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Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats

Casado-Sainz, A. and Gudmundsen, F. and Baerentzen, S. and Lange, D. and Ringsted, A. and Martinez-Tejada, I. and Medina, S. and Lee, H. and Svarer, C. and Keller, S.H. and Schain, M. and Kjaerby, C. and Fisher, P.M. and Cumming, P. and Palner, M. (2021) Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats. Neuropsychopharmacology, 47 (2), pp. 454-464. Springer Nature. doi: 10.1038/s41386-021-01207-y. ISSN 0893-133X.

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Official URL: https://www.nature.com/articles/s41386-021-01207-y

Abstract

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [¹⁸F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [¹⁸F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity).

Item URL in elib:https://elib.dlr.de/147638/
Document Type:Article
Title:Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Casado-Sainz, A.UNSPECIFIEDUNSPECIFIED
Gudmundsen, F.UNSPECIFIEDUNSPECIFIED
Baerentzen, S.UNSPECIFIEDUNSPECIFIED
Lange, D.denise.lange (at) dlr.deUNSPECIFIED
Ringsted, A.UNSPECIFIEDUNSPECIFIED
Martinez-Tejada, I.UNSPECIFIEDUNSPECIFIED
Medina, S.UNSPECIFIEDUNSPECIFIED
Lee, H.UNSPECIFIEDUNSPECIFIED
Svarer, C.UNSPECIFIEDUNSPECIFIED
Keller, S.H.UNSPECIFIEDUNSPECIFIED
Schain, M.UNSPECIFIEDUNSPECIFIED
Kjaerby, C.UNSPECIFIEDUNSPECIFIED
Fisher, P.M.UNSPECIFIEDUNSPECIFIED
Cumming, P.UNSPECIFIEDUNSPECIFIED
Palner, M.UNSPECIFIEDUNSPECIFIED
Date:1 November 2021
Journal or Publication Title:Neuropsychopharmacology
Refereed publication:Yes
Open Access:No
Gold Open Access:No
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:47
DOI :10.1038/s41386-021-01207-y
Page Range:pp. 454-464
Publisher:Springer Nature
ISSN:0893-133X
Status:Published
Keywords:Neuroscience, Behavioural methods, Human behaviour
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Aeronautics
HGF - Program Themes:other
DLR - Research area:Aeronautics
DLR - Program:L - no assignment
DLR - Research theme (Project):L - no assignment
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Sleep and Human Factors Research
Deposited By: Sender, Alina
Deposited On:06 Jan 2022 12:45
Last Modified:06 Jan 2022 12:45

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