Article

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

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.

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    • "This resilient phenotype is important in understanding the underlying biological processes associated with stress susceptibility and resiliency (Charney, 2004; Taliaz et al., 2011). However, the neural substrates and molecular mechanisms that mediate resistance to the deleterious effects of stress remain unclear (Krishnan et al., 2007; Friedman et al., 2014). As one of most malleable brain regions targeted by stress stimulation (McEwen et al., 2012), the hippocampus shoulders the responsibility of balancing function and vulnerability to stress damage by adaptive neuron dendritic remodeling, such as growth and shrinkage of dendritic trees and spines (Sousa et al., 2000; McEwen, 2010). "

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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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    • "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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