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Despite extensive associations between genetic mutations and these disorders, the molecular contributions to goal-directed dysfunction remain unclear. We examined mice with constitutive and brain region-specific mutations in Neurexin1\u03b1, a neuropsychiatric disease-associated synaptic molecule, in value-based choice paradigms. We found Neurexin1\u03b1 knockouts exhibited reduced selection of beneficial outcomes and impaired avoidance of costlier options. Reinforcement modeling suggested that this was driven by deficits in updating and representation of value. Disruption of Neurexin1\u03b1 within telencephalic excitatory projection neurons, but not thalamic neurons, recapitulated choice abnormalities of global Neurexin1\u03b1 knockouts. Furthermore, this selective forebrain excitatory knockout of Neurexin1\u03b1 perturbed value-modulated neural signals within striatum, a central node in feedback-based reinforcement learning. By relating deficits in value-based decision-making to region-specific Nrxn1\u03b1 disruption and changes in value-modulated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction.<\/jats:p>","DOI":"10.7554\/elife.54838","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T08:16:07Z","timestamp":1607069767000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.54838","source":"Crossref","is-referenced-by-count":25,"title":["Disruption of Nrxn1\u03b1 within excitatory forebrain circuits drives value-based dysfunction"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6732-2897","authenticated-orcid":true,"given":"Opeyemi O","family":"Alabi","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Philadelphia, United States"},{"name":"Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0607-5164","authenticated-orcid":true,"given":"M Felicia","family":"Davatolhagh","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Philadelphia, United States"},{"name":"Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Fortunato","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-0543","authenticated-orcid":true,"given":"Luigim","family":"Vargas Cifuentes","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Philadelphia, United States"},{"name":"Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph W","family":"Kable","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6569-706X","authenticated-orcid":true,"given":"Marc Vincent","family":"Fuccillo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00050","article-title":"Behavioral paradigms to probe individual mouse differences in Value-Based decision making","volume":"13","author":"Alabi","year":"2019","journal-title":"Frontiers in Neuroscience"},{"key":"bib2","article-title":"Nrxn_BehaviorAndAnalysis","volume-title":"Software Heritage","author":"Alabi","year":"2020","unstructured":"Alabi O. 2020. 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