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Journal ArticleDOI

Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions

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.
About: This article is published in Cell.The article was published on 2007-10-19 and is currently open access. It has received 1863 citations till now. The article focuses on the topics: Social defeat.
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

Journal ArticleDOI
TL;DR: The current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder, is reviewed and it is argued for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders.
Abstract: Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.

1,765 citations

Journal ArticleDOI
TL;DR: It is shown here that patients with depression can be subdivided into four neurophysiological subtypes defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks, which may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.
Abstract: Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes (‘biotypes’) defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

1,503 citations

Journal ArticleDOI
TL;DR: This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression, and discusses some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.
Abstract: Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioural domains. A recent literature has identified important structural and functional alterations within the brain's reward circuitry--particularly in the ventral tegmental area-nucleus accumbens pathway--that are associated with symptoms such as anhedonia and aberrant reward-associated perception and memory. This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.

1,365 citations

Journal ArticleDOI
TL;DR: Research has shown that resilience is mediated by adaptive changes in several neural circuits involving numerous neurotransmitter and molecular pathways, which shape the functioning of the neural circuits that regulate reward, fear, emotion reactivity and social behaviour.
Abstract: Every individual experiences stressful life events. In some cases acute or chronic stress leads to depression and other psychiatric disorders, but most people are resilient to such effects. Recent research has begun to identify the environmental, genetic, epigenetic and neural mechanisms that underlie resilience, and has shown that resilience is mediated by adaptive changes in several neural circuits involving numerous neurotransmitter and molecular pathways. These changes shape the functioning of the neural circuits that regulate reward, fear, emotion reactivity and social behaviour, which together are thought to mediate successful coping with stress.

1,117 citations

References
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Book
31 Jul 2001
TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.
Abstract: "The Mouse Brain in Stereotaxic Coordinates" is the most widely used and cited atlas of the mouse brain in print. It provides researchers and students with both accurate stereotaxic coordinates for laboratory use, and detailed delineations and indexing of structures for reference. The accompanying DVD provides drawings of brains structures that can be used as templates for making figures for publication. The 3rd edition is both a major revision and an expansion of previous editions. Delineations and photographs in the horizontal plane of section now complement the coronal and sagittal series, and all the tissue sections are now shown in high resolution digital color photography. The photographs of the sections and the intermediate sections are also provided on the accompanying DVD in high-resolution JP 2000 format. The delineations of structures have been revised, and naming conventions made consistent with Paxinos and Watson's "Rat Brain in Stereotaxic Coordinates, 6th Edition". The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use. This edition is in full color throughout. It includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material. Coronal and sagittal diagrams are completely reworked and updated. Rhombomeric borders are included in sagittal figures, for the first time in mammals. Microscopic plates are scanned with a new method in much higher quality.

15,681 citations

Journal ArticleDOI
TL;DR: Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumAs.
Abstract: Background: Data were obtained on the general population epidemiology of DSM-III-R posttraumatic stress disorder (PTSD), including information on estimated lifetime prevalence, the kinds of traumas most often associated with PTSD, sociodemographic correlates, the comorbidity of PTSD with other lifetime psychiatric disorders, and the duration of an index episode. Methods: Modified versions of the DSM-III-R PTSD module from the Diagnostic Interview Schedule and of the Composite International Diagnostic Interview were administered to a representative national sample of 5877 persons aged 15 to 54 years in the part II subsample of the National Comorbidity Survey. Results: The estimated lifetime prevalence of PTSD is 7.8%. Prevalence is elevated among women and the previously married. The traumas most commonly associated with PTSD are combat exposure and witnessing among men and rape and sexual molestation among women. Posttraumatic stress disorder is strongly comorbid with other lifetime DSM-III-R disorders. Survival analysis shows that more than one third of people with an index episode of PTSD fail to recover even after many years. Conclusions: Posttraumatic stress disorder is more prevalent than previously believed, and is often persistent. Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumas. (Arch Gen Psychiatry. 1995;52:1048-1060)

9,690 citations


"Molecular Adaptations Underlying Su..." refers background in this paper

  • ...A majority of humans exposed to stressful events do not show signs of psychopathology such as posttraumatic stress disorder (PTSD) or depression (Charney, 2004; Kessler et al., 1995; Yehuda, 2004)....

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Journal ArticleDOI
24 Jan 2003-Cell
TL;DR: A role is demonstrated for BDNF and its val/met polymorphism in human memory and hippocampal function and it is suggested val/ met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.

3,599 citations


"Molecular Adaptations Underlying Su..." refers background in this paper

  • ...…October 19, 2007 ª2007 Elsevier Inc. 401 Met allele suggest that while this variant may confer unfavorable effects on hippocampal function (Chen et al., 2006; Egan et al., 2003), its effects on mesolimbic BDNF signaling may represent a compensatory biological advantage under adverse conditions....

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  • ...Humans possessing this polymorphism display a selective impairment in episodic memory and abnormal hippocampal activation (Egan et al., 2003)....

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  • ...To test this hypothesis, we examined the consequence of a naturally occurring human single-nucleotide polymorphism (SNP) in the BDNF prodomain (G196A, Val66Met), which impairs activity-dependent BDNF secretion (Chen et al., 2004; Egan et al., 2003)....

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Journal ArticleDOI
28 Mar 2002-Neuron
TL;DR: A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome, and advances will fundamentally improve the treatment and prevention of depression.

2,768 citations

Journal ArticleDOI
10 Feb 2006-Science
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.

1,873 citations


"Molecular Adaptations Underlying Su..." refers background or methods or result in this paper

  • ...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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