The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output

  1. Jennifer Brown
  2. Wei-Xing Pan
  3. Joshua T Dudman  Is a corresponding author
  1. Janelia Farm Research Campus, Howard Hughes Medical Institute, United States

Abstract

Dysfunction of the basal ganglia produces severe deficits in the timing, initiation, and vigor of movement. These diverse impairments suggest a control system gone awry. In engineered systems feedback is critical for control. By contrast, models of the basal ganglia highlight feedforward circuitry and ignore intrinsic feedback circuits. Here we show that feedback via axon collaterals of substantia nigra projection neurons control the gain of the basal ganglia output. Through a combination of physiology, optogenetics, anatomy and circuit mapping we elaborate a general circuit mechanism for gain control in a microcircuit lacking interneurons. Our data suggest that diverse tonic firing rates, weak unitary connections and a spatially diffuse collateral circuit with distinct topography and kinetics from feedforward input is sufficient to implement divisive feedback inhibition. The importance of feedback for engineered systems implies that the intranigral microcircuit, despite its absence from canonical models, could be essential to basal ganglia function.

Article and author information

Author details

  1. Jennifer Brown

    Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wei-Xing Pan

    Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Joshua T Dudman

    Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    For correspondence
    dudmanj@janelia.hhmi.org
    Competing interests
    The authors declare that no competing interests exist.

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 (#08-36, 11-69) of the Janelia Farm Research Campus. The animal care and use program at Janelia Farm Research Campus is accredited by The Association for Assessment and Accreditation of Laboratory Animal Care, International (AAALACi).

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Publication history

  1. Received: January 26, 2014
  2. Accepted: May 17, 2014
  3. Accepted Manuscript published: May 21, 2014 (version 1)
  4. Version of Record published: June 24, 2014 (version 2)

Copyright

© 2014, Brown 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

  • 3,942
    Page views
  • 575
    Downloads
  • 39
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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. Jennifer Brown
  2. Wei-Xing Pan
  3. Joshua T Dudman
(2014)
The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output
eLife 3:e02397.
https://doi.org/10.7554/eLife.02397

Further reading

    1. Developmental Biology
    2. Neuroscience
    Kenneth Kin Lam Wong, Tongchao Li ... Liqun Luo
    Research Article

    How does wiring specificity of neural maps emerge during development? Formation of the adult Drosophila olfactory glomerular map begins with patterning of projection neuron (PN) dendrites at the early pupal stage. To better understand the origin of wiring specificity of this map, we created genetic tools to systematically characterize dendrite patterning across development at PN type-specific resolution. We find that PNs use lineage and birth order combinatorially to build the initial dendritic map. Specifically, birth order directs dendrite targeting in rotating and binary manners for PNs of the anterodorsal and lateral lineages, respectively. Two-photon- and adaptive optical lattice light-sheet microscope-based time-lapse imaging reveals that PN dendrites initiate active targeting with direction-dependent branch stabilization on the timescale of seconds. Moreover, PNs that are used in both the larval and adult olfactory circuits prune their larval-specific dendrites and re-extend new dendrites simultaneously to facilitate timely olfactory map organization. Our work highlights the power and necessity of type-specific neuronal access and time-lapse imaging in identifying wiring mechanisms that underlie complex patterns of functional neural maps.

    1. Neuroscience
    Benjamin D Pedigo, Mike Powell ... Joshua T Vogelstein
    Research Article

    Comparing connectomes can help explain how neural connectivity is related to genetics, disease, development, learning, and behavior. However, making statistical inferences about the significance and nature of differences between two networks is an open problem, and such analysis has not been extensively applied to nanoscale connectomes. Here, we investigate this problem via a case study on the bilateral symmetry of a larval Drosophila brain connectome. We translate notions of'bilateral symmetry' to generative models of the network structure of the left and right hemispheres, allowing us to test and refine our understanding of symmetry. We find significant differences in connection probabilities both across the entire left and right networks and between specific cell types. By rescaling connection probabilities or removing certain edges based on weight, we also present adjusted definitions of bilateral symmetry exhibited by this connectome. This work shows how statistical inferences from networks can inform the study of connectomes, facilitating future comparisons of neural structures.