Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits

  1. William T Birdsong  Is a corresponding author
  2. Bart C Jongbloets
  3. Kim A Engeln
  4. Dong Wang
  5. Gregory Scherrer
  6. Tianyi Mao  Is a corresponding author
  1. Oregon Health and Science University, United States
  2. Stanford University, United States

Abstract

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. All code and data are deposited in https://gitlab.com/maolab/opi_syn_circuit. ecfa1f13.

Article and author information

Author details

  1. William T Birdsong

    Vollum Institute, Oregon Health and Science University, Portland, United States
    For correspondence
    wtbird@med.umich.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Bart C Jongbloets

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kim A Engeln

    Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dong Wang

    Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Department of Neurosurgery, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Gregory Scherrer

    Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tianyi Mao

    Vollum Institute, Oregon Health and Science University, Portland, United States
    For correspondence
    mao@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3532-8319

Funding

National Institute of Neurological Disorders and Stroke (R01NS081071)

  • Tianyi Mao

New York Stem Cell Foundation

  • Gregory Scherrer

National Institute on Drug Abuse (R01DA042779)

  • William T Birdsong

National Institute on Drug Abuse (R01DA044481)

  • Gregory Scherrer

National Institute on Drug Abuse (R01NS106301)

  • Gregory Scherrer

National Institute of Neurological Disorders and Stroke (R01NS104944)

  • Tianyi Mao

National Institute of Neurological Disorders and Stroke (U01NS094247)

  • Tianyi Mao

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 procedures were approved by Oregon Health & Science University Institutional Animal Care and Use Committee (IACUC) and all experiments were performed strictly according the approved protocols. IACUC protocol IP00000955, and Institutional Biosafety Committee protocol IBC-10-40.

Reviewing Editor

  1. Olivier J Manzoni, Aix-Marseille University, INSERM, INMED, France

Publication history

  1. Received: January 14, 2019
  2. Accepted: May 15, 2019
  3. Accepted Manuscript published: May 17, 2019 (version 1)
  4. Version of Record published: May 29, 2019 (version 2)

Copyright

© 2019, Birdsong 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

  • 3,350
    Page views
  • 643
    Downloads
  • 34
    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. William T Birdsong
  2. Bart C Jongbloets
  3. Kim A Engeln
  4. Dong Wang
  5. Gregory Scherrer
  6. Tianyi Mao
(2019)
Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits
eLife 8:e45146.
https://doi.org/10.7554/eLife.45146

Further reading

    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.

    1. Neuroscience
    Sinisa Pajevic, Dietmar Plenz ... R Douglas Fields
    Research Article

    Temporal synchrony of signals arriving from different neurons or brain regions is essential for proper neural processing. Nevertheless, it is not well understood how such synchrony is achieved and maintained in a complex network of time-delayed neural interactions. Myelin plasticity, accomplished by oligodendrocytes (OLs), has been suggested as an efficient mechanism for controlling timing in brain communications through adaptive changes of axonal conduction velocity and consequently conduction time delays, or latencies; however, local rules and feedback mechanisms that OLs use to achieve synchronization are not known. We propose a mathematical model of oligodendrocyte-mediated myelin plasticity (OMP) in which OLs play an active role in providing such feedback. This is achieved without using arrival times at the synapse or modulatory signaling from astrocytes; instead, it relies on the presence of global and transient OL responses to local action potentials in the axons they myelinate. While inspired by OL morphology, we provide the theoretical underpinnings that motivated the model and explore its performance for a wide range of its parameters. Our results indicate that when the characteristic time of OL’s transient intracellular responses to neural spikes is between 10 and 40 ms and the firing rates in individual axons are relatively low (⪅ 10 Hz), the OMP model efficiently synchronizes correlated and time-locked signals while latencies in axons carrying independent signals are unaffected. This suggests a novel form of selective synchronization in the CNS in which oligodendrocytes play an active role by modulating the conduction delays of correlated spike trains as they traverse to their targets.