{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:21:42Z","timestamp":1788776502781,"version":"build-2803163510"},"reference-count":66,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010029","name":"Lancaster University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010029","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Autism Research"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>2p16.3 deletion, involving <jats:italic>NEUREXIN1<\/jats:italic> (<jats:italic>NRXN1<\/jats:italic>) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how <jats:italic>NRXN1<\/jats:italic> heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of <jats:italic>Nrxn1\u03b1<\/jats:italic> heterozygosity on cerebral metabolism, in mice, using <jats:sup>14<\/jats:sup>C\u20102\u2010deoxyglucose imaging. We also assess performance in an olfactory\u2010based discrimination and reversal learning (OB\u2010DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and <jats:italic>Nrxn1\u03b1<\/jats:italic> genotype. Our data show that <jats:italic>Nrxn1\u03b1<\/jats:italic> heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raph\u00e9 nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of <jats:italic>Nrxn1\u03b1<\/jats:italic> genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in <jats:italic>Nrxn1\u03b1<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> mice. Behaviorally, <jats:italic>Nrxn1\u03b1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male <jats:italic>Nrxn1\u03b1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in <jats:italic>Nrxn1\u03b1<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that <jats:italic>Nrxn1<\/jats:italic>\u03b1 heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that <jats:italic>Nrxn1\u03b1<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Lay Summary<\/jats:title><jats:p>Deletion of the chromosomal region 2p16.3, involving reduced <jats:italic>NEUREXIN1<\/jats:italic> gene expression, dramatically increases the risk of developing autism. Here, we show that reduced <jats:italic>Neurexin1\u03b1<\/jats:italic> 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/aur.2685","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T09:05:21Z","timestamp":1644483921000},"page":"614-627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Altered medial prefrontal cortex and dorsal raph\u00e9 activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism\u2010associated 2p16.3 deletion"],"prefix":"10.1002","volume":"15","author":[{"given":"Rebecca B.","family":"Hughes","sequence":"first","affiliation":[{"name":"Division of Biomedical and Life Sciences, Faculty of Health and Medicine Lancaster University  Lancaster 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