Specialized coding patterns among dorsomedial prefrontal neuronal ensembles predict conditioned reward seeking

Abstract

Non-overlapping cell populations within dorsomedial prefrontal cortex (dmPFC), defined by gene expression or projection target, control dissociable aspects of reward seeking through unique activity patterns. However, even within these defined cell populations considerable cell-to-cell variability is found, suggesting that greater resolution is needed to understand information processing in dmPFC. Here we use two-photon calcium imaging in awake, behaving mice to monitor the activity of dmPFC excitatory neurons throughout Pavlovian reward conditioning. We characterize five unique neuronal ensembles that each encode specialized information related to a sucrose reward, reward-predictive cues, and behavioral responses to those cues. The ensembles differentially emerge across daily training sessions - and stabilize after learning - in a manner that improves the predictive validity of dmPFC activity dynamics for deciphering variables related to behavioral conditioning. Our results characterize the complex dmPFC neuronal ensemble dynamics that stably predict reward availability and initiation of conditioned reward seeking following cue-reward learning.

Data availability

All data generated for this study are available on Dryad Digital Repository, accessible here: https://doi.org/10.5061/dryad.xksn02vg8. We are in the process of uploading raw videos for these data to the Image Data Resource (https://idr.openmicroscopy.org/), as there is a 3 week lead time to get the data uploaded and special considerations are required for datasets of >1TB. Code will be uploaded to GitHub upon publication. All data, code, and raw imaging files will be uploaded to these open-source repositories prior to publication.

The following data sets were generated

Article and author information

Author details

  1. Roger I Grant

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Elizabeth M Doncheck

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kelsey M Vollmer

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kion T Winston

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elizaveta V Romanova

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Preston N Siegler

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Heather Holman

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christopher W Bowen

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. James M Otis

    Neuroscience, Medical University of South Carolina, Charleston, SC, United States
    For correspondence
    otis@musc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0953-9283

Funding

National Institute of Drug Abuse (R01-DA051650)

  • James M Otis

MUSC Cocaine and Opioid Center on Addiction Pilot Award (P50-DA046374)

  • Roger I Grant

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

Ethics

Animal experimentation: Experiments were performed in the dark phase and in accordance with the NIH Guide for the Care and Use of Laboratory Animals with approval from the Institutional Animal Care and Use Committee at the Medical University of South Carolina (Approval ID: IACUC-2018-00363; Renewed November 30, 2020).

Reviewing Editor

  1. Mario Penzo, National Institute of Mental Health, United States

Version history

  1. Received: December 15, 2020
  2. Accepted: June 22, 2021
  3. Accepted Manuscript published: June 29, 2021 (version 1)
  4. Version of Record published: July 13, 2021 (version 2)

Copyright

© 2021, Grant 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

  • 2,207
    Page views
  • 318
    Downloads
  • 14
    Citations

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

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. Roger I Grant
  2. Elizabeth M Doncheck
  3. Kelsey M Vollmer
  4. Kion T Winston
  5. Elizaveta V Romanova
  6. Preston N Siegler
  7. Heather Holman
  8. Christopher W Bowen
  9. James M Otis
(2021)
Specialized coding patterns among dorsomedial prefrontal neuronal ensembles predict conditioned reward seeking
eLife 10:e65764.
https://doi.org/10.7554/eLife.65764

Share this article

https://doi.org/10.7554/eLife.65764

Further reading

    1. Developmental Biology
    2. Neuroscience
    Athina Keramidioti, Sandra Schneid ... Charles N David
    Research Article

    The Hydra nervous system is the paradigm of a ‘simple nerve net’. Nerve cells in Hydra, as in many cnidarian polyps, are organized in a nerve net extending throughout the body column. This nerve net is required for control of spontaneous behavior: elimination of nerve cells leads to polyps that do not move and are incapable of capturing and ingesting prey (Campbell, 1976). We have re-examined the structure of the Hydra nerve net by immunostaining fixed polyps with a novel antibody that stains all nerve cells in Hydra. Confocal imaging shows that there are two distinct nerve nets, one in the ectoderm and one in the endoderm, with the unexpected absence of nerve cells in the endoderm of the tentacles. The nerve nets in the ectoderm and endoderm do not contact each other. High-resolution TEM (transmission electron microscopy) and serial block face SEM (scanning electron microscopy) show that the nerve nets consist of bundles of parallel overlapping neurites. Results from transgenic lines show that neurite bundles include different neural circuits and hence that neurites in bundles require circuit-specific recognition. Nerve cell-specific innexins indicate that gap junctions can provide this specificity. The occurrence of bundles of neurites supports a model for continuous growth and differentiation of the nerve net by lateral addition of new nerve cells to the existing net. This model was confirmed by tracking newly differentiated nerve cells.

    1. Neuroscience
    Anna-Maria Grob, Hendrik Heinbockel ... Lars Schwabe
    Research Article

    Maintaining an accurate model of the world relies on our ability to update memory representations in light of new information. Previous research on the integration of new information into memory mainly focused on the hippocampus. Here, we hypothesized that the angular gyrus, known to be involved in episodic memory and imagination, plays a pivotal role in the insight-driven reconfiguration of memory representations. To test this hypothesis, participants received continuous theta burst stimulation (cTBS) over the left angular gyrus or sham stimulation before gaining insight into the relationship between previously separate life-like animated events in a narrative-insight task. During this task, participants also underwent EEG recording and their memory for linked and non-linked events was assessed shortly thereafter. Our results show that cTBS to the angular gyrus decreased memory for the linking events and reduced the memory advantage for linked relative to non-linked events. At the neural level, cTBS targeting the angular gyrus reduced centro-temporal coupling with frontal regions and abolished insight-induced neural representational changes for events linked via imagination, indicating impaired memory reconfiguration. Further, the cTBS group showed representational changes for non-linked events that resembled the patterns observed in the sham group for the linked events, suggesting failed pruning of the narrative in memory. Together, our findings demonstrate a causal role of the left angular gyrus in insight-related memory reconfigurations.