CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits

Nat Neurosci. 2009 Feb;12(2):200-9. doi: 10.1038/nn.2257. Epub 2009 Jan 18.


Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K(+) channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Affective Symptoms / drug therapy
  • Affective Symptoms / genetics
  • Affective Symptoms / physiopathology
  • Animals
  • Anxiety / drug therapy
  • Anxiety / genetics
  • Anxiety / physiopathology*
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • CREB-Binding Protein / physiology*
  • Female
  • Gene Expression Profiling
  • Imipramine / pharmacology
  • Lac Operon
  • Male
  • Mice
  • Mice, Transgenic
  • Nucleus Accumbens / physiology*
  • Potassium Channels / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Sexual Behavior, Animal / drug effects
  • Sexual Behavior, Animal / physiology
  • Social Isolation*


  • Adrenergic Uptake Inhibitors
  • Potassium Channels
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Crebbp protein, rat
  • Imipramine