title: Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper.
abstract: 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.
authors.affiliation: Department of Biomedicine, Section on Physiology, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. janne.gronli@biomed.uib.no
authors.forename: Janne
authors.initials: J
authors.lastname: Grønli
authors.forename: Clive
authors.initials: C
authors.lastname: Bramham
authors.forename: Robert
authors.initials: R
authors.lastname: Murison
authors.forename: Tambudzai
authors.initials: T
authors.lastname: Kanhema
authors.forename: Eldbjørg
authors.initials: E
authors.lastname: Fiske
authors.forename: Bjørn
authors.initials: B
authors.lastname: Bjorvatn
authors.forename: Reidun
authors.initials: R
authors.lastname: Ursin
authors.forename: Chiara M
authors.initials: CM
authors.lastname: Portas
mesh_terms: D000818:Animals; D001069:Appetite Regulation; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002908:Chronic Disease; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000378:metabolism*; D013395:Sucrose / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D013395:Sucrose