title: Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice.
abstract: Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3β (GSK3β) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3β expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress.
  
  
  
  Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3β, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan, and.
authors.forename: Fumihiro
authors.identifier: 0000-0001-7966-2928
authors.initials: F
authors.lastname: Higuchi
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan, and s-uchida@yamaguchi-u.ac.jp.
authors.forename: Shusaku
authors.identifier: 0000-0002-1451-6222
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan, and.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamagata
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Abe-Higuchi
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Hobara
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hara
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Shintaku
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan, and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Yukihiro
authors.identifier: 0000-0002-3410-2924
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan, and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Takayoshi
authors.identifier: 0000-0003-2439-879X
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Yoshifumi
authors.identifier: 0000-0001-8096-339X
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D024841:Fluoroquinolones / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D007099:Imipramine / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D013315:Stress, Psychological / Q000503:physiopathology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D024841:Fluoroquinolones; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D020319:Oligodeoxyribonucleotides, Antisense; D059005:Topoisomerase II Inhibitors; C057477:clinafloxacin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D007099:Imipramine
keywords: anxiety; depression; epigenetics; hippocampus; microRNA; stress