title: The microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression.
abstract: MicroRNAs (miRNAs) are small, non-coding RNAs acting as post-transcriptional regulators of gene expression. Though implicated in multiple CNS disorders, miRNAs have not been examined in any psychiatric disease state in anterior cingulate cortex (AnCg), a brain region centrally involved in regulating mood. We performed qPCR analyses of 29 miRNAs previously implicated in psychiatric illness (major depressive disorder (MDD), bipolar disorder (BP) and/or schizophrenia (SZ)) in AnCg of patients with MDD and BP versus controls. miR-132, miR-133a and miR-212 were initially identified as differentially expressed in BP, miR-184 in MDD and miR-34a in both MDD and BP (although none survived multiple correction testing and must be considered preliminary). In silico target prediction algorithms identified putative targets of differentially expressed miRNAs. Nuclear Co-Activator 1 (NCOA1), Nuclear Co-Repressor 2 (NCOR2) and Phosphodiesterase 4B (PDE4B) were selected based upon predicted targeting by miR-34a (with NCOR2 and PDE4B both targeted by miR-184) and published relevance to psychiatric illness. Luciferase assays identified PDE4B as a target of miR-34a and miR-184, while NCOA1 and NCOR2 were targeted by miR-34a and 184, respectively. qPCR analyses were performed to determine whether changes in miRNA levels correlated with mRNA levels of validated targets. NCOA1 showed an inverse correlation with miR-34a in BP, while NCOR2 demonstrated a positive correlation. In sum, this is the first study to demonstrate miRNA changes in AnCg in psychiatric illness and validate miR-34a as differentially expressed in CNS in MDD. These findings support a mechanistic role for miRNAs in the regulation of stress-responsive genes disrupted in psychiatric illness.
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA; Neuroscience Graduate Program, University of Michigan, 4137 Undergraduate Science Building (USB), 204 Washtenaw Avenue, Ann Arbor, MI, 48109, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Azevedo
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA; Neuroscience Graduate Program, University of Michigan, 4137 Undergraduate Science Building (USB), 204 Washtenaw Avenue, Ann Arbor, MI, 48109, USA; Neuroscience Program, Oberlin College, Science Center A261, 119 Woodland St., Oberlin, OH, 44074, USA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Carter
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA; Pritzker Neuropsychiatric Disorders Research Consortium, USA; Department of Psychiatry, University of Michigan, 530 Church St, Ann Arbor, MI, 48109, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Meng
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA; Neuroscience Graduate Program, University of Michigan, 4137 Undergraduate Science Building (USB), 204 Washtenaw Avenue, Ann Arbor, MI, 48109, USA; Department of Biological Chemistry, University of Michigan, 5301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Turner
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA.
authors.forename: Manhong
authors.initials: M
authors.lastname: Dai
authors.affiliation: Pritzker Neuropsychiatric Disorders Research Consortium, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Rd, Stanford, CA, 94305, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Schatzberg
authors.affiliation: Pritzker Neuropsychiatric Disorders Research Consortium, USA; Department of Psychiatry, Weill Cornell Medical College, 525 East 68th Street, New York, NY, 10065, USA.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Barchas
authors.affiliation: Pritzker Neuropsychiatric Disorders Research Consortium, USA; Center for Neuroscience, University of California - Davis, 1544 Newton Court, Davis, CA, 95618, USA.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Jones
authors.affiliation: Pritzker Neuropsychiatric Disorders Research Consortium, USA; Psychiatry and Human Behavior, University of California - Irvine, 101 The City Dr S, Orange, CA, 92868, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Bunney
authors.affiliation: Pritzker Neuropsychiatric Disorders Research Consortium, USA; Hudson Alpha Institute for Biotechnology, 601 Genome Way Northwest, Huntsville, AL, 35806, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA; Neuroscience Graduate Program, University of Michigan, 4137 Undergraduate Science Building (USB), 204 Washtenaw Avenue, Ann Arbor, MI, 48109, USA; Pritzker Neuropsychiatric Disorders Research Consortium, USA; Department of Psychiatry, University of Michigan, 530 Church St, Ann Arbor, MI, 48109, USA.
authors.forename: Huda
authors.initials: H
authors.lastname: Akil
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA; Neuroscience Graduate Program, University of Michigan, 4137 Undergraduate Science Building (USB), 204 Washtenaw Avenue, Ann Arbor, MI, 48109, USA; Pritzker Neuropsychiatric Disorders Research Consortium, USA; Department of Psychiatry, University of Michigan, 530 Church St, Ann Arbor, MI, 48109, USA.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watson
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA; Neuroscience Graduate Program, University of Michigan, 4137 Undergraduate Science Building (USB), 204 Washtenaw Avenue, Ann Arbor, MI, 48109, USA; Pritzker Neuropsychiatric Disorders Research Consortium, USA; Department of Psychiatry, University of Michigan, 530 Church St, Ann Arbor, MI, 48109, USA. Electronic address: mutant@umich.edu.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D001714:Bipolar Disorder / Q000473:pathology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism; D003865:Major Depressive Disorder / Q000473:pathology*; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D016296:Mutagenesis; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics; D014162:Transfection; D055815:Young Adult
chemical_list: D035683:MicroRNAs; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Anterior cingulate cortex; Mood disorders; microRNA