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Journal ArticleDOI

Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress

TL;DR: It is shown that viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived neurotrophic factor is required for the development of experience-dependent social aversion in mice experiencing repeated aggression.
Abstract: Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
Citations
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Journal ArticleDOI
15 Oct 2008-Nature
TL;DR: Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits and show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.
Abstract: Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

2,535 citations


Cites background from "Essential Role of BDNF in the Mesol..."

  • ...Third, in other regions — for example the VTA and NAc — BDNF exerts a potent pro-depressant effect: chronic stress increases the amount of BDNF within the NA...

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Journal ArticleDOI
19 Oct 2007-Cell
TL;DR: It is shown that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior and validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance.

1,863 citations


Cites background or methods or result from "Essential Role of BDNF in the Mesol..."

  • ...Increased BDNF Signaling within the NAc Mediates Susceptibility Because chronic social defeat increases BDNF protein levels in the NAc on days 11 and 39 (Berton et al., 2006), we tested whether this response differs between Susceptible and Unsusceptible mice....

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  • ...Subjects and Drugs Male 7-week-old c57bl/6 (Jackson), CD1 retired breeders (Charles River), 9- to 13-week-old floxed BDNF mice (Berton et al., 2006), and 10- to 14-week-old BDNF Met/Met and Val/Val mice (Chen et al....

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  • ...To test this prediction, we examined the behavioral effects of an established method to locally delete the bdnf gene from the NAc by stereotaxically infusing adenoassociated virus (AAV) that expresses Cre-recombinase into the NAc of floxed BDNF mice (Berton et al., 2006; Graham et al., 2007)....

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  • ...33 gauge needles were used to bilaterally infuse 0.5 ml of virus (or BDNF) into NAc or VTA at a rate of 0.1 ml/min (Berton et al., 2006)....

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  • ...We have previously shown that c57bl/6 mice subjected to chronic social defeat (10 such defeats over 10 days) display a long-lasting reduction in social interaction (Berton et al., 2006; Tsankova et al., 2006), which is measured by comparing the time a mouse spends in an interaction zone with a social target to the time in that zone in the absence of a social target....

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Journal ArticleDOI
TL;DR: It is proposed that the NAc and VTA contribute importantly to the pathophysiology and symptomatology of depression and may even be involved in its etiology.

1,859 citations

Journal ArticleDOI
TL;DR: This review presents the major current approaches to understanding the biologic mechanisms of major depression and defines depression as a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism.
Abstract: Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower definition of severe depression, which they call melancholia or vital depression. 3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder. 4 Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major depression.

1,841 citations


Cites background from "Essential Role of BDNF in the Mesol..."

  • ...in various brain regions [42,43], it is reasonable to postulate that improving BDNF function may be beneficial to the hippocampal neurons that are susceptible to stress-induced damages....

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Journal ArticleDOI
TL;DR: An important role for histone remodeling in the pathophysiology and treatment of depression is underscored and the therapeutic potential for hist one methylation and deacetylation inhibitors in depression is highlighted.
Abstract: To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.

1,691 citations

References
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Journal ArticleDOI
TL;DR: It is suggested that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli and is a distinct component of motivation and reward.

3,833 citations

Journal ArticleDOI
TL;DR: Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.
Abstract: The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.

3,012 citations

Journal ArticleDOI
TL;DR: The scientific investigation of behavioral processes by animal learning theory and economic utility theory has produced a theoretical framework that can help to elucidate the neural correlates for reward functions in learning, goal-directed approach behavior, and decision making under uncertainty.
Abstract: The functions of rewards are based primarily on their effects on behavior and are less directly governed by the physics and chemistry of input events as in sensory systems. Therefore, the investigation of neural mechanisms underlying reward functions requires behavioral theories that can conceptualize the different effects of rewards on behavior. The scientific investigation of behavioral processes by animal learning theory and economic utility theory has produced a theoretical framework that can help to elucidate the neural correlates for reward functions in learning, goal-directed approach behavior, and decision making under uncertainty. Individual neurons can be studied in the reward systems of the brain, including dopamine neurons, orbitofrontal cortex, and striatum. The neural activity can be related to basic theoretical terms of reward and uncertainty, such as contiguity, contingency, prediction error, magnitude, probability, expected value, and variance.

1,419 citations

Journal ArticleDOI
18 Jul 2002-Neuron
TL;DR: In this article, the authors used fMRI to scan 36 women as they played an iterated Prisoner's Dilemma Game with another woman to investigate the neurobiological basis of cooperative social behavior.

1,302 citations

Journal ArticleDOI
TL;DR: Differential regulation of neuropeptide receptor expression may explain species differences in the ability to form pair bonds and have intriguing implications for the neurobiology of social attachment in the authors' own species.
Abstract: A neurobiological model for pair-bond formation has emerged from studies in monogamous rodents. The neuropeptides oxytocin and vasopressin contribute to the processing of social cues necessary for individual recognition. Mesolimbic dopamine is involved in reinforcement and reward learning. Concurrent activation of neuropeptide and dopamine receptors in the reward centers of the brain during mating results in a conditioned partner preference, observed as a pair bond. Differential regulation of neuropeptide receptor expression may explain species differences in the ability to form pair bonds. These and other studies discussed here have intriguing implications for the neurobiology of social attachment in our own species.

1,287 citations