title: Hippocampal Sirtuin 1 Signaling Mediates Depression-like Behavior.
abstract: Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Recent evidence has suggested that sirtuins (SIRTs) play a key role in cognition and synaptic plasticity, yet their role in mood regulation remains controversial. Here, we aimed to investigate whether SIRT function is associated with chronic stress-elicited depression-like behaviors and neuronal atrophy.
  
  
  
  We measured SIRT expression and activity in a mouse model of depression. We injected mice with a SIRT1 activator or inhibitor and measured their depression-like behaviors and dendritic spine morphology. To assess the role of SIRT1 directly, we used a viral-mediated gene transfer to overexpress the wild-type SIRT1 or dominant negative SIRT1 and evaluated their depression-like behaviors. Finally, we examined the role of extracellular signal-regulated protein kinases 1 and 2, a potential downstream target of SIRT1, in depression-like behavior.
  
  
  
  We found that chronic stress reduced SIRT1 activity in the dentate gyrus of the hippocampus. Pharmacologic and genetic inhibition of hippocampal SIRT1 function led to an increase in depression-like behaviors. Conversely, SIRT1 activation blocked both the development of depression-related phenotypes and aberrant dendritic structures elicited by chronic stress exposure. Furthermore, hippocampal SIRT1 activation increased the phosphorylation level of extracellular signal-regulated protein kinases 1 and 2 in the stressed condition, and viral-mediated activation and inhibition of hippocampal extracellular signal-regulated protein kinase 2 led to antidepressive and prodepressive behaviors, respectively.
  
  
  
  Our results suggest that the hippocampal SIRT1 pathway contributes to the chronic stress-elicited depression-related phenotype and aberrant dendritic atrophy.
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi.
authors.forename: Naoko
authors.initials: N
authors.lastname: Abe-Higuchi
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan. Electronic address: s-uchida@yamaguchi-u.ac.jp.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamagata
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Higuchi
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Hobara
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hara
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D003712:Dendrites / Q000473:pathology*; D018891:Dentate Gyrus / Q000378:metabolism; D003863:Depression / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D007099:Imipramine / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009284:Naphthols / Q000008:administration & dosage / Q000494:pharmacology; D000077185:Resveratrol; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D001549:Benzamides; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D009284:Naphthols; C584666:SRT2104; D013267:Stilbenes; C439060:sirtinol; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D007099:Imipramine; D000077185:Resveratrol
keywords: Anxiety; Chronic stress; Dendritic atrophy; Depression; Hippocampus; Sirtuin