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.

  • Biological Psychiatry 02/2015; 77(4):310-1. DOI:10.1016/j.biopsych.2014.11.009 · 9.47 Impact Factor
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    ABSTRACT: Chronic, in particular chronic psychosocial, stress is a burden of modern societies and known to be a risk factor for numerous somatic and affective disorders (in detail referenced below). However, based on the limited existence of appropriate, and clinically relevant, animal models for studying the effects of chronic stress, the detailed behavioral, physiological, neuronal, and immunological mechanisms linking stress and such disorders are insufficiently understood. To date, most chronic stress studies in animals employ intermittent exposure to the same (homotypic) or to different (heterotypic) stressors of varying duration and intensity. Such models are only of limited value, since they do not adequately reflect the chronic and continuous situation that humans typically experience. Furthermore, application of different physical or psychological stimuli renders comparisons to the mainly psychosocial stressors faced by humans, as well as between the different stress studies almost impossible. In contrast, rodent models of chronic psychosocial stress represent situations more akin to those faced by humans and consequently seem to hold more clinical relevance. Our laboratory has developed a model in which mice are exposed to social stress for 19 continuous days, namely the chronic subordinate colony housing (CSC) paradigm, to help bridge this gap. The main aim of the current review article is to provide a detailed summary of the behavioral, physiological, neuronal, and immunological consequences of the CSC paradigm, and wherever possible relate the findings to other stress models and to the human situation.
    Frontiers in Psychiatry 01/2015; 6:18. DOI:10.3389/fpsyt.2015.00018
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    ABSTRACT: The present study investigated the effects of chronic social defeat stress on several behavioral parameters, and the expression of dopaminergic markers, i.e, dopamine D1 receptors (D1Rs), D2Rs, and dopamine and cyclic adenosine 3', 5'-monophosphate regulated phosphoprotein-32 (DARPP-32), in the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HIP) of mouse brains. After 10 days of social defeat stress, the defeated mice were divided into two groups: one group underwent a series of behavioral tests. The other group was sacrificed on the 11(th) day and tissue samples were collected for Western blotting. The behavioral tests comprised tests of locomotion, light/dark preference, social interaction, as well as the novel object recognition test (NORT), Morris water maze, and forced swimming test (FST). We measured the expression of D1Rs, D2Rs, total DARPP-32, phospho-Thr34 or Thr75-DARPP-32 using Western blotting. The defeated mice showed increased anxiety- and depression-like behaviors, and impaired cognition. No significant differences in D1Rs and D2Rs expression were shown between defeated and control mice in any area studied. A significantly increased expression in total DARPP-32, and phospho-DARPP-32 was observed in the PFC or AMY of defeated mice. These data suggest that alterations in dopaminergic markers may be involved in anxiety- and depression-like behaviors, and cognitive impairment induced by social defeat stress. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 01/2015; 288. DOI:10.1016/j.neuroscience.2014.12.043 · 3.33 Impact Factor

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