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).

The following data sets were generated
    1. Alabi
    2. O
    (2020) Neurexin Photometry
    Dryad Digital Repository, 10.5061/dryad.vhhmgqnrq.

Article and author information

Author details

  1. Opeyemi O Alabi

    Neuroscience, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. M Felicia Davatolhagh

    Neuroscience, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mara Robinson

    Neuroscience, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael P Fortunato

    Neuroscience, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Luigim Vargas-Cifuentes

    Neuroscience, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Joseph W Kable

    Department of Psychology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Marc Vincent Fuccillo

    Neuroscience, University of Pennsylvania, Philadelphia, United States
    For correspondence
    fuccillo@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6569-706X

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.

Reviewing Editor

  1. Mary Kay Lobo, University of Maryland, United States

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.

Version history

  1. Received: January 2, 2020
  2. Accepted: December 3, 2020
  3. Accepted Manuscript published: December 4, 2020 (version 1)
  4. Version of Record published: December 24, 2020 (version 2)

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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  1. Opeyemi O Alabi
  2. M Felicia Davatolhagh
  3. Mara Robinson
  4. Michael P Fortunato
  5. Luigim Vargas-Cifuentes
  6. Joseph W Kable
  7. Marc Vincent Fuccillo
(2020)
Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction
eLife 9:e54838.
https://doi.org/10.7554/eLife.54838

Share this article

https://doi.org/10.7554/eLife.54838

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