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).

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

  • 2,533
    views
  • 344
    downloads
  • 24
    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. 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. Neuroscience
    Cristina Gil Avila, Elisabeth S May ... Markus Ploner
    Research Article

    Chronic pain is a prevalent and debilitating condition whose neural mechanisms are incompletely understood. An imbalance of cerebral excitation and inhibition (E/I), particularly in the medial prefrontal cortex (mPFC), is believed to represent a crucial mechanism in the development and maintenance of chronic pain. Thus, identifying a non-invasive, scalable marker of E/I could provide valuable insights into the neural mechanisms of chronic pain and aid in developing clinically useful biomarkers. Recently, the aperiodic component of the electroencephalography (EEG) power spectrum has been proposed to represent a non-invasive proxy for E/I. We, therefore, assessed the aperiodic component in the mPFC of resting-state EEG recordings in 149 people with chronic pain and 115 healthy participants. We found robust evidence against differences in the aperiodic component in the mPFC between people with chronic pain and healthy participants, and no correlation between the aperiodic component and pain intensity. These findings were consistent across different subtypes of chronic pain and were similarly found in a whole-brain analysis. Their robustness was supported by preregistration and multiverse analyses across many different methodological choices. Together, our results suggest that the EEG aperiodic component does not differentiate between people with chronic pain and healthy individuals. These findings and the rigorous methodological approach can guide future studies investigating non-invasive, scalable markers of cerebral dysfunction in people with chronic pain and beyond.

    1. Neuroscience
    Gyeong Hee Pyeon, Hyewon Cho ... Yong Sang Jo
    Research Article

    Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, their activation would modulate both passive nad active defensive behaviors depending on the magnitude and context of the threat. However, most prior research has focused on the role of CGRP neurons in passive freezing responses, with limited exploration of their involvement in active defensive behaviors. To address this, we examined the role of CGRP neurons in active defensive behavior using a predator-like robot programmed to chase mice. Our electrophysiological results revealed that CGRP neurons encode the intensity of aversive stimuli through variations in firing durations and amplitudes. Optogenetic activation of CGRP neuron during robot chasing elevated flight responses in both conditioning and retention tests, presumably by amyplifying the perception of the threat as more imminent and dangerous. In contrast, animals with inactivated CGRP neurons exhibited reduced flight responses, even when the robot was programmed to appear highly threatening during conditioning. These findings expand the understanding of CGRP neurons in the PBN as a critical alarm system, capable of dynamically regulating active defensive behaviors by amplifying threat perception, ensuring adaptive responses to varying levels of danger.