Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders

  1. Cian O'Donnell  Is a corresponding author
  2. J Tiago Gonçalves
  3. Carlos Portera-Cailliau
  4. Terrence J Sejnowski  Is a corresponding author
  1. University of Bristol, United Kingdom
  2. Albert Einstein College of Medicine, United States
  3. University of California, Los Angeles, United States
  4. Howard Hughes Medical Institute, Salk Institute for Biological Studies, United States

Abstract

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here we combined computational simulations with analysis of in vivo 2-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: 1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; 2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; 3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher-dimensional models that can better capture the multidimensional computational functions of neural circuits.

Data availability

The following previously published data sets were used

Article and author information

Author details

  1. Cian O'Donnell

    Department of Computer Science, University of Bristol, Bristol, United Kingdom
    For correspondence
    cian.odonnell@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2031-9177
  2. J Tiago Gonçalves

    Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Carlos Portera-Cailliau

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Terrence J Sejnowski

    Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    terry@salk.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0622-7391

Funding

FRAXA Research Foundation (Postdoctoral fellowship)

  • Cian O'Donnell

Howard Hughes Medical Institute

  • Cian O'Donnell
  • Terrence J Sejnowski

Sloan-Swartz

  • Cian O'Donnell
  • Terrence J Sejnowski

Dana Foundation

  • J Tiago Gonçalves
  • Carlos Portera-Cailliau

John Merck Fund (20160969)

  • Carlos Portera-Cailliau

Simons Foundation (295438)

  • Carlos Portera-Cailliau

National Institute of Neurological Disorders and Stroke (RC1NS068093)

  • J Tiago Gonçalves
  • Carlos Portera-Cailliau

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD054453)

  • J Tiago Gonçalves
  • Carlos Portera-Cailliau

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were conducted according the US National Institutes of Health guidelines for animal research, under an animal protocol (ARC#2007-035) approved by the Chancellor's Animal Research Committee and the Office for the Protection of Research Subjects at the University of California, Los Angeles.

Copyright

© 2017, O'Donnell 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

  • 7,552
    views
  • 1,115
    downloads
  • 50
    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. Cian O'Donnell
  2. J Tiago Gonçalves
  3. Carlos Portera-Cailliau
  4. Terrence J Sejnowski
(2017)
Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders
eLife 6:e26724.
https://doi.org/10.7554/eLife.26724

Share this article

https://doi.org/10.7554/eLife.26724

Further reading

    1. Neuroscience
    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.

    1. Neuroscience
    Zhujun Shao, Mengya Zhang, Qing Yu
    Research Article

    When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.