TY - JOUR
T1 - Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior
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 C.
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 - Dud, Iulia
AU - Voinescu, Bogdan
AU - Dittmann, Ralf
AU - Banaschewski, Tobias
AU - Brandeis, Daniel
AU - Mechler, Konstantin
AU - Berg, Ruth
AU - Wolf, Isabella
AU - Häge, Alexander
AU - Landauer, Michael
AU - Hohmann, Sarah
AU - Schlier, Regina Boecker
AU - Ruff, Matthias
AU - Mandl, René
AU - Dijkhuizen, Rick
AU - Blezer, Erwin
AU - Mol, Wouter
AU - Otte, Willem
AU - Durston, Sarah
AU - Oranje, Bob
AU - Dijkhuizen, Rick
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
C2 - 32151497
AN - SCOPUS:85082416823
SN - 0924-977X
VL - 33
SP - 58
EP - 70
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
ER -