Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior

TACTICS Consortium

doi:10.1016/j.euroneuro.2020.02.004

Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior

TACTICS Consortium

Research output: Contribution to journal › Article (Academic Journal) › peer-review

6 Citations (Scopus)

Abstract

Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.

Original language	English
Pages (from-to)	58-70
Number of pages	13
Journal	European Neuropsychopharmacology
Volume	33
DOIs	https://doi.org/10.1016/j.euroneuro.2020.02.004
Publication status	Published - 1 Apr 2020

Bibliographical note

Funding Information:
This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. The TACTICS consortium consists of Jan Buitelaar, Saskia de Ruiter, Jilly Naaijen, Sophie Akkermans, Maarten Mennes, Marcel Zwiers, Shahrzad Ilbegi, Leonie Hennissen, Jeffrey Glennon, Ilse van de Vondervoort, Katarzyna Kapusta, Natalia Bielczyk, Houshang Amiri, Martha Havenith, Barbara Franke, Geert Poelmans, Janita Bralten, Tom Heskes, Elena Sokolova, Perry Groot from Radboud University Medical Center Nijmegen, the Netherlands; Steven Williams, Declan Murphy, David Lythgoe, Muriel Bruchhage, Iulia Dud, Bogdan Voinescu from King's College London, United Kingdom; Ralf Dittmann, Tobias Banaschewski, Daniel Brandeis, Konstantin Mechler, Ruth Berg, Isabella Wolf, Alexander Häge, Michael Landauer, Sarah Hohmann, Regina Boecker-Schlier, Matthias Ruff from Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany; Rick Dijkhuizen, Erwin Blezer, Milou Straathof, Kajo van der Marel, Pim Pullens, Wouter Mol, Annette van der Toorn, Willem Otte, Caroline van Heijningen, Sarah Durston, Vincent Mensen, Bob Oranje, René Mandl from University Medical Center Utrecht, Utrecht, the Netherlands; Daphna Joel from Tel Aviv University, Tel Aviv, Israel; John Cryan from University College Cork, Cork City, Ireland; Tracey Petryshen, David Pauls, Mai Saito from Massachusetts General Hospital, Boston, MA, USA; Angelique Heckman from Genoway, Lyon, France; Sabine Bahn from University of Cambridge, Cambridge, United Kingdom; Ameli Schwalber from concentris research management GmbH, Fürstenfeldbruck, Germany; and Ioana Florea from Lundbeck, Valby, Denmark.

Funding Information:
This work was supported by the Netherlands Organization for Scientific Research (dr. R.M. Dijkhuizen: NWO-VICI 016.130.662, dr. W.M. Otte: NWO-VENI 016.168.038), and the Dutch Brain Foundation (dr. W.M. Otte: F2014(1)-06). The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007–2013) TACTICS under grant agreement no. 278948. All funding sources have had no further role in study design; in the collection, analyses and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Publisher Copyright:
© 2020 Elsevier B.V. and ECNP

Keywords

Adolescents
Diffusion-weighted MRI
Frontostriatal circuitry
Obsessive compulsive disorder
Quinpirole rat model
Resting-state fMRI

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@article{f8d183e65596456586a6378d83105acf,

title = "Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior",

abstract = "Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.",

keywords = "Adolescents, Diffusion-weighted MRI, Frontostriatal circuitry, Obsessive compulsive disorder, Quinpirole rat model, Resting-state fMRI",

author = "{TACTICS Consortium} and Milou Straathof and Blezer, {Erwin L.A.} and {van Heijningen}, Caroline and Smeele, {Christel E.} and {van der Toorn}, Annette and Buitelaar, {Jan K.} and {de Ruiter}, Saskia and Jilly Naaijen and Sophie Akkermans and Maarten Mennes and Marcel Zwiers and Shahrzad Ilbegi and Leonie Hennissen and Jeffrey Glennon and {van de Vondervoort}, Ilse and Katarzyna Kapusta and Bielczyk, {Na AAtalia} and Houshang Amiri and Martha Havenith and Barbara Franke and Geert Poelmans and Janita Bralten and Tom Heskes and Elena Sokolova and Perry Groot and Steven Williams and Murphy, {De AAclan} and David Lythgoe and Muriel Bruchhage and Bogdan Voinescu",

note = "Funding Information: This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. The TACTICS consortium consists of Jan Buitelaar, Saskia de Ruiter, Jilly Naaijen, Sophie Akkermans, Maarten Mennes, Marcel Zwiers, Shahrzad Ilbegi, Leonie Hennissen, Jeffrey Glennon, Ilse van de Vondervoort, Katarzyna Kapusta, Natalia Bielczyk, Houshang Amiri, Martha Havenith, Barbara Franke, Geert Poelmans, Janita Bralten, Tom Heskes, Elena Sokolova, Perry Groot from Radboud University Medical Center Nijmegen, the Netherlands; Steven Williams, Declan Murphy, David Lythgoe, Muriel Bruchhage, Iulia Dud, Bogdan Voinescu from King's College London, United Kingdom; Ralf Dittmann, Tobias Banaschewski, Daniel Brandeis, Konstantin Mechler, Ruth Berg, Isabella Wolf, Alexander H{\"a}ge, Michael Landauer, Sarah Hohmann, Regina Boecker-Schlier, Matthias Ruff from Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany; Rick Dijkhuizen, Erwin Blezer, Milou Straathof, Kajo van der Marel, Pim Pullens, Wouter Mol, Annette van der Toorn, Willem Otte, Caroline van Heijningen, Sarah Durston, Vincent Mensen, Bob Oranje, Ren{\'e} Mandl from University Medical Center Utrecht, Utrecht, the Netherlands; Daphna Joel from Tel Aviv University, Tel Aviv, Israel; John Cryan from University College Cork, Cork City, Ireland; Tracey Petryshen, David Pauls, Mai Saito from Massachusetts General Hospital, Boston, MA, USA; Angelique Heckman from Genoway, Lyon, France; Sabine Bahn from University of Cambridge, Cambridge, United Kingdom; Ameli Schwalber from concentris research management GmbH, F{\"u}rstenfeldbruck, Germany; and Ioana Florea from Lundbeck, Valby, Denmark. Funding Information: This work was supported by the Netherlands Organization for Scientific Research (dr. R.M. Dijkhuizen: NWO-VICI 016.130.662, dr. W.M. Otte: NWO-VENI 016.168.038), and the Dutch Brain Foundation (dr. W.M. Otte: F2014(1)-06). The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007–2013) TACTICS under grant agreement no. 278948. All funding sources have had no further role in study design; in the collection, analyses and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Publisher Copyright: {\textcopyright} 2020 Elsevier B.V. and ECNP",

year = "2020",

month = apr,

day = "1",

doi = "10.1016/j.euroneuro.2020.02.004",

language = "English",

volume = "33",

pages = "58--70",

journal = "European Neuropsychopharmacology",

issn = "0924-977X",

publisher = "Elsevier",

}

TY - JOUR

T1 - Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior

AU - TACTICS Consortium

AU - Straathof, Milou

AU - Blezer, Erwin L.A.

AU - van Heijningen, Caroline

AU - Smeele, Christel E.

AU - van der Toorn, Annette

AU - Buitelaar, Jan K.

AU - de Ruiter, Saskia

AU - Naaijen, Jilly

AU - Akkermans, Sophie

AU - Mennes, Maarten

AU - Zwiers, Marcel

AU - Ilbegi, Shahrzad

AU - Hennissen, Leonie

AU - Glennon, Jeffrey

AU - van de Vondervoort, Ilse

AU - Kapusta, Katarzyna

AU - Bielczyk, Na AAtalia

AU - Amiri, Houshang

AU - Havenith, Martha

AU - Franke, Barbara

AU - Poelmans, Geert

AU - Bralten, Janita

AU - Heskes, Tom

AU - Sokolova, Elena

AU - Groot, Perry

AU - Williams, Steven

AU - Murphy, De AAclan

AU - Lythgoe, David

AU - Bruchhage, Muriel

AU - Voinescu, Bogdan

N1 - Funding Information: This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. The TACTICS consortium consists of Jan Buitelaar, Saskia de Ruiter, Jilly Naaijen, Sophie Akkermans, Maarten Mennes, Marcel Zwiers, Shahrzad Ilbegi, Leonie Hennissen, Jeffrey Glennon, Ilse van de Vondervoort, Katarzyna Kapusta, Natalia Bielczyk, Houshang Amiri, Martha Havenith, Barbara Franke, Geert Poelmans, Janita Bralten, Tom Heskes, Elena Sokolova, Perry Groot from Radboud University Medical Center Nijmegen, the Netherlands; Steven Williams, Declan Murphy, David Lythgoe, Muriel Bruchhage, Iulia Dud, Bogdan Voinescu from King's College London, United Kingdom; Ralf Dittmann, Tobias Banaschewski, Daniel Brandeis, Konstantin Mechler, Ruth Berg, Isabella Wolf, Alexander Häge, Michael Landauer, Sarah Hohmann, Regina Boecker-Schlier, Matthias Ruff from Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany; Rick Dijkhuizen, Erwin Blezer, Milou Straathof, Kajo van der Marel, Pim Pullens, Wouter Mol, Annette van der Toorn, Willem Otte, Caroline van Heijningen, Sarah Durston, Vincent Mensen, Bob Oranje, René Mandl from University Medical Center Utrecht, Utrecht, the Netherlands; Daphna Joel from Tel Aviv University, Tel Aviv, Israel; John Cryan from University College Cork, Cork City, Ireland; Tracey Petryshen, David Pauls, Mai Saito from Massachusetts General Hospital, Boston, MA, USA; Angelique Heckman from Genoway, Lyon, France; Sabine Bahn from University of Cambridge, Cambridge, United Kingdom; Ameli Schwalber from concentris research management GmbH, Fürstenfeldbruck, Germany; and Ioana Florea from Lundbeck, Valby, Denmark. Funding Information: This work was supported by the Netherlands Organization for Scientific Research (dr. R.M. Dijkhuizen: NWO-VICI 016.130.662, dr. W.M. Otte: NWO-VENI 016.168.038), and the Dutch Brain Foundation (dr. W.M. Otte: F2014(1)-06). The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007–2013) TACTICS under grant agreement no. 278948. All funding sources have had no further role in study design; in the collection, analyses and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Publisher Copyright: © 2020 Elsevier B.V. and ECNP

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.

AB - Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.

KW - Adolescents

KW - Diffusion-weighted MRI

KW - Frontostriatal circuitry

KW - Obsessive compulsive disorder

KW - Quinpirole rat model

KW - Resting-state fMRI

UR - http://www.scopus.com/inward/record.url?scp=85082416823&partnerID=8YFLogxK

U2 - 10.1016/j.euroneuro.2020.02.004

DO - 10.1016/j.euroneuro.2020.02.004

M3 - Article (Academic Journal)

C2 - 32151497

AN - SCOPUS:85082416823

SN - 0924-977X

VL - 33

SP - 58

EP - 70

JO - European Neuropsychopharmacology

JF - European Neuropsychopharmacology

ER -

Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior

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Keywords

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