Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction
- University of Pennsylvania, United States
Abstract
Goal-directed behaviors are essential for normal function and significantly impaired in neuropsychiatric disorders. 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 Neurexin1α, a neuropsychiatric disease-associated synaptic molecule, in value-based choice paradigms. We found Neurexin1α knockouts exhibited reduced selection of beneficial outcomes and impaired avoidance of costlier options. Reinforcement modeling suggested this was driven by deficits in updating and representation of value. Disruption of Neurexin1α within telencephalic excitatory projection neurons, but not thalamic neurons, recapitulated choice abnormalities of global Neurexin1α knockouts. Furthermore, this selective forebrain excitatory knockout of Neurexin1α 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 Nrxn1α disruption and changes in value-modulated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction.
Data availability
Source files have been placed on Dryad (Alabi, Opeyemi (2020), Neurexin Photometry, Dryad, Dataset, https://doi.org/10.5061/dryad.vhhmgqnrq) and code is at Fuccillo lab Github account (https://github.com/oalabi76/Nrxn_BehaviorAndAnalysis).
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Neurexin PhotometryDryad Digital Repository, 10.5061/dryad.vhhmgqnrq.
Article and author information
Author details
Marc Vincent Fuccillo
Funding
National Institutes of Health (R00MH099243)
- Marc Vincent Fuccillo
National Institutes of Health (R01MH115030)
- Marc Vincent Fuccillo
National Institutes of Health (F31MH114528)
- Opeyemi O Alabi
Children's Hospital of Philadelphia (IDDRC Young Investigator)
- Marc Vincent Fuccillo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#805643) of the University of Pennsylvania.
Copyright
© 2020, Alabi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction
eLife 9:e54838.
https://doi.org/10.7554/eLife.54838
