A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

Alexander K. Hafez; Amber J. Zimmerman; Grigorios Papageorgiou; Jayapriya Chandrasekaran; Stephen K. Amoah; Rixing Lin; Evelyn Lozano; Caroline Pierotti; Michela Dell'Orco; Brigham J. Hartley; Begüm Alural; Jasmin Lalonde; John Matthew Esposito; Sabina Berretta; Alessio Squassina; Caterina Chillotti; Georgios Voloudakis; Zhiping Shao; John F. Fullard; Kristen J. Brennand; Gustavo Turecki; Panos Roussos; Roy H. Perlis; Stephen J. Haggarty; Nora Perrone-Bizzozero; Jonathan L. Brigman; Nikolaos Mellios

doi:10.1016/j.celrep.2021.110282

A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

Alexander K. Hafez, Amber J. Zimmerman, Grigorios Papageorgiou, Jayapriya Chandrasekaran, Stephen K. Amoah, Rixing Lin, Evelyn Lozano, Caroline Pierotti, Michela Dell'Orco, Brigham J. Hartley, Begüm Alural, Jasmin Lalonde, John Matthew Esposito, Sabina Berretta, Alessio Squassina, Caterina Chillotti, Georgios Voloudakis, Zhiping Shao, John F. Fullard, Kristen J. BrennandGustavo Turecki, Panos Roussos, Roy H. Perlis, Stephen J. Haggarty, Nora Perrone-Bizzozero, Jonathan L. Brigman, Nikolaos Mellios

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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.

Original language	English
Article number	110282
Journal	Cell Reports
Volume	38
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.110282
State	Published - 18 Jan 2022

Keywords

Homer1
OFC
bipolar disorder
circHomer1
circRNAs
cognitive flexibility
reversal learning

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10.1016/j.celrep.2021.110282

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Hafez, A. K., Zimmerman, A. J., Papageorgiou, G., Chandrasekaran, J., Amoah, S. K., Lin, R., Lozano, E., Pierotti, C., Dell'Orco, M., Hartley, B. J., Alural, B., Lalonde, J., Esposito, J. M., Berretta, S., Squassina, A., Chillotti, C., Voloudakis, G., Shao, Z., Fullard, J. F., ... Mellios, N. (2022). A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning. Cell Reports, 38(3), [110282]. https://doi.org/10.1016/j.celrep.2021.110282

@article{127fa4a028884510b321da335dd5133c,

title = "A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning",

abstract = "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.",

keywords = "Homer1, OFC, bipolar disorder, circHomer1, circRNAs, cognitive flexibility, reversal learning",

author = "Hafez, {Alexander K.} and Zimmerman, {Amber J.} and Grigorios Papageorgiou and Jayapriya Chandrasekaran and Amoah, {Stephen K.} and Rixing Lin and Evelyn Lozano and Caroline Pierotti and Michela Dell'Orco and Hartley, {Brigham J.} and Beg{\"u}m Alural and Jasmin Lalonde and Esposito, {John Matthew} and Sabina Berretta and Alessio Squassina and Caterina Chillotti and Georgios Voloudakis and Zhiping Shao and Fullard, {John F.} and Brennand, {Kristen J.} and Gustavo Turecki and Panos Roussos and Perlis, {Roy H.} and Haggarty, {Stephen J.} and Nora Perrone-Bizzozero and Brigman, {Jonathan L.} and Nikolaos Mellios",

note = "Funding Information: This work was supported by the NIGMS P20 grant ( 1P20-GM121176 ; N.M., A.K.H., and S.K.A.), a Young Investigator Grant (FP00000839; N.M.) by the Brain & Behavior Research Foundation , and a high-priority, short-term R56 award from the NIMH (1R56-MH119150; N.M.). This work was partially supported by NIH grants 5R01-AA026583 , R01-MH101454 , R01-MH106056 , R33-MH087896 , R01-AG067025 , R01-AG065582 , R01-AG050986 , R01-MH110921 , U01-MH116442 , R01-MH125246 , R01-MH106056 , and R01-MH109897 . Further support was available by the Veterans Affairs Merit grant BX002395 (to P.R.), a BBRF Young Investigator Grant (K.J.B.), the MGH Research Scholars Program (S.J.H.), and the New York Stem Cell Foundation (K.J.B.). B.A. was supported by the Scientific and Technological Council of Turkey (2214/A) International Research Fellowship Program. We would like to thank Dr. Maree Webster and the SMRI brain bank for providing us with postmortem brain specimen. We would also like to thank Brian Rodriguez, Cole Bird, and Mate Fisher for technical assistance; Dr. Fernando Valenzuela for advice on the manuscript; and the UNM Clinical & Translational Science Center (CTSC) for allowing us access to ddPCR equipment. The authors gratefully acknowledge use of the Center of Biomedical Research Excellence (COBRE) data (P20-GM103472) and the Function Biomedical Informatics Research Network (FBIRN) data. Funding Information: This work was supported by the NIGMS P20 grant (1P20-GM121176; N.M. A.K.H. and S.K.A.), a Young Investigator Grant (FP00000839; N.M.) by the Brain & Behavior Research Foundation, and a high-priority, short-term R56 award from the NIMH (1R56-MH119150; N.M.). This work was partially supported by NIH grants 5R01-AA026583, R01-MH101454, R01-MH106056, R33-MH087896, R01-AG067025, R01-AG065582, R01-AG050986, R01-MH110921, U01-MH116442, R01-MH125246, R01-MH106056, and R01-MH109897. Further support was available by the Veterans Affairs Merit grant BX002395 (to P.R.), a BBRF Young Investigator Grant (K.J.B.), the MGH Research Scholars Program (S.J.H.), and the New York Stem Cell Foundation (K.J.B.). B.A. was supported by the Scientific and Technological Council of Turkey (2214/A) International Research Fellowship Program. We would like to thank Dr. Maree Webster and the SMRI brain bank for providing us with postmortem brain specimen. We would also like to thank Brian Rodriguez, Cole Bird, and Mate Fisher for technical assistance; Dr. Fernando Valenzuela for advice on the manuscript; and the UNM Clinical & Translational Science Center (CTSC) for allowing us access to ddPCR equipment. The authors gratefully acknowledge use of the Center of Biomedical Research Excellence (COBRE) data (P20-GM103472) and the Function Biomedical Informatics Research Network (FBIRN) data. N.M. conceived the hypothesis; designed, performed, and supervised experiments; analyzed data; and wrote the manuscript. J.L.B. and N.P.-B. designed and supervised experiments, analyzed data, and provided feedback on the hypothesis and manuscript. A.K.H. A.J.Z. and G.P. designed and performed experiments, analyzed data, provided feedback on the hypothesis, and helped in manuscript preparation. All other authors performed experiments and analyzed data. All authors reviewed the paper. 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.). Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = jan,

day = "18",

doi = "10.1016/j.celrep.2021.110282",

language = "English",

volume = "38",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

Hafez, AK, Zimmerman, AJ, Papageorgiou, G, Chandrasekaran, J, Amoah, SK, Lin, R, Lozano, E, Pierotti, C, Dell'Orco, M, Hartley, BJ, Alural, B, Lalonde, J, Esposito, JM, Berretta, S, Squassina, A, Chillotti, C, Voloudakis, G, Shao, Z, Fullard, JF, Brennand, KJ, Turecki, G, Roussos, P, Perlis, RH, Haggarty, SJ, Perrone-Bizzozero, N, Brigman, JL & Mellios, N 2022, 'A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning', Cell Reports, vol. 38, no. 3, 110282. https://doi.org/10.1016/j.celrep.2021.110282

TY - JOUR

T1 - A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

AU - Hafez, Alexander K.

AU - Zimmerman, Amber J.

AU - Papageorgiou, Grigorios

AU - Chandrasekaran, Jayapriya

AU - Amoah, Stephen K.

AU - Lin, Rixing

AU - Lozano, Evelyn

AU - Pierotti, Caroline

AU - Dell'Orco, Michela

AU - Hartley, Brigham J.

AU - Alural, Begüm

AU - Lalonde, Jasmin

AU - Esposito, John Matthew

AU - Berretta, Sabina

AU - Squassina, Alessio

AU - Chillotti, Caterina

AU - Voloudakis, Georgios

AU - Shao, Zhiping

AU - Fullard, John F.

AU - Brennand, Kristen J.

AU - Turecki, Gustavo

AU - Roussos, Panos

AU - Perlis, Roy H.

AU - Haggarty, Stephen J.

AU - Perrone-Bizzozero, Nora

AU - Brigman, Jonathan L.

AU - Mellios, Nikolaos

N1 - Funding Information: This work was supported by the NIGMS P20 grant ( 1P20-GM121176 ; N.M., A.K.H., and S.K.A.), a Young Investigator Grant (FP00000839; N.M.) by the Brain & Behavior Research Foundation , and a high-priority, short-term R56 award from the NIMH (1R56-MH119150; N.M.). This work was partially supported by NIH grants 5R01-AA026583 , R01-MH101454 , R01-MH106056 , R33-MH087896 , R01-AG067025 , R01-AG065582 , R01-AG050986 , R01-MH110921 , U01-MH116442 , R01-MH125246 , R01-MH106056 , and R01-MH109897 . Further support was available by the Veterans Affairs Merit grant BX002395 (to P.R.), a BBRF Young Investigator Grant (K.J.B.), the MGH Research Scholars Program (S.J.H.), and the New York Stem Cell Foundation (K.J.B.). B.A. was supported by the Scientific and Technological Council of Turkey (2214/A) International Research Fellowship Program. We would like to thank Dr. Maree Webster and the SMRI brain bank for providing us with postmortem brain specimen. We would also like to thank Brian Rodriguez, Cole Bird, and Mate Fisher for technical assistance; Dr. Fernando Valenzuela for advice on the manuscript; and the UNM Clinical & Translational Science Center (CTSC) for allowing us access to ddPCR equipment. The authors gratefully acknowledge use of the Center of Biomedical Research Excellence (COBRE) data (P20-GM103472) and the Function Biomedical Informatics Research Network (FBIRN) data. Funding Information: This work was supported by the NIGMS P20 grant (1P20-GM121176; N.M. A.K.H. and S.K.A.), a Young Investigator Grant (FP00000839; N.M.) by the Brain & Behavior Research Foundation, and a high-priority, short-term R56 award from the NIMH (1R56-MH119150; N.M.). This work was partially supported by NIH grants 5R01-AA026583, R01-MH101454, R01-MH106056, R33-MH087896, R01-AG067025, R01-AG065582, R01-AG050986, R01-MH110921, U01-MH116442, R01-MH125246, R01-MH106056, and R01-MH109897. Further support was available by the Veterans Affairs Merit grant BX002395 (to P.R.), a BBRF Young Investigator Grant (K.J.B.), the MGH Research Scholars Program (S.J.H.), and the New York Stem Cell Foundation (K.J.B.). B.A. was supported by the Scientific and Technological Council of Turkey (2214/A) International Research Fellowship Program. We would like to thank Dr. Maree Webster and the SMRI brain bank for providing us with postmortem brain specimen. We would also like to thank Brian Rodriguez, Cole Bird, and Mate Fisher for technical assistance; Dr. Fernando Valenzuela for advice on the manuscript; and the UNM Clinical & Translational Science Center (CTSC) for allowing us access to ddPCR equipment. The authors gratefully acknowledge use of the Center of Biomedical Research Excellence (COBRE) data (P20-GM103472) and the Function Biomedical Informatics Research Network (FBIRN) data. N.M. conceived the hypothesis; designed, performed, and supervised experiments; analyzed data; and wrote the manuscript. J.L.B. and N.P.-B. designed and supervised experiments, analyzed data, and provided feedback on the hypothesis and manuscript. A.K.H. A.J.Z. and G.P. designed and performed experiments, analyzed data, provided feedback on the hypothesis, and helped in manuscript preparation. All other authors performed experiments and analyzed data. All authors reviewed the paper. 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.). Publisher Copyright: © 2021 The Authors

PY - 2022/1/18

Y1 - 2022/1/18

N2 - 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.

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.

KW - Homer1

KW - OFC

KW - bipolar disorder

KW - circHomer1

KW - circRNAs

KW - cognitive flexibility

KW - reversal learning

UR - http://www.scopus.com/inward/record.url?scp=85122939254&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.110282

DO - 10.1016/j.celrep.2021.110282

M3 - Article

C2 - 35045295

AN - SCOPUS:85122939254

SN - 2211-1247

VL - 38

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 110282

ER -

A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

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