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: 32.24). 11/2007; 131(2):391-404. DOI: 10.1016/j.cell.2007.09.018
Source: PubMed


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.

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Available from: Olivier Berton, Oct 04, 2015
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    • "Although decreases in social interaction are most common in anxiety states, it is important to note that social dysfunction represents one of the core symptoms of depressionrelated diseases (Merikangas and Angst 1995). Other Bstress^ neuropeptides, such as corticotropin-releasing factor and cholecystokinin , have been shown to reduce social interaction (Dunn and File 1987; To and Bagdy 1999), and chronic stress can also dramatically impact social interaction (Becker et al. 2008; Berton et al. 2006; Krishnan et al. 2007). A previous report that mice with a deletion of the PACAP gene show increased social interaction and an attenuation of social defeat-induced social withdrawal is in line with our results (Hattori et al. 2012; Lehmann et al. 2012). "
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    ABSTRACT: Major depressive disorder (MDD) is a chronic, life-threatening psychiatric condition characterized by depressed mood, psychomotor alterations, and a markedly diminished interest or pleasure in most activities known as anhedonia. Available pharmacotherapies have limited success and the need for new strategies is clear. Recent studies attribute a major role to the pituitary adenylate cyclase-activating polypeptide (PACAP) system in mediating the response to stress. PACAP knockout mice display profound alterations in depressive-like behaviors, and genetic association studies have demonstrated that genetic variants of the PACAP gene are associated with MDD. However, the effects of PACAP administration on depressive-like behaviors in rodents have not yet been systematically examined. The present study investigated the effects of central administration of PACAP in rats on depressive-like behaviors, using well-established animal models that represent some of the endophenotypes of depression. We used intracranial self-stimulation (ICSS) to assess the brain reward function, saccharin preference test to assess anhedonia, social interaction to assess social withdrawal, and forced swim test (FST) to assess behavioral despair. PACAP raised the current threshold for ICSS, elevation blocked by the PACAP antagonist PACAP(6-38). PACAP reduced the preference for a sweet saccharin solution and reduced the time the rats spent interacting with a novel animal. Interestingly, PACAP administration did not affect immobility in the FST. Our results demonstrate a role for the central PACAP/PAC1R system in the regulation of depressive-like behaviors and suggest that hyperactivity of the PACAP/PAC1R system may contribute to the pathophysiology of depression, particularly the associated anhedonic symptomatology and social dysfunction.
    Psychopharmacology 08/2015; 232(20). DOI:10.1007/s00213-015-4045-4 · 3.88 Impact Factor
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    • "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). "
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    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 · 3.27 Impact Factor
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    • "Defeated inbred mice exhibit a spectrum of subsequent individual social interaction tendencies that can be segregated in to susceptible (interaction is reduced) and resistant (interaction persists) groups (Krishnan et al., 2007; Meduri et al., 2013). Though all defeated mice regardless of group display enhanced blood corticosterone levels, those mice classified as susceptible exhibit physiological (e.g., increased nucleus accumbens BDNF) and behavioral (e.g., potentiated cocaine place preference, increased anxiety-like behavior) changes compared to their control and resistant defeated counterparts (Krishnan et al., 2007). In contrast, resistant mice have elevated fear expression and impaired fear extinction (Meduri et al., 2013). "
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    ABSTRACT: The corticotropin releasing factor (CRF) system plays a critical role in responses to stressful stimuli, and is expressed in many areas of the brain involved in processing fear, anxiety, and social behaviors. To better understand the mechanisms by which the CRF system modulates responses to stressful events and social stimuli, we employed a mouse model that selectively disrupts NMDA receptor function via NMDA receptor subunit NR1 (Grin1) knockout specifically in Cre-expressing CRF neurons. These animals (Cre+/(fGrin1+)) were compared with littermates lacking Cre expression (Cre-/(fGrin1+)). Following cue discrimination fear conditioning, male Cre+/(fGrin1+) mice showed increased fear expression to the tone paired with a foot shock (CS+) while still discriminating the CS+ from a tone never paired with a foot shock (CS-). In contrast to males, female mice learned and discriminated fear cues equivalently across the genotypes. Similarly, no genotype differences in sociability or social novelty were observed in female mice, but Cre+/(fGrin1+) males displayed greater naive sociability and preference for social novelty than Cre-/(fGrin1+) littermates. Furthermore, the level of social withdrawal exhibited by male Cre+/(fGrin1+) mice susceptible to social defeat stress relative to same genotype controls was significantly more pronounced than that displayed by susceptible Cre-/(fGrin1+) mice compared to control Cre-/(fGrin1+) mice. Together, these results demonstrate increased fear, social, and stress responsiveness specifically in male Cre+/(fGrin1+) mice. Our findings indicate that NMDA-mediated glutamatergic regulation of CRF neurons is important for appropriately regulating fear and social responses, likely functioning to promote survival under aversive circumstances. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 04/2015; 58. DOI:10.1016/j.psyneuen.2015.04.010 · 4.94 Impact Factor
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