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Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models

Academic Article
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Overview

authors

  • Wilkinson, M. B.
  • Xiao, G.
  • Kumar, A.
  • LaPlant, Q.
  • Renthal, W.
  • Sikder, D.
  • Kodadek, Thomas
  • Nestler, E. J.

publication date

  • 2009

journal

  • Journal of Neuroscience  Journal

abstract

  • Although it is a widely studied psychiatric syndrome, major depressive disorder remains a poorly understood illness, especially with regard to the disconnect between treatment initiation and the delayed onset of clinical improvement. We have recently validated chronic social defeat stress in mice as a model in which a depression-like phenotype is reversed by chronic, but not acute, antidepressant administration. Here, we use chromatin immunoprecipitation (ChIP)-chip assays--ChIP followed by genome wide promoter array analyses--to study the effects of chronic defeat stress on chromatin regulation in the mouse nucleus accumbens (NAc), a key brain reward region implicated in depression. Our results demonstrate that chronic defeat stress causes widespread and long-lasting changes in gene regulation, including alterations in repressive histone methylation and in phospho-CREB (cAMP response element-binding protein) binding, in the NAc. We then show similarities and differences in this regulation to that observed in another mouse model of depression, prolonged adult social isolation. In the social defeat model, we observed further that many of the stress-induced changes in gene expression are reversed by chronic imipramine treatment, and that resilient mice-those resistant to the deleterious effects of defeat stress-show patterns of chromatin regulation in the NAc that overlap dramatically with those seen with imipramine treatment. These findings provide new insight into the molecular basis of depression-like symptoms and the mechanisms by which antidepressants exert their delayed clinical efficacy. They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress.

subject areas

  • Animals
  • Antidepressive Agents, Tricyclic
  • Behavior, Animal
  • CREB-Binding Protein
  • Chromatin
  • Chromatin Immunoprecipitation
  • Depression
  • Disease Models, Animal
  • Dominance-Subordination
  • Gene Expression
  • Genome-Wide Association Study
  • Histones
  • Imipramine
  • Male
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Nucleus Accumbens
  • Social Isolation
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Identity

PubMed Central ID

  • PMC2717944

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.0932-09.2009

PubMed ID

  • 19535594
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Additional Document Info

start page

  • 7820

end page

  • 7832

volume

  • 29

issue

  • 24

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