Dynamic Expression Changes in the Transcriptome of the Prefrontal Cortex after Repeated Exposure to Cocaine in Mice

Li, Mingzhen; Xu, Ping; Xu, Yanhua; Teng, Huajing; Tian, Wei; Du, Quansheng; Zhao, Mei

doi:10.3389/fphar.2017.00142

Cited by 17 publications

(32 citation statements)

References 46 publications

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“…Recent evidence shows histone lysine demethylase, KDM6B, is significantly increased during cocaine withdrawal in the mPFC (Li et al , 2017; Sadakierska-Chudy et al , 2017); however, the mechanisms involved in this change are unknown. KDM6B, also known as one of the JmjC domain-containing proteins (JMJD3), catalyzes the removal of methyl marks from histone 3 at lysine 27 (H3K27).…”

Section: Introductionmentioning

confidence: 99%

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

et al. 2018

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Epigenetic remodeling contributes to synaptic plasticity via modification of gene expression, which underlies cocaine-induced long-term memory. A prevailing hypothesis in drug addiction is that drugs of abuse rejuvenate developmental machinery to render reward circuitry highly plastic and thus engender drug memories to be highly stable. Identification and reversal of these pathological pathways are therefore critical for cocaine abuse treatment. Previous studies revealed an interesting finding in which the mRNA of histone lysine demethylase, KDM6B, is upregulated in the medial prefrontal cortex (mPFC) during early cocaine withdrawal. However, whether and how it contributes to drug-seeking behavior remain unknown. Here we used a conditioned place preference paradigm to investigate the potential role of KDM6B in drug-associated memory. We found that KDM6B protein levels selectively increased in the mPFC during cocaine withdrawal. Notably, systemic injection of KDM6B inhibitor, GSK-J4, disrupted both reconsolidation of cocaine-conditioned memory and cocaine-primed reinstatement, suggesting dual effects of KDM6B in cocaine reward memory. In addition, we found that NMDAR expression and function were both enhanced during early cocaine withdrawal in mPFC. Injection of GSK-J4 selectively reversed this cocaine-induced increase of NR2A expression and synaptic function, suggesting that mal-adaptation of cocaine-induced synaptic plasticity in mPFC largely underlies KDM6B-mediated cocaine-associated memory. Altogether, these data suggest that KDM6B plays an essential role in cocaine-associated memory, which mainly acts through enhancing cocaine-induced synaptic plasticity in the mPFC. Our findings revealed a novel role of KDM6B in cocaine-associated memory and inhibition of KDM6B is a potential strategy to alleviate drug-seeking behavior.

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Section: Introductionmentioning

confidence: 99%

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

et al. 2018

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“…RNASeq studies can provide an overwhelming amount of transcriptomic data; however, integrating the results from different studies has been difficult. For example, RNASeq analyses performed 2 hours, 24 hours, and 7 days after cocaine exposure yielded profoundly different results [72]. Differences in the depth of sequencing analysis and the completeness of the reporting of the sequencing data have made comparisons even more challenging.…”

Section: Discussionmentioning

confidence: 99%

“…Nine studies report RNASeq data for the nucleus accumbens, striatum, or prefrontal cortex of mice [13, 19, 23, 26, 72–75] or monkeys [76]; however, not all had been treated with psychostimulants. The number of differentially expressed transcripts varied widely, with 4513 identified in cocaine-treated mice [74] and 328 identified in monkeys [76].…”

Section: Discussionmentioning

confidence: 99%

“…The number of differentially expressed transcripts varied widely, with 4513 identified in cocaine-treated mice [74] and 328 identified in monkeys [76]. Although self-administration [19, 26, 76] is more like the human situation, the more common experimenter-administered approach [13, 23, 72, 74, 75] allows for analysis of more animals, a key to the reliable detection of reproducible differences. The drug dosages have also varied, as have the times of administration (7 to 100 days) and withdrawal (2 hours to 30 days).…”

Section: Discussionmentioning

confidence: 99%

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Sex-Specific Gene Expression in the Mouse Nucleus Accumbens Before and After Cocaine Exposure

LaRese

Rheaume

Abraham

et al. 2019

Journal of the Endocrine Society

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The nucleus accumbens plays a major role in the response of mammals to cocaine. In animal models and human studies, the addictive effects of cocaine and relapse probability have been shown to be greater in females. Sex-specific differential expression of key transcripts at baseline and after prolonged withdrawal could underlie these differences. To distinguish between these possibilities, gene expression was analyzed in four groups of mice (cycling females, ovariectomized females treated with estradiol or placebo, and males) 28 days after they had received seven daily injections of saline or cocaine. As expected, sensitization to the locomotor effects of cocaine was most pronounced in the ovariectomized mice receiving estradiol, was greater in cycling females than in males, and failed to occur in ovariectomized/placebo mice. After the 28-day withdrawal period, RNA prepared from the nucleus accumbens of the individual cocaine- or saline-injected mice was subjected to RNA sequencing analysis. Baseline expression of 3% of the nucleus accumbens transcripts differed in the cycling female mice compared with the male mice. Expression of a similar number of transcripts was altered by ovariectomy or was responsive to estradiol treatment. Nucleus accumbens transcripts differentially expressed in cycling female mice withdrawn from cocaine exhibited substantial overlap with those differentially expressed in cocaine-withdrawn male mice. A small set of transcripts were similarly affected by cocaine in the placebo- or estradiol-treated ovariectomized mice. Sex and hormonal status have profound effects on RNA expression in the nucleus accumbens of naive mice. Prolonged withdrawal from cocaine alters the expression of a much smaller number of common and sex hormone-specific transcripts.

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“…The MAPK signaling cascade involves the activation of extracellular signal-regulated kinases-1 and -2 (ERK1 and ERK2) and is known to play an important role in the control of synaptic plasticity in the adult brain ( Thomas and Huganir, 2004 ). In fact, MAPK/ERK signaling contributes to various behavioral effects of cocaine, such as psychomotor sensitization, conditioned place preference, and reconsolidation of memories for cocaine cues ( Lu et al, 2004 , 2005 , 2006 ) ( Radwanska et al, 2005 ). Our previous study also demonstrated that cocaine treatment induced long-lasting changes of the ERK signaling pathway in the PFC ( Li et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Sequencing Reveals Candidate NF-κB Target Genes Involved in Repeated Cocaine Administration

Wang

Teng

Sapozhnikov

et al. 2018

International Journal of Neuropsychopharmacology

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BackgroundDrug-induced alterations in gene expression play an important role in the development of addictive behavior. Numerous transcription factors have been implicated in mediating the gene expression changes that occur in drug addiction. Nuclear factor kappa B is an inducible transcription factor complex that is rapidly activated by diverse stimuli.MethodsWe performed next-generation high-throughput sequencing of the prefrontal cortex in a mouse model of repeated cocaine administration combined with pharmacological nuclear factor kappa B inhibition to identify nuclear factor kappa B target genes that participate in the cocaine addiction process.ResultsWe found that the nuclear factor kappa B antagonist sodium diethyldithiocarbamate trihydrate significantly reversed the cocaine-induced expression changes of the amphetamine addiction pathway. Genes that demonstrated differential expression in response to cocaine treatment that was also reversed by sodium diethyldithiocarbamate trihydrate were enriched for the axon guidance pathway. Furthermore, the nuclear factor kappa B homo-dimer motif could be mapped to 86 of these sodium diethyldithiocarbamate trihydrate-reversed genes, which were also enriched for axon guidance.ConclusionsWe suggest that nuclear factor kappa B directly modifies the expression of axon guidance pathway members, leading to cocaine sensitization. Our findings reveal the role of prefrontal cortex nuclear factor kappa B activity in addiction and uncover the molecular mechanisms by which nuclear factor kappa B drives changes in the addicted brain.

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Dynamic Expression Changes in the Transcriptome of the Prefrontal Cortex after Repeated Exposure to Cocaine in Mice

Cited by 17 publications

References 46 publications

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

Sex-Specific Gene Expression in the Mouse Nucleus Accumbens Before and After Cocaine Exposure

Transcriptome Sequencing Reveals Candidate NF-κB Target Genes Involved in Repeated Cocaine Administration

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