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

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.

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.

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.

Metrics

  • 5,319
    views
  • 659
    downloads
  • 47
    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. 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

Further reading

    1. Neuroscience
    2. Physics of Living Systems
    Moritz Schloetter, Georg U Maret, Christoph J Kleineidam
    Research Article

    Neurons generate and propagate electrical pulses called action potentials which annihilate on arrival at the axon terminal. We measure the extracellular electric field generated by propagating and annihilating action potentials and find that on annihilation, action potentials expel a local discharge. The discharge at the axon terminal generates an inhomogeneous electric field that immediately influences target neurons and thus provokes ephaptic coupling. Our measurements are quantitatively verified by a powerful analytical model which reveals excitation and inhibition in target neurons, depending on position and morphology of the source-target arrangement. Our model is in full agreement with experimental findings on ephaptic coupling at the well-studied Basket cell-Purkinje cell synapse. It is able to predict ephaptic coupling for any other synaptic geometry as illustrated by a few examples.

    1. Neuroscience
    Sven Ohl, Martin Rolfs
    Research Article

    Detecting causal relations structures our perception of events in the world. Here, we determined for visual interactions whether generalized (i.e. feature-invariant) or specialized (i.e. feature-selective) visual routines underlie the perception of causality. To this end, we applied a visual adaptation protocol to assess the adaptability of specific features in classical launching events of simple geometric shapes. We asked observers to report whether they observed a launch or a pass in ambiguous test events (i.e. the overlap between two discs varied from trial to trial). After prolonged exposure to causal launch events (the adaptor) defined by a particular set of features (i.e. a particular motion direction, motion speed, or feature conjunction), observers were less likely to see causal launches in subsequent ambiguous test events than before adaptation. Crucially, adaptation was contingent on the causal impression in launches as demonstrated by a lack of adaptation in non-causal control events. We assessed whether this negative aftereffect transfers to test events with a new set of feature values that were not presented during adaptation. Processing in specialized (as opposed to generalized) visual routines predicts that the transfer of visual adaptation depends on the feature similarity of the adaptor and the test event. We show that the negative aftereffects do not transfer to unadapted launch directions but do transfer to launch events of different speeds. Finally, we used colored discs to assign distinct feature-based identities to the launching and the launched stimulus. We found that the adaptation transferred across colors if the test event had the same motion direction as the adaptor. In summary, visual adaptation allowed us to carve out a visual feature space underlying the perception of causality and revealed specialized visual routines that are tuned to a launch’s motion direction.