Learning of probabilistic punishment as a model of anxiety produces changes in action but not punisher encoding in the dmPFC and VTA

  1. David S Jacobs
  2. Madeleine C Allen
  3. Junchol Park
  4. Bita Moghaddam  Is a corresponding author
  1. Oregon Health and Science University, United States
  2. Janelia Research Campus, United States

Abstract

Previously, we developed a novel model for anxiety during motivated behavior by training rats to perform a task where actions executed to obtain a reward were probabilistically punished and observed that after learning, neuronal activity in the ventral tegmental area (VTA) and dorsomedial prefrontal cortex (dmPFC) represent the relationship between action and punishment risk (Park & Moghaddam, 2017). Here we used male and female rats to expand on the previous work by focusing on neural changes in the dmPFC and VTA that were associated with the learning of probabilistic punishment, and anxiolytic treatment with diazepam after learning. We find that adaptive neural responses of dmPFC and VTA during the learning of anxiogenic contingencies are independent from the punisher experience and occur primarily during the peri-action and reward period. Our results also identify peri-action ramping of VTA neural calcium activity, and VTA-dmPFC correlated activity, as potential markers for the anxiolytic properties of diazepam.

Data availability

Data generated for analyses has been deposited on Dryad. Source code for analysis is available on github (https://github.com/MoghaddamLab).

The following data sets were generated

Article and author information

Author details

  1. David S Jacobs

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Madeleine C Allen

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Junchol Park

    Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bita Moghaddam

    Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, United States
    For correspondence
    bita@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5205-417X

Funding

National Institute of Mental Health (MH115026)

  • Bita Moghaddam

National Institute on Drug Abuse (DA007262)

  • David S Jacobs
  • Madeleine C Allen

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

Reviewing Editor

  1. Geoffrey Schoenbaum, National Institute on Drug Abuse, National Institutes of Health, United States

Ethics

Animal experimentation: All experimental procedures were approved by the OHSU Institutional Animal Use and Care Committee (Protocol #: 15065884) and were conducted in accordance with National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Version history

  1. Preprint posted: March 29, 2022 (view preprint)
  2. Received: March 29, 2022
  3. Accepted: August 30, 2022
  4. Accepted Manuscript published: September 14, 2022 (version 1)
  5. Version of Record published: September 30, 2022 (version 2)

Copyright

© 2022, Jacobs 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

  • 1,067
    views
  • 292
    downloads
  • 6
    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. David S Jacobs
  2. Madeleine C Allen
  3. Junchol Park
  4. Bita Moghaddam
(2022)
Learning of probabilistic punishment as a model of anxiety produces changes in action but not punisher encoding in the dmPFC and VTA
eLife 11:e78912.
https://doi.org/10.7554/eLife.78912

Share this article

https://doi.org/10.7554/eLife.78912

Further reading

    1. Cell Biology
    2. Neuroscience
    Marcos Moreno-Aguilera, Alba M Neher ... Carme Gallego
    Research Article Updated

    Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.

    1. Genetics and Genomics
    2. Neuroscience
    Kenneth Chiou, Noah Snyder-Mackler
    Insight

    Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.