Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
- University of California, San Diego, United States
- Columbia University, United States
- Universidad de Buenos Aires, Argentina
Abstract
In the striatum, acetylcholine (ACh) neuron activity is modulated co-incident with dopamine (DA) release in response to unpredicted rewards and reward predicting cues and both neuromodulators are thought to regulate each other. While this co-regulation has been studied using stimulation studies, the existence of this mutual regulation in vivo during natural behavior is still largely unexplored. One long-standing controversy has been whether striatal DA is responsible for the induction of the cholinergic pause or whether D2R modulate a pause that is induced by other mechanisms. Here, we used genetically encoded sensors in combination with pharmacological and genetic inactivation of D2Rs from cholinergic interneurons (CINs) to simultaneously measure ACh and DA levels after CIN D2R inactivation in mice. We found that CIN D2Rs are not necessary for the initiation of cue induced decrease in ACh levels. Rather, they prolong the duration of the decrease and inhibit ACh rebound levels. Notably, the change in task evoked ACh levels is not associated with altered DA levels. Moreover, D2R inactivation strongly decreased the temporal correlation between DA and ACh signals not only at cue presentation but also during the intertrial interval pointing to a general mechanism by which D2Rs coordinate both signals. At the behavioral level D2R antagonism increased the latency to lever press, which was not observed in CIN-selective D2R knock out mice. Press latency correlated with the cue evoked decrease in ACh levels and artificial inhibition of CINs revealed that longer inhibition shortens the latency to press compared to shorter inhibition. This supports a role of the ACh signal and it’s regulation by D2Rs in the motivation to initiate actions.
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All data generated or analyzed during this study are included in the manuscript
Article and author information
Author details
Marie Anais Labouesse
Christoph Kellendonk
Funding
National Institute of Neurological Disorders and Stroke (F99/K00 D-SPAN NS120642)
- Kelly M Martyniuk
National Institute of Mental Health (R01MH124858)
- Christoph Kellendonk
National Institute of Mental Health (R01MH093672)
- Christoph Kellendonk
European Molecular Biology Organization (Individual Fellowship)
- Arturo Torres-Herraez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental procedures were conducted following NIH guidelines and were approved by Institutional Animal Care and Use Committees by Columbia University and the New York State Psychiatric Institute (NYSPI protocol #1621).
Copyright
© 2022, Martyniuk 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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Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
eLife 11:e76111.
https://doi.org/10.7554/eLife.76111
