Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure

Abstract

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyper-activity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively, however, the underlying mechanisms are unknown. Here we show that alcohol exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid (eCB) signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation specific mechanism gating OFC activity in alcohol exposed mice.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data for all figures has been provided.

Article and author information

Author details

  1. Rafael Renteria

    Department of Psychology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6199-0293
  2. Christian Cazares

    The Neurosciences Graduate Program, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8899-2109
  3. Emily T Baltz

    The Neurosciences Graduate Program, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9770-3666
  4. Drew C Schreiner

    Department of Psychology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ege A Yalcinbas

    The Neurosciences Graduate Program, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9480-7192
  6. Thomas Steinkellner

    Department of Neurosciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Thomas S Hnasko

    Department of Neurosciences, The Neurosciences Graduate Program, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6176-8513
  8. Christina M Gremel

    Department of Psychology, The Neurosciences Graduate Program, University of California, San Diego, La Jolla, United States
    For correspondence
    cgremel@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8710-0543

Funding

National Institutes of Health (AA026077-01A1)

  • Christina M Gremel

National Institutes of Health (F32 AA026776)

  • Rafael Renteria

National Science Foundation (NSF-GRFP DGE-2038238)

  • Emily T Baltz

National Science Foundation (NSF-GRFP DGE-1650112)

  • Christian Cazares

National Institutes of Health (F31 AA027439)

  • Drew C Schreiner

National Institutes of Health (R01DA036612)

  • Thomas S Hnasko

National Institutes of Health (R01NS106822)

  • Thomas S Hnasko

National Institutes of Health (T01BX003759)

  • Thomas S Hnasko

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments were approved by the Institutional Animal Care and Use Committees of the University of California San Diego and experiments were conducted according to NIH guidelines.

Reviewing Editor

  1. Laura A Bradfield, University of Technology Sydney, Australia

Publication history

  1. Received: January 29, 2021
  2. Accepted: March 16, 2021
  3. Accepted Manuscript published: March 17, 2021 (version 1)
  4. Version of Record published: April 1, 2021 (version 2)

Copyright

© 2021, Renteria 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

  • 986
    Page views
  • 123
    Downloads
  • 3
    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. Rafael Renteria
  2. Christian Cazares
  3. Emily T Baltz
  4. Drew C Schreiner
  5. Ege A Yalcinbas
  6. Thomas Steinkellner
  7. Thomas S Hnasko
  8. Christina M Gremel
(2021)
Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure
eLife 10:e67065.
https://doi.org/10.7554/eLife.67065

Further reading

    1. Neuroscience
    Guy Avraham, Jordan A Taylor ... Samuel David McDougle
    Research Article

    Traditional associative learning tasks focus on the formation of associations between salient events and arbitrary stimuli that predict those events. This is exemplified in cerebellar-dependent delay eyeblink conditioning, where arbitrary cues such as a light or tone act as conditioning stimuli (CSs) that predict aversive sensations at the cornea (unconditioned stimulus, US). Here we ask if a similar framework could be applied to another type of cerebellar-dependent sensorimotor learning – sensorimotor adaptation. Models of sensorimotor adaptation posit that the introduction of an environmental perturbation results in an error signal that is used to update an internal model of a sensorimotor map for motor planning. Here we take a step towards an integrative account of these two forms of cerebellar-dependent learning, examining the relevance of core concepts from associative learning for sensorimotor adaptation. Using a visuomotor adaptation reaching task, we paired movement-related feedback (US) with neutral auditory or visual contextual cues that served as conditioning stimuli (CSs). Trial-by-trial changes in feedforward movement kinematics exhibited three key signatures of associative learning: Differential conditioning, sensitivity to the CS-US interval, and compound conditioning. Moreover, after compound conditioning, a robust negative correlation was observed between responses to the two elemental CSs of the compound (i.e., overshadowing), consistent with the additivity principle posited by theories of associative learning. The existence of associative learning effects in sensorimotor adaptation provides a proof-of-concept for linking cerebellar-dependent learning paradigms within a common theoretical framework.

    1. Neuroscience
    Yu-Chi Chen, Aurina Arnatkevičiūtė ... Kevin M Aquino
    Research Article

    Asymmetries of the cerebral cortex are found across diverse phyla and are particularly pronounced in humans, with important implications for brain function and disease. However, many prior studies have confounded asymmetries due to size with those due to shape. Here, we introduce a novel approach to characterize asymmetries of the whole cortical shape, independent of size, across different spatial frequencies using magnetic resonance imaging data in three independent datasets. We find that cortical shape asymmetry is highly individualized and robust, akin to a cortical fingerprint, and identifies individuals more accurately than size-based descriptors, such as cortical thickness and surface area, or measures of inter-regional functional coupling of brain activity. Individual identifiability is optimal at coarse spatial scales (~37 mm wavelength), and shape asymmetries show scale-specific associations with sex and cognition, but not handedness. While unihemispheric cortical shape shows significant heritability at coarse scales (~65 mm wavelength), shape asymmetries are determined primarily by subject-specific environmental effects. Thus, coarse-scale shape asymmetries are highly personalized, sexually dimorphic, linked to individual differences in cognition, and are primarily driven by stochastic environmental influences.