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      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

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          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.

          Lay Summary

          Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1α expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism.

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          Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

          The CNV analysis group of the Psychiatric Genomic Consortium analyzes a large schizophrenia cohort to examine genomic copy number variants (CNVs) and disease risk. They find an enrichment of CNV burden in cases versus controls and identify 8 genome-wide significant loci as well as novel suggestive loci conferring either risk or protection to schizophrenia.
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            Scikitlearn: Machine learning in Python

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              Medial frontal cortex mediates perceptual attentional set shifting in the rat.

              If rodents do not display the behavioral complexity that is subserved in primates by prefrontal cortex, then evolution of prefrontal cortex in the rat should be doubted. Primate prefrontal cortex has been shown to mediate shifts in attention between perceptual dimensions of complex stimuli. This study examined the possibility that medial frontal cortex of the rat is involved in the shifting of perceptual attentional set. We trained rats to perform an attentional set-shifting task that is formally the same as a task used in monkeys and humans. Rats were trained to dig in bowls for a food reward. The bowls were presented in pairs, only one of which was baited. The rat had to select the bowl in which to dig by its odor, the medium that filled the bowl, or the texture that covered its surface. In a single session, rats performed a series of discriminations, including reversals, an intradimensional shift, and an extradimensional shift. Bilateral lesions by injection of ibotenic acid in medial frontal cortex resulted in impairment in neither initial acquisition nor reversal learning. We report here the same selective impairment in shifting of attentional set in the rat as seen in primates with lesions of prefrontal cortex. We conclude that medial frontal cortex of the rat has functional similarity to primate lateral prefrontal cortex.
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                Author and article information

                Contributors
                n.dawson1@lancaster.ac.uk
                Journal
                Autism Res
                Autism Res
                10.1002/(ISSN)1939-3806
                AUR
                Autism Research
                John Wiley & Sons, Inc. (Hoboken, USA )
                1939-3792
                1939-3806
                10 February 2022
                April 2022
                : 15
                : 4 ( doiID: 10.1002/aur.v15.4 )
                : 614-627
                Affiliations
                [ 1 ] Division of Biomedical and Life Sciences, Faculty of Health and Medicine Lancaster University Lancaster UK
                [ 2 ] School of Biomedical Sciences University of Leeds Leeds UK
                Author notes
                [*] [* ] Correspondence

                Neil Dawson, Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.

                Email: n.dawson1@ 123456lancaster.ac.uk

                Author information
                https://orcid.org/0000-0003-0123-897X
                Article
                AUR2685
                10.1002/aur.2685
                9303357
                35142069
                7c9540d6-6d1a-4cb4-bf1c-105b75e94fc8
                © 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 http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 January 2022
                : 12 October 2021
                : 24 January 2022
                Page count
                Figures: 4, Tables: 0, Pages: 14, Words: 11449
                Funding
                Funded by: Lancaster University , doi 10.13039/100010029;
                Categories
                Research Article
                MODELS
                Research Articles
                Custom metadata
                2.0
                April 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:21.07.2022

                cognitive neuroscience,copy number variation/copy number variants,frontal lobe,genotype–phenotype correlation,imaging genetics,mouse models,serotonin

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