.ynstr.2014.10.008
  • Source
    • "e ventral tegmental area promotes reward sensitivity and presumably reward learning ( Koo et al . , 2012 ) . Moreover , depressive - like behaviors induced by chronic exposure to stressors are related to lower BDNF levels in the hippocampus , but higher BDNF levels in the ventral tegmental area and the nucleus accumbens [ ( Berton et al . , 2006 ; Krishnan et al . , 2007 ) ; see also ( Yu and Chen , 2011 ) ] ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Animal work implicates the brain-derived neurotrophic factor (BDNF) in function of the ventral striatum (VS), a region known for its role in processing valenced feedback. Recent evidence in humans shows that the BDNF Val66Met polymorphism modulates VS activity in anticipation of monetary feedback. However, it remains unclear whether the polymorphism impacts the processing of self-attributed feedback differently from feedback attributed to an external agent. In this study, we emphasize the importance of the feedback attribution because agency is central to computational accounts of striatum and cognitive accounts of valence processing. We used functional magnetic resonance imaging and a task, in which financial gains/losses are either attributable to performance (self-attributed, SA) or chance (externally-attributed, EA) to ask whether the BDNF Val66Met polymorphism predicts VS activity. We found that the BDNF Val66Met polymorphism influenced how feedback valence and agency information were combined in the VS and in the right inferior frontal junction (IFJ). Specifically, Met carriers' VS response to valenced feedback depended on agency information, while Val/Val carriers' VS response did not. This context-specific modulation of valence effectively amplified VS responses to SA losses in Met carriers. The IFJ response to SA losses also differentiated Val/Val from Met carriers. These results may point to a reduced allocation of attention and altered motivational salience to SA losses in Val/Val compared to Met carriers. Implications for major depressive disorder are discussed.
    Neuroscience 09/2014; 280. DOI:10.1016/j.neuroscience.2014.09.014 · 3.33 Impact Factor
Show more