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Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels

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...

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Autores principales: Martyniuk, Kelly M, Torres-Herraez, Arturo, Lowes, Daniel C, Rubinstein, Marcelo, Labouesse, Marie A, Kellendonk, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363114/
https://www.ncbi.nlm.nih.gov/pubmed/35856493
http://dx.doi.org/10.7554/eLife.76111
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author Martyniuk, Kelly M
Torres-Herraez, Arturo
Lowes, Daniel C
Rubinstein, Marcelo
Labouesse, Marie A
Kellendonk, Christoph
author_facet Martyniuk, Kelly M
Torres-Herraez, Arturo
Lowes, Daniel C
Rubinstein, Marcelo
Labouesse, Marie A
Kellendonk, Christoph
author_sort Martyniuk, Kelly M
collection PubMed
description 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 DA D2 receptors (D2Rs) 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 cue-evoked ACh levels is not associated with altered cue-evoked DA release. 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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spelling pubmed-93631142022-08-10 Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels Martyniuk, Kelly M Torres-Herraez, Arturo Lowes, Daniel C Rubinstein, Marcelo Labouesse, Marie A Kellendonk, Christoph eLife Neuroscience 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 DA D2 receptors (D2Rs) 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 cue-evoked ACh levels is not associated with altered cue-evoked DA release. 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. eLife Sciences Publications, Ltd 2022-07-20 /pmc/articles/PMC9363114/ /pubmed/35856493 http://dx.doi.org/10.7554/eLife.76111 Text en © 2022, Martyniuk et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Martyniuk, Kelly M
Torres-Herraez, Arturo
Lowes, Daniel C
Rubinstein, Marcelo
Labouesse, Marie A
Kellendonk, Christoph
Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
title Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
title_full Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
title_fullStr Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
title_full_unstemmed Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
title_short Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels
title_sort dopamine d2rs coordinate cue-evoked changes in striatal acetylcholine levels
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363114/
https://www.ncbi.nlm.nih.gov/pubmed/35856493
http://dx.doi.org/10.7554/eLife.76111
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