A dopamine-induced gene expression signature regulates neuronal function and cocaine response

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Abstract

Single-nucleus RNA-seq reveals a dynamic and cell-specific gene program in striatal neurons that contributes to cocaine response.

Abstract

Drugs of abuse elevate dopamine levels in the nucleus accumbens (NAc) and alter transcriptional programs believed to promote long-lasting synaptic and behavioral adaptations. Here, we leveraged single-nucleus RNA-sequencing to generate a comprehensive molecular atlas of cell subtypes in the NAc, defining both sex-specific and cell type–specific responses to acute cocaine experience in a rat model system. Using this transcriptional map, we identified an immediate early gene expression program that is up-regulated following cocaine experience in vivo and dopamine receptor activation in vitro. Multiplexed induction of this gene program with a large-scale CRISPR-dCas9 activation strategy initiated a secondary synapse-centric transcriptional profile, altered striatal physiology in vitro, and enhanced cocaine sensitization in vivo. Together, these results define the transcriptional response to cocaine with cellular precision and demonstrate that drug-responsive gene programs can potentiate both physiological and behavioral adaptations to drugs of abuse.

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Most cited references 49

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Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

G Di Chiara, A. Imperato (1988)

The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.

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Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol.

Jesus Bertran-Gonzalez, Clémentine Bosch, Matthieu Maroteaux … (2008)

Psychostimulants and other drugs of abuse activate extracellular signal-regulated kinase (ERK) in the striatum, through combined stimulation of dopamine D(1) receptors (D1Rs) and glutamate NMDA receptors. Antipsychotic drugs activate similar signaling proteins in the striatum by blocking dopamine D(2) receptors (D2Rs). However, the neurons in which these pathways are activated by psychotropic drugs are not precisely identified. We used transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter (drd1a-EGFP) or D2R promoter (drd2-EGFP). We confirmed the expression of drd1a-EGFP in striatonigral and drd2-EGFP in striatopallidal neurons. Drd2-EGFP was also expressed in cholinergic interneurons, whereas no expression of either promoter was detected in GABAergic interneurons. Acute cocaine treatment increased phosphorylation of ERK and its direct or indirect nuclear targets, mitogen- and stress-activated kinase-1 (MSK1) and histone H3, exclusively in D1R-expressing output neurons in the dorsal striatum and nucleus accumbens. Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing neurons but was also observed in D2R-expressing neurons. One week after repeated cocaine administration, cocaine-induced signaling responses were decreased, with the exception of enhanced ERK phosphorylation in dorsal striatum. The responses remained confined to D1R neurons. In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons. Our results demonstrate that cocaine and haloperidol specifically activate signaling pathways in two completely segregated populations of striatal output neurons, providing direct evidence for the selective mechanisms by which these drugs exert their long-term effects.

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Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens.

Alexander Day, M Wightman, Mitchell F. Roitman … (2007)

The ability to predict favorable outcomes using environmental cues is an essential part of learned behavior. Dopamine neurons in the midbrain encode such stimulus-reward relationships in a manner consistent with contemporary learning models, but it is unclear how encoding this translates into actual dopamine release in target regions. Here, we sampled dopamine levels in the rat nucleus accumbens on a rapid (100 ms) timescale using electrochemical technology during a classical conditioning procedure. Early in conditioning, transient dopamine-release events signaled a primary reward, but not predictive cues. After repeated cue-reward pairings, dopamine signals shifted in time to predictive cue onset and were no longer observed at reward delivery. In the absence of stimulus-reward conditioning, there was no shift in the dopamine signal. Consistent with proposed roles in reward prediction and incentive salience, these results indicate that rapid dopamine release provides a reward signal that is dynamically modified by associative learning.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: June 2020

Publication date (Electronic): 24 June 2020

Volume: 6

Issue: 26

Electronic Location Identifier: eaba4221

Affiliations

[1 ]Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

[2 ]Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Author notes

[*]

These authors contributed equally to this work.

[†]

Present address: Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD 21224, USA.

[‡ ]Corresponding author. Email: jjday@ 123456uab.edu

Author information

Katherine E. Savell http://orcid.org/0000-0001-8811-8254

Jennifer J. Tuscher http://orcid.org/0000-0002-8798-4545

Morgan E. Zipperly http://orcid.org/0000-0003-1838-2900

Corey G. Duke http://orcid.org/0000-0003-1102-9549

Robert A. Phillips III http://orcid.org/0000-0003-3560-4747

Faraz A. Sultan http://orcid.org/0000-0001-5999-2700

Jeremy J. Day http://orcid.org/0000-0002-7361-3399

Article

Publisher ID: aba4221

DOI: 10.1126/sciadv.aba4221

PMC ID: 7314536

PubMed ID: 32637607

SO-VID: 5594e34f-afeb-465b-8e21-2bc5a88f9dcd

Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 02 December 2019

Date accepted : 08 May 2020

Funding

Funded by: doi http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;

Award ID: MH114990

Funded by: doi http://dx.doi.org/10.13039/100000026, National Institute on Drug Abuse;

Award ID: DA039650

Funded by: doi http://dx.doi.org/10.13039/100000026, National Institute on Drug Abuse;

Award ID: DA034681

Funded by: doi http://dx.doi.org/10.13039/100000026, National Institute on Drug Abuse;

Award ID: DA042514

Funded by: doi http://dx.doi.org/10.13039/100000026, National Institute on Drug Abuse;

Award ID: DA041778

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A dopamine-induced gene expression signature regulates neuronal function and cocaine response

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Neuronal Signaling

Most cited references 49

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol.

Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens.

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