title: SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens.
abstract: Depression is a recurring and life-threatening illness that affects up to 120 million people worldwide. In the present study, we show that chronic social defeat stress, an ethologically validated model of depression in mice, increases SIRT1 levels in the nucleus accumbens (NAc), a key brain reward region. Increases in SIRT1, a well characterized class III histone deacetylase, after chronic social defeat suggest a role for this enzyme in mediating depression-like behaviors. When resveratrol, a pharmacological activator of SIRT1, was directly infused bilaterally into the NAc, we observed an increase in depression- and anxiety-like behaviors. Conversely, intra-NAc infusions of EX-527, a SIRT1 antagonist, reduced these behaviors; EX-527 also reduced acute stress responses in stress-naive mice. Next, we increased SIRT1 levels directly in NAc by use of viral-mediated gene transfer and observed an increase in depressive- and anxiety-like behaviors when mice were assessed in the open-field, elevated-plus-maze, and forced swim tests. Using a Cre-inducible viral vector system to overexpress SIRT1 selectively in dopamine D1 or D2 subpopulations of medium spiny neurons (MSNs) in the NAc, we found that SIRT1 promotes depressive-like behaviors only when overexpressed in D1 MSNs, with no effect seen in D2 MSNs. Conversely, selective ablation of SIRT1 in the NAc using viral-Cre in floxed Sirt1 mice resulted in decreased depression- and anxiety-like behaviors. Together, these results demonstrate that SIRT1 plays an essential role in the NAc in regulating mood-related behavioral abnormalities and identifies a novel signaling pathway for the development of innovative antidepressants to treat major depressive disorders.
  
  
  
  In this study, we demonstrate a pivotal role for SIRT1 in anxiety- and depression-like behaviors in the nucleus accumbens (NAc), a key brain reward region. We show that stress stably induces SIRT1 expression in this brain region and that altering SIRT1 activity using a pharmacological or genetic approach regulates anxiety- and depression-like behaviors. These results suggest that SIRT1 plays an essential role in regulating mood-related behaviors and introduces a novel signaling pathway for the development of innovative antidepressants to treat depression and other stress-related disorders. A recent groundbreaking publication by the CONVERGE Consortium (2015) identified a reproducible association of the SIRT1 locus with major depression in humans. Therefore, our results are timely and have significant translational relevance.
authors: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
authors: Hee-Dae
authors: 0000-0002-5428-6847
authors: HD
authors: Kim
authors: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
authors: Jennifer
authors: 0000-0001-7861-5345
authors: J
authors: Hesterman
authors: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
authors: Tanessa
authors: 0000-0002-7673-3636
authors: T
authors: Call
authors: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
authors: Samantha
authors: 0000-0003-3784-885X
authors: S
authors: Magazu
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors: Elizabeth
authors: E
authors: Keeley
authors: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004.
authors: Kristyna
authors: 0000-0001-6902-1991
authors: K
authors: Armenta
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors: Hope
authors: H
authors: Kronman
authors: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Rachael L
authors: RL
authors: Neve
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors: Eric J
authors: 0000-0002-7905-2000
authors: EJ
authors: Nestler
authors: Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004, dferguson@email.arizona.edu.
authors: Deveroux
authors: 0000-0001-9302-5992
authors: D
authors: Ferguson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism; D013550:Swimming / Q000523:psychology
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D000928:Antidepressive Agents; D002227:Carbazoles; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: anxiety; cell-type specific; depression; epigenetic; stress; striatum