Chronic Stress Triggers Social Aversion via Glucocorticoid Receptor in Dopaminoceptive Neurons

Molecular Genetics, Neurophysiology and Behavior Group, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7224, 75005 Paris, France.
Science (Impact Factor: 33.61). 01/2013; 339(6117):332-335. DOI: 10.1126/science.1226767
Source: PubMed


Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.

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    • "The role of GR in dopamine circuitry was explored using floxed GR mice crossed with dopaminoceptive/dopaminergic-specific Cre mice (Ambroggi et al, 2009). GR in dopaminoceptive neurons projecting from the ventral tegmental area (VTA) of the brainstem to the nucleus accumbens (NAc), cortex, and dorsal striatum, is critical for the normal social aversion response to repeated aggression stress (Barik et al, 2013). Deletion of GR specifically in nucleus accumbens neurons (GR D1Cre mice) completely abrogates the development of social aversion, while mice with deletion of GR in dopaminergic neurons of the VTA (GR "
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    ABSTRACT: The normal function of the hypothalamic-pituitary-adrenal (HPA) axis, and resultant glucocorticoid (GC) secretion, is essential for human health. Disruption of GC regulation is associated with both pathologic, psychological and physiological disease states such as depression, post-traumatic stress disorder, hypertension, diabetes, and osteopenia, amongst others. As such, understanding the mechanisms by which HPA output is tightly regulated in its responses to environmental stressors and circadian cues has been an active area of investigation for decades. Over the last 20 years, however, advances in gene targeting and genome modification in rodent models has allowed the detailed dissection of roles for key molecular mediators and brain regions responsible for this control in vivo to emerge. Here, we summarize work done to elucidate the function of critical neuropeptide systems, GC-signaling targets, and inflammation-associated pathways in HPA axis regulation and behavior, and highlight areas for future investigation.Neuropsychopharmacology accepted article preview online, 20 July 2015. doi:10.1038/npp.2015.215.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.215 · 7.05 Impact Factor
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    • "Likewise, the neural activities of AC might be regulated by serotonin, which can explain the suppressive effect of stress observed in this study. Moreover, other neuromodulators, such as dopamine and GABA etc., are also reported to be involved in the modulation of neural response under different behavioral states (McAlonan et al., 2006; Barik et al., 2013). Because AC neurons receive multiple modulations together, the net effect of stress on each neuron is dependent on the balance of excitatory and inhibitory modulation. "
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    ABSTRACT: Stress is known to elicit various adaptive or maladaptive responses in the nervous system function. Psychophysical studies have revealed that stress exposure induced the changes in auditory response that can be interpreted as a transient, stress-induced hypersensitivity to sounds. However, the underlying neural mechanism remains unresolved. Thus, in this study, we explored the neural activities of auditory cortex (AC) in response to stress. We elicited stress by physically immobilizing rats and recorded the extracellular single-unit activities through the electrodes chronically implanted in the AC of rats. By comparing the spike activities of the same rat before, during and after immobilization, we found temporal and significant changes in the sound-evoked neural activities. In most cases, acute restraint stress enhanced neural responses evoked by pure-tones and click-trains, but in a minority of neurons, stress suppressed responses. The immobilization-induced enhancement was more frequently found in the neurons that originally had a low responsibility for sound stimuli. The enhancement effects on pure-tone response were reflected by an increase of response magnitude, decrease of response latency, and extension of bandwidth of tuning curve (BW). But the spontaneous firing rate and best frequency (BF) remained unchanged. Stress also increased the ability of neural response to synchronize to click-trains, even in the neurons whose response magnitude was not significantly increased. Taken together, these results provide direct evidence that stress alters the function of auditory system at the level of AC. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 02/2015; 290. DOI:10.1016/j.neuroscience.2015.01.074 · 3.36 Impact Factor
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    • "An individual's ability to prevent, correct, or escape stressful situations to reach a state of personal well-being reflects the overall health of society . Numerous studies have addressed the short-and long-term effects of chronic stress on brain physiology and plasticity, on cognitive function in adults, and on cognitive function during childhood and adolescence (Veenema, 2009; Marquez et al., 2013); other studies have focused on the social impact of chronic stress and the triggering of aggressiveness (Sandi et al., 2008; McEwen, 2012; Barik et al., 2013). Aggressive behavior is common and adaptive between rodents of the same species and, like all mammals, they cope with social threats by making physiological and behavioral adjustments that can increase their ability to escape or fight. "
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    ABSTRACT: Adult C57BL/6J mice are known to exhibit high level of social flexibility while mice lacking the β2 subunit of nicotinic receptors (β2-/- mice) present social rigidity. We asked ourselves what would be the consequences of a restraint acute stress (45 min) on social interactions in adult mice of both genotypes, hence the contribution of neuronal nicotinic receptors in this process. We therefore dissected social interaction complexity of stressed and not stressed dyads of mice in a social interaction task. We also measured plasma corticosterone levels in our experimental conditions. We showed that a single stress exposure occurring in adulthood reduced and disorganized social interaction complexity in both C57BL/6J and β2-/- mice. These stress-induced maladaptive social interactions involved alteration of distinct social categories and strategies in both genotypes, suggesting a dissociable impact of stress depending on the functioning of the cholinergic nicotinic system. In both genotypes, social behaviors under stress were coupled to aggressive reactions with no plasma corticosterone changes. Thus, aggressiveness appeared a general response independent of nicotinic function. We demonstrate here that a single stress exposure occurring in adulthood is sufficient to impoverish social interactions: stress impaired social flexibility in C57BL/6J mice whereas it reinforced β2-/- mice behavioral rigidity.
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