Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper

Pharmacol Biochem Behav. 2006 Dec;85(4):842-9. doi: 10.1016/j.pbb.2006.11.021. Epub 2007 Jan 3.


Chronic stress is linked to development of depression and may trigger neurobiological changes underlying the disease. Downregulation of the secretory peptide brain-derived neurotrophic factor (BDNF) and the transcriptional regulator calcium/cyclic-AMP responsive binding protein (CREB) have been implicated in stress and depression-related pathology in animal studies. When animals are exposed to the chronic mild stress (CMS) protocol, multiple depression-like symptoms are observed. Here we investigated the effect of CMS on BDNF protein expression and CREB activation in the dentate gyrus and hippocampus proper. Rats exposed for 5 weeks to repeated, unpredictable, mild stressors showed reduced BDNF expression and inhibited phosphorylation of CREB (Ser-133) in the dentate gyrus (-25.0%+/-3.5% and -29.7+/-7.3%, respectively), whereas no significant effects were observed in the hippocampus proper. CMS-treated rats consumed less sucrose compared to control rats, indicating a state of anhedonia. Moreover, phospho-CREB levels in the dentate gyrus were positively correlated with the animals' sucrose intake at the end of the CMS protocol. These results couple chronic mild stress to a downregulation of CREB activity and BDNF protein expression specifically within the dentate gyrus and support the possibility that the BDNF-CREB system plays an important role in the response to environmental challenges.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite Regulation
  • Brain-Derived Neurotrophic Factor / biosynthesis*
  • Chronic Disease
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Dentate Gyrus / metabolism*
  • Hippocampus / metabolism*
  • Male
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Stress, Psychological / metabolism*
  • Sucrose / metabolism


  • Brain-Derived Neurotrophic Factor
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Sucrose