Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation
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.
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Cholinergic Interneurons and Dopamine in the Nucleus AccumbensDryad Digital Repository, doi:10.7272/Q68P5XST.
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Author details
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.
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