PMID- 35045295
OWN - NLM
STAT- MEDLINE
DCOM- 20220214
LR  - 20240511
IS  - 2211-1247 (Electronic)
VI  - 38
IP  - 3
DP  - 2022 Jan 18
TI  - A bidirectional competitive interaction between circHomer1 and Homer1b within the 
      orbitofrontal cortex regulates reversal learning.
PG  - 110282
LID - S2211-1247(21)01797-6 [pii]
LID - 10.1016/j.celrep.2021.110282 [doi]
AB  - Although circular RNAs (circRNAs) are enriched in the brain, their relevance for 
      brain function and psychiatric disorders is poorly understood. Here, we show that 
      circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in 
      both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of 
      subjects with psychiatric disorders. We further demonstrate that in vivo 
      circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of 
      Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA 
      and that Homer1b-specific KD increases synaptic circHomer1 levels and improves 
      OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b 
      in vivo co-KD results in a complete rescue in circHomer1-associated alterations 
      in both chance reversal learning and synaptic gene expression. Lastly, we uncover 
      an RNA-binding protein that can directly bind to circHomer1 and promote its 
      biogenesis. Taken together, our data provide mechanistic insights into the 
      importance of circRNAs in brain function and disease.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Hafez, Alexander K
AU  - Hafez AK
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA; Autophagy Inflammation and Metabolism Center of Biomedical 
      Research Excellence, University of New Mexico Health Sciences Center, 
      Albuquerque, NM, USA.
FAU - Zimmerman, Amber J
AU  - Zimmerman AJ
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Papageorgiou, Grigorios
AU  - Papageorgiou G
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Chandrasekaran, Jayapriya
AU  - Chandrasekaran J
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Amoah, Stephen K
AU  - Amoah SK
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA; Autophagy Inflammation and Metabolism Center of Biomedical 
      Research Excellence, University of New Mexico Health Sciences Center, 
      Albuquerque, NM, USA.
FAU - Lin, Rixing
AU  - Lin R
AD  - McGill Group for Suicide Studies, Douglas Mental Health University Institute, 
      Department of Psychiatry, McGill University, Montreal, QC, Canada.
FAU - Lozano, Evelyn
AU  - Lozano E
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Pierotti, Caroline
AU  - Pierotti C
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Dell'Orco, Michela
AU  - Dell'Orco M
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Hartley, Brigham J
AU  - Hartley BJ
AD  - Pamela Sklar Division of Psychiatric Genomics, Friedman Brain Institute, 
      Departments of Genetics and Genomic Sciences, Neuroscience, and Psychiatry, Icahn 
      School of Medicine at Mount Sinai, New York, NY, USA.
FAU - Alural, Begum
AU  - Alural B
AD  - Center for Genomic Medicine, Chemical Neurobiology Laboratory, Departments of 
      Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA, USA.
FAU - Lalonde, Jasmin
AU  - Lalonde J
AD  - Center for Genomic Medicine, Chemical Neurobiology Laboratory, Departments of 
      Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA, USA.
FAU - Esposito, John Matthew
AU  - Esposito JM
AD  - Translational Neuroscience Laboratory, Mclean Hospital, Belmont, MA, USA.
FAU - Berretta, Sabina
AU  - Berretta S
AD  - Translational Neuroscience Laboratory, Mclean Hospital, Belmont, MA, USA; 
      Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Program in 
      Neuroscience, Harvard Medical School, Boston, MA, USA.
FAU - Squassina, Alessio
AU  - Squassina A
AD  - Department of Biomedical Sciences, Section of Neuroscience and Clinical 
      Pharmacology, University of Cagliari, Cagliari, Italy.
FAU - Chillotti, Caterina
AU  - Chillotti C
AD  - Unit of Clinical Pharmacology, University Hospital Agency of Cagliari, Cagliari, 
      Italy.
FAU - Voloudakis, Georgios
AU  - Voloudakis G
AD  - Pamela Sklar Division of Psychiatric Genomics, New York, NY, USA; Department of 
      Genetics and Genomic Sciences, New York, NY, USA; Icahn Institute for Data 
      Science and Genomic Technology, New York, NY, USA; Department of Psychiatry, 
      Icahn School of Medicine at Mount Sinai, New York, NY, USA.
FAU - Shao, Zhiping
AU  - Shao Z
AD  - Pamela Sklar Division of Psychiatric Genomics, New York, NY, USA; Department of 
      Genetics and Genomic Sciences, New York, NY, USA; Icahn Institute for Data 
      Science and Genomic Technology, New York, NY, USA.
FAU - Fullard, John F
AU  - Fullard JF
AD  - Pamela Sklar Division of Psychiatric Genomics, New York, NY, USA; Department of 
      Genetics and Genomic Sciences, New York, NY, USA; Icahn Institute for Data 
      Science and Genomic Technology, New York, NY, USA.
FAU - Brennand, Kristen J
AU  - Brennand KJ
AD  - Pamela Sklar Division of Psychiatric Genomics, Friedman Brain Institute, 
      Departments of Genetics and Genomic Sciences, Neuroscience, and Psychiatry, Icahn 
      School of Medicine at Mount Sinai, New York, NY, USA.
FAU - Turecki, Gustavo
AU  - Turecki G
AD  - McGill Group for Suicide Studies, Douglas Mental Health University Institute, 
      Department of Psychiatry, McGill University, Montreal, QC, Canada.
FAU - Roussos, Panos
AU  - Roussos P
AD  - Pamela Sklar Division of Psychiatric Genomics, New York, NY, USA; Department of 
      Genetics and Genomic Sciences, New York, NY, USA; Icahn Institute for Data 
      Science and Genomic Technology, New York, NY, USA; Department of Psychiatry, 
      Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mental Illness 
      Research, Education and Clinical Centers, James J. Peters VA Medical Center, 
      Bronx, NY, USA.
FAU - Perlis, Roy H
AU  - Perlis RH
AD  - Harvard Medical School, Department of Psychiatry, Boston, MA, USA; Center for 
      Experimental Drugs and Diagnostics, Center for Genomic Medicine, Massachusetts 
      General Hospital, Boston, MA, USA.
FAU - Haggarty, Stephen J
AU  - Haggarty SJ
AD  - Center for Genomic Medicine, Chemical Neurobiology Laboratory, Departments of 
      Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA, USA.
FAU - Perrone-Bizzozero, Nora
AU  - Perrone-Bizzozero N
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Brigman, Jonathan L
AU  - Brigman JL
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Mellios, Nikolaos
AU  - Mellios N
AD  - Department of Neurosciences, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA; Autophagy Inflammation and Metabolism Center of Biomedical 
      Research Excellence, University of New Mexico Health Sciences Center, 
      Albuquerque, NM, USA. Electronic address: nmellios@salud.unm.edu.
LA  - eng
GR  - R01 MH125899/MH/NIMH NIH HHS/United States
GR  - R01 MH109897/MH/NIMH NIH HHS/United States
GR  - R33 MH087896/MH/NIMH NIH HHS/United States
GR  - F31 MH122121/MH/NIMH NIH HHS/United States
GR  - R01 AG067025/AG/NIA NIH HHS/United States
GR  - R01 AG065582/AG/NIA NIH HHS/United States
GR  - R56 MH119150/MH/NIMH NIH HHS/United States
GR  - P20 GM103472/GM/NIGMS NIH HHS/United States
GR  - U01 MH116442/MH/NIMH NIH HHS/United States
GR  - R01 AA025652/AA/NIAAA NIH HHS/United States
GR  - R01 AG050986/AG/NIA NIH HHS/United States
GR  - P20 GM121176/GM/NIGMS NIH HHS/United States
GR  - R01 MH106056/MH/NIMH NIH HHS/United States
GR  - R01 MH101454/MH/NIMH NIH HHS/United States
GR  - R01 AA026583/AA/NIAAA NIH HHS/United States
GR  - I01 BX002395/BX/BLRD VA/United States
GR  - R01 MH125246/MH/NIMH NIH HHS/United States
GR  - R01 MH110921/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 0 (Homer Scaffolding Proteins)
RN  - 0 (RNA, Circular)
SB  - IM
MH  - Animals
MH  - Bipolar Disorder/metabolism
MH  - Gene Expression Regulation/*physiology
MH  - Gene Knockdown Techniques
MH  - Homer Scaffolding Proteins/*metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Prefrontal Cortex/*metabolism
MH  - RNA, Circular/*metabolism
MH  - Reversal Learning/*physiology
PMC - PMC8809079
MID - NIHMS1772785
OTO - NOTNLM
OT  - Homer1
OT  - OFC
OT  - bipolar disorder
OT  - circHomer1
OT  - circRNAs
OT  - cognitive flexibility
OT  - reversal learning
COIS- Declaration of interests A.K.H. and N.M. have a financial interest as co-founders 
      of Circular Genomics Inc. and are inventors of patents related to the use of 
      circRNAs for brain disease diagnostics (N.M.) or therapeutics (N.M. and A.K.H.).
EDAT- 2022/01/20 06:00
MHDA- 2022/02/15 06:00
PMCR- 2022/02/02
CRDT- 2022/01/19 20:08
PHST- 2020/11/23 00:00 [received]
PHST- 2021/06/28 00:00 [revised]
PHST- 2021/12/28 00:00 [accepted]
PHST- 2022/01/19 20:08 [entrez]
PHST- 2022/01/20 06:00 [pubmed]
PHST- 2022/02/15 06:00 [medline]
PHST- 2022/02/02 00:00 [pmc-release]
AID - S2211-1247(21)01797-6 [pii]
AID - 10.1016/j.celrep.2021.110282 [doi]
PST - ppublish
SO  - Cell Rep. 2022 Jan 18;38(3):110282. doi: 10.1016/j.celrep.2021.110282.