Motivated cocaine seeking lead to transgenerational epigenetic inheritance of vulnerability to cocaine addiction
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE72401 | GEO | 2017/03/17
SECONDARY ACCESSION(S): PRJNA293970
REPOSITORIES: GEO
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Project description:A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaine’s rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2 MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.
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Project description:Maintenance of the drug-addicted state involves changes in gene expression in different neuronal cell types and neural circuits. Midbrain dopamine neurons in particular mediate numerous responses to drugs of abuse. Long noncoding RNAs (lncRNAs) regulate CNS gene expression through a variety of mechanisms, but very little is known about their role in drug abuse. The proportion of lncRNAs that are primate-specific provides a strong rationale for their study in human drug abusers. We examined the profile of lncRNA expression in postmortem human midbrain specimens from chronic cocaine abusers and well-matched control subjects (n=11 subject pairs) using a custom lncRNA microarray. Differential expression was validated by quantitative PCR, and cellular localization investigated by in situ hybridization histochemistry.A profile of lncRNAs significantly dysregulated in chronic cocaine abusers was determined. LncRNAs with dopamine cell-specific expression, differential subcellular distribution, covariance with protein-coding genes, and tissue-specific drug-responsiveness were identified. Dysregulation of midbrain lncRNA expression may reflect pathophysiological processes associated with chronic cocaine abuse. LncRNAs may be central mediators of cellular responses to drug abuse.
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