Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain’s Reward Circuitry

Walker, Deena M.; Cates, Hannah M.; Loh, Yong Hwee E.; Purushothaman, Immanuel; Ramakrishnan, Aarthi; Cahill, Kelly; Lardner, Casey K.; Godino, Arthur; Kronman, Hope; Rabkin, Jacqui; Lorsch, Zachary S.; Mews, Philipp; Doyle, Marie; Feng, Jian; Labonté, Benoit; Koo, Ja Wook; Bagot, Rosemary C.; Logan, Ryan W.; Seney, Marianne L.; Calipari, Erin S.; Shen, Li; Nestler, Eric J.

doi:10.1016/j.biopsych.2018.04.009

Cited by 137 publications

(205 citation statements)

References 56 publications

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“…Following chronic drug administration, druginduced dopaminergic signaling in the NAc is potentiated (46,47), providing multiple opportunities for induction of long-lasting changes in gene expression that are observed after repeated drug use (8,9,52). While a candidate gene approach has been critical in understanding some of the fundamental transcriptional changes following exposure to drugs of abuse, activity-dependent transcriptional events produce coordinated changes that may be distinct from isolated changes in expression of a single gene.…”

Section: Controlmentioning

confidence: 99%

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

Savell

Zipperly

Tuscher

et al. 2019

Preprint

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Drug addiction is a worldwide health problem, with overdose rates of both psychostimulants and opioids currently on the rise in many developed countries. Drugs of abuse elevate dopamine levels in the nucleus accumbens (NAc) and alter transcriptional programs believed to promote long-lasting synaptic and behavioral adaptations. However, even with well-studied drugs such as cocaine, druginduced transcriptional responses remain poorly understood due to the cellular heterogeneity of the NAc and complex drug actions via multiple neurotransmitter systems. Here, we leveraged highthroughput single-nucleus RNA-sequencing to create 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 specific neuronal subpopulations that are activated by cocaine, and defined an immediate early gene expression program that is upregulated following cocaine experience in vivo and dopamine (DA) receptor activation in vitro. To characterize the neuronal response to this DA-mediated gene expression signature, we engineered a large-scale CRISPR/dCas9 activation strategy to recreate this program. Multiplexed induction of this gene program initiated a secondary synapse-centric transcriptional profile, altered striatal physiology in vitro, and enhanced cocaine sensitization in vivo. Taken together, these results define the genome-wide transcriptional response to cocaine with cellular precision, and demonstrate that drug-responsive gene programs are sufficient to initiate both physiological and behavioral adaptations to drugs of abuse.NEARLY 5 MILLION Americans reported cocaine use in 2017, and recent increases in cocaine-related drug overdoses present significant public health challenges (1). A hallmark trait of drugs of abuse is the acute elevation of dopamine (DA) in the nucleus accumbens (NAc), a central integrator of the reward circuit (2-4). Abused drugs produce increases in DA that are greater in both concentration and duration than natural rewards (2,5,6), and this signaling is hypothesized to underlie maladaptive reinforcement after repeated drug use (7). Exposure to drugs of abuse results in significant transcriptional and epigenetic reorganization in the NAc (8-13), initiating synaptic and behavioral plasticity associated with the transition to drug addiction (7,14,15). However, even with well-studied drugs such as cocaine, drug-induced transcriptional responses remain poorly understood. This is in part due to the cellular heterogeneity of the NAc, which is a diverse structure containing multiple neuronal and non-neuronal subpopulations and complex neuronal circuitry. Additionally, many drugs of abuse engage multiple neurotransmitter systems in the NAc (16-22), and the specific contributions of DA-dependent transcriptional programs to neuronal physiology and behavior is not clear. Further, although drug experience leads to large scale transcriptional changes in the NAc, previou...

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Section: Controlmentioning

confidence: 99%

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

Savell

Zipperly

Tuscher

et al. 2019

Preprint

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“…Gene expression analyses in reward-related regions over time following drug exposure show mechanisms that underlie drug response, drug-seeking and drug-taking. 132,133 Differential gene expression analysis in the mouse nucleus accumbens before and after prolonged cocaine withdrawal have showed profound effects of sex and hormonal status in drug naïve states and fewer differentially expressed genes unique to each sex, post-cocaine exposure. 134 Sex-specific differences in the brain tissue transcriptome in drug-naive vs postdrug exposure states indicate genes that mediate sex differences in the initial response to cocaine administration and those involved in withdrawal.…”

Section: Sex Differences In Transcriptional Response To Drugsmentioning

confidence: 99%

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis

Datta

Schoenrock

Bubier

et al. 2020

Genes Brain and Behavior

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Despite substantial evidence for sex differences in addiction epidemiology, addiction‐relevant behaviors and associated neurobiological phenomena, the mechanisms and implications of these differences remain unknown. Genetic analysis in model organism is a potentially powerful and effective means of discovering the mechanisms that underlie sex differences in addiction. Human genetic studies are beginning to show precise risk variants that influence the mechanisms of addiction but typically lack sufficient power or neurobiological mechanistic access, particularly for the discovery of the mechanisms that underlie sex differences. Our thesis in this review is that genetic variation in model organisms are a promising approach that can complement these investigations to show the biological mechanisms that underlie sex differences in addiction.

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“…The work by Deena Walker and colleagues (3) provides a transcriptome-wide analysis of the molecular changes induced by cocaine self-administration as a function of withdrawal time and brain region, and specifically tests the short- and long-term withdrawal effects on cocaine self-administration. This analysis takes advantage of a rich dataset and signifies a bioinformatics tour-de-force.…”

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confidence: 99%

“…This is based on the hypothesis that overlapping expression changes in the brain may be key sites for therapeutic intervention. Their analysis identified the well-characterized addiction regulator CREB as a proof-of-principle example, as well as a number of nuclear receptors that have received limited attention for addiction-related disorders (3). These include peroxisome proliferator-activated receptors for which there are therapeutic agents that have shown some efficacy in preclinical addiction models (5), suggesting that this approach may aid in the discovery of new molecular targets.…”

mentioning

confidence: 99%

“…Walker et al (2018) examined transcriptome profiling after both short (24-hour) and long (30-day) abstinence from cocaine self-administration together with time-matched cocaine and saline treatments in the long abstinence group (3). The cocaine treatment would be expected to increase relapse-like behaviors, but no operant behavior was studied (levers were retracted) during withdrawal.…”

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confidence: 99%

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Persistence of Drug Memories: Melting Transcriptomes

Mayfield

Harris

2018

Biological Psychiatry

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Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain’s Reward Circuitry

Abstract: This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.

Cited by 137 publications

References 56 publications

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

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

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis

Persistence of Drug Memories: Melting Transcriptomes

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