Hughes, RB, Whittingham-Dowd, J, Clapcote, SJ orcid.org/0000-0002-6662-5690 et al. (2 more authors) (2022) Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion. Autism research : official journal of the International Society for Autism Research, 15 (4). pp. 614-627. ISSN 1939-3792
Abstract
2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1α heterozygosity on cerebral metabolism, in mice, using 14C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1α genotype. Our data show that Nrxn1α heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1α genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1α+/− mice. Behaviorally, Nrxn1α+/− mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1α+/− mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1α+/− mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1α heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1α+/− mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) |
Keywords: | cognitive neuroscience; copy number variation/copy number variants; frontal lobe; genotype–phenotype correlation; imaging genetics; mouse models; serotonin |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 16 Feb 2022 14:51 |
Last Modified: | 25 Jun 2023 22:54 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/aur.2685 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:183609 |