1. Neuroscience
Download icon

Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times

Research Article
  • Cited 10
  • Views 3,320
  • Annotations
Cite this article as: eLife 2020;9:e54936 doi: 10.7554/eLife.54936

Abstract

Dopamine (DA) neurons are known to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in supporting learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction, a behavior we observed to generate spatially segregated RPE and salience signals. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed that DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate that salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.

Data availability

All data generated or analysed during this study will be included in the manuscript as supporting files. Code for all steps is available on GitHub:https://github.com/neurocaience/deepfreeze/ (Cai et al. 2020)

Article and author information

Author details

  1. Lili X Cai

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Katherine Pizano

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gregory W Gundersen

    Computer Science, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cameron L Hayes

    Princeton Neuroscience Institute, Princeton University, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0388-5807
  5. Weston T Fleming

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sebastian Holt

    Neuroscience, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Julia M Cox

    Neuroscience, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ilana B Witten

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    For correspondence
    iwitten@princeton.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0548-2160

Funding

NIH (T32MH065214)

  • Lili X Cai

NYSCF

  • Ilana B Witten

ARO (W911NF1710554)

  • Ilana B Witten

NIH (1R01MH106689-01A1)

  • Ilana B Witten

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 followed guidelines established by the National Institutes of Health and reviewed by Princeton University Institutional Animals Care and Use Committee (IACUC protocol 1876-18).

Reviewing Editor

  1. Naoshige Uchida, Harvard University, United States

Publication history

  1. Received: January 7, 2020
  2. Accepted: June 5, 2020
  3. Accepted Manuscript published: June 10, 2020 (version 1)
  4. Accepted Manuscript updated: June 11, 2020 (version 2)
  5. Version of Record published: July 15, 2020 (version 3)
  6. Version of Record updated: July 27, 2020 (version 4)

Copyright

© 2020, Cai 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

  • 3,320
    Page views
  • 505
    Downloads
  • 10
    Citations

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

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)

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

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

Further reading

    1. Cell Biology
    2. Neuroscience
    Rene Solano Fonseca et al.
    Research Article Updated

    Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Lloyd Davis et al.
    Tools and Resources Updated

    Synthetic strategies for optically controlling gene expression may enable the precise spatiotemporal control of genes in any combination of cells that cannot be targeted with specific promoters. We develop an improved genetic code expansion system in Caenorhabditis elegans and use it to create a photoactivatable Cre recombinase. We laser-activate Cre in single neurons within a bilaterally symmetric pair to selectively switch on expression of a loxP-controlled optogenetic channel in the targeted neuron. We use the system to dissect, in freely moving animals, the individual contributions of the mechanosensory neurons PLML/PLMR to the C. elegans touch response circuit, revealing distinct and synergistic roles for these neurons. We thus demonstrate how genetic code expansion and optical targeting can be combined to break the symmetry of neuron pairs and dissect behavioural outputs of individual neurons that cannot be genetically targeted.