1. Neuroscience

Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction

  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  Is a corresponding author
  1. University of Pennsylvania, United States
https://doi.org/10.7554/eLife.54838
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.
    https://doi.org/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.

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.

Metrics

  • 1,248
    views
  • 153
    downloads
  • 17
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Rhythmic circuit function is more robust to changes in synaptic than intrinsic conductances

    Zachary Fournier, Leandro M Alonso, Eve Marder
    Research Article

    Circuit function results from both intrinsic conductances of network neurons and the synaptic conductances that connect them. In models of neural circuits, different combinations of maximal conductances can give rise to similar activity. We compared the robustness of a neural circuit to changes in their intrinsic versus synaptic conductances. To address this, we performed a sensitivity analysis on a population of conductance-based models of the pyloric network from the crustacean stomatogastric ganglion (STG). The model network consists of three neurons with nine currents: a sodium current (Na), three potassium currents (Kd, KCa, KA), two calcium currents (CaS and CaT), a hyperpolarization-activated current (H), a non-voltage-gated leak current (leak), and a neuromodulatory current (MI). The model cells are connected by seven synapses of two types, glutamatergic and cholinergic. We produced one hundred models of the pyloric network that displayed similar activities with values of maximal conductances distributed over wide ranges. We evaluated the robustness of each model to changes in their maximal conductances. We found that individual models have different sensitivities to changes in their maximal conductances, both in their intrinsic and synaptic conductances. As expected, the models become less robust as the extent of the changes increases. Despite quantitative differences in their robustness, we found that in all cases, the model networks are more sensitive to the perturbation of their intrinsic conductances than their synaptic conductances.

    1. Neuroscience

    Cognition: When working memory works for our goals

    Jacob A Miller
    Insight

    When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.

    1. Neuroscience

    Cerebellar Purkinje cells control posture in larval zebrafish (Danio rerio)

    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.