1. Neuroscience

Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation

  1. Ali Mohebi
  2. Val L Collins
  3. Joshua D Berke  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.85011
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  1. Ali Mohebi
  2. Val L Collins
  3. Joshua D Berke
(2023)
Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation
eLife 12:e85011.
https://doi.org/10.7554/eLife.85011
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Abstract

Motivation to work for potential rewards is critically dependent on dopamine (DA) in the nucleus accumbens (NAc). DA release from NAc axons can be controlled by at least two distinct mechanisms: 1) action potentials propagating from DA cell bodies in the ventral tegmental area (VTA), and 2) activation of β2* nicotinic receptors by local cholinergic interneurons (CINs). How CIN activity contributes to NAc DA dynamics in behaving animals is not well understood. We monitored DA release in the NAc Core of awake, unrestrained rats using the DA sensor RdLight1, while simultaneously monitoring or manipulating CIN activity at the same location. CIN stimulation rapidly evoked DA release, and in contrast to slice preparations, this DA release showed no indication of short-term depression or receptor desensitization. The sound of unexpected food delivery evoked a brief joint increase in CIN population activity and DA release, with a second joint increase as rats approached the food. In an operant task, we observed fast ramps in CIN activity during approach behaviors, either to start the trial or to collect rewards. These CIN ramps co-occurred with DA release ramps, without corresponding changes in the firing of lateral VTA DA neurons. Finally, we examined the effects of blocking CIN influence over DA release through local NAc infusion of DHβE, a selective antagonist of β2* nicotinic receptors. DHβE dose-dependently interfered with motivated approach decisions, mimicking the effects of a DA antagonist. Our results support a key influence of CINs over motivated behavior via the local regulation of DA release.

Data availability

All data generated or analyzed during this study will be made publicly available at the time of publication on Dryad servers.

The following data sets were generated

Article and author information

Author details

  1. Ali Mohebi

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Val L Collins

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Joshua D Berke

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    For correspondence
    joshua.berke@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1436-6823

Funding

National Institute on Drug Abuse (R01DA045783)

  • Joshua D Berke

National Institute of Neurological Disorders and Stroke (R01NS123516)

  • Joshua D Berke

National Institute of Neurological Disorders and Stroke (R01NS116626)

  • Joshua D Berke

National Institute on Alcohol Abuse and Alcoholism (R21AA027157)

  • Joshua D Berke

National Institute of Mental Health (K01MH126223)

  • Ali Mohebi

Brain and Behavior Research Foundation (NARSAD YIA 29361)

  • Ali Mohebi

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

Reviewing Editor

  1. Joseph F Cheer, University of Maryland School of Medicine, United States

Ethics

Animal experimentation: In the conduct of this study, the animals involved were accommodated at the University of California San Francisco (UCSF) Animal Research Facility, which is accredited by AAALAC (#001084). The facility strictly adheres to institutional, federal, and AAALAC guidelines to ensure the highest standards of animal care. Procedures such as euthanasia for perfusion fixation were performed under profound anesthesia to minimize discomfort. The use of animals in this study was in strict compliance with the Public Health Service Policy on Humane Care and Use of Laboratory Animals. The UCSF Institutional Animal Care and Use Committee granted approval for this study (protocol # AN196232-01B). Furthermore, UCSF holds a PHS-approved Animal Welfare Assurance D16-00253/A3400-01, further affirming our commitment to ethical animal use.

Version history

  1. Preprint posted: November 6, 2022 (view preprint)
  2. Received: November 19, 2022
  3. Accepted: May 30, 2023
  4. Accepted Manuscript published: June 5, 2023 (version 1)
  5. Version of Record published: June 12, 2023 (version 2)

Copyright

© 2023, Mohebi 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.

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  1. Ali Mohebi
  2. Val L Collins
  3. Joshua D Berke
(2023)
Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation
eLife 12:e85011.
https://doi.org/10.7554/eLife.85011

Share this article

https://doi.org/10.7554/eLife.85011

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    Acetylcholine is widely believed to modulate the release of dopamine in the striatum of mammals. Experiments in brain slices clearly show that synchronous activation of striatal cholinergic interneurons is sufficient to drive dopamine release via axo-axonal stimulation of nicotinic acetylcholine receptors. However, evidence for this mechanism in vivo has been less forthcoming. Mohebi, Collins and Berke recently reported that, in awake behaving rats, optogenetic activation of striatal cholinergic interneurons with blue light readily evokes dopamine release measured with the red fluorescent sensor RdLight1 (Mohebi et al., 2023). Here, we show that blue light alone alters the fluorescent properties of RdLight1 in a manner that may be misconstrued as phasic dopamine release, and that this artefactual photoactivation can account for the effects attributed to cholinergic interneurons. Our findings indicate that measurements of dopamine using the red-shifted fluorescent sensor RdLight1 should be interpreted with caution when combined with optogenetics. In light of this and other publications that did not observe large acetylcholine-evoked dopamine transients in vivo, the conditions under which such release occurs in behaving animals remain unknown.

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