title: Sirtuin activity in dentate gyrus contributes to chronic stress-induced behavior and extracellular signal-regulated protein kinases 1 and 2 cascade changes in the hippocampus.
abstract: BACKGROUND
  Exposure to chronic stress produces negative effects on mood and hippocampus-dependent memory formation. Alterations in signaling cascades and histone acetylation present a mechanism of modulation of transcription that may underlie stress-dependent processes in the hippocampus critical to learning and memory and development of depressive behaviors.
  
  
  METHODS
  The rat model of chronic variable stress (CVS) was used to investigate the role of changes in protein acetylation and other molecular components of hippocampus-dependent memory formation and anhedonic behavior in response to CVS.
  
  
  RESULTS
  Chronic variable stress treatment decreased both extracellular signal-regulated protein kinases 1 and 2 activation and Bcl-2 expression in all three regions of the hippocampus that corresponded behaviorally with a decrease in memory for the novel object location task and increased anhedonia. Extracellular signal-regulated protein kinases 1 and 2 activation was not significantly affected in the amygdala and increased in the medial prefrontal cortex by CVS. Chronic variable stress had no significant effect on activation of Akt in the hippocampus. We investigated molecular and behavioral effects of infusion of the sirtuin inhibitor, sirtinol, into the dentate gyrus (DG). Sirtinol infusion into the DG prevented the CVS-mediated decrease in extracellular signal-regulated protein kinases 1 and 2 activity and Bcl-2 expression, as well as histone acetylation in the DG previously observed following CVS. This corresponded to enhanced performance on the novel object location memory task, as well as reduced anhedonic behavior.
  
  
  CONCLUSIONS
  These results suggest that changes in sirtuin activity contribute to changes in molecular cascades and histone acetylation within the hippocampus observed following CVS and may represent a novel therapeutic target for stress-induced depression.
authors.affiliation: Neuroscience Program, Tulane University, New Orleans, Louisiana.
authors.forename: Chantelle L
authors.initials: CL
authors.lastname: Ferland
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Hawley
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Puckett
authors.forename: Kezia
authors.initials: K
authors.lastname: Wineberg
authors.forename: Farah D
authors.initials: FD
authors.lastname: Lubin
authors.forename: Gary P
authors.initials: GP
authors.lastname: Dohanich
authors.forename: Laura A
authors.initials: LA
authors.lastname: Schrader
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D018891:Dentate Gyrus / Q000378:metabolism*; D004195:Disease Models, Animal; D005518:Food Preferences / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism*; D013315:Stress, Psychological / Q000097:blood / Q000473:pathology*; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013549:Sweetening Agents; D013395:Sucrose; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D056564:Sirtuin 1; D003345:Corticosterone
keywords: Anhedonia; Bcl-2; epigenetics; hippocampus; histone acetylation; spatial memory