Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum
Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum
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DOI：
10.1016/j.neuron.2005.09.023
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发表时间：
2005-10-20
期刊：
影响因子：
16.2
通讯作者：
Nestler, EJ
中科院分区：
文献类型：
--
作者：
Kumar, A;Choi, KH;Nestler, EJ
鉴于可卡因通过调控基因表达诱导神经适应性，我们研究了特定基因启动子的染色质重塑是否可能是一个关键机制。我们发现可卡因在纹状体的不同基因启动子上诱导特异性组蛋白修饰，纹状体是可卡因行为影响的主要神经基质。在cFos启动子处，单次可卡因注射后30分钟内可观察到H4超乙酰化，而慢性可卡因未观察到组蛋白修饰，这与可卡因急性而非慢性诱导cFos的能力一致。相比之下，在BDNF和Cdk5启动子（由慢性而非急性可卡因诱导的基因）上，仅在慢性可卡因中观察到H3超乙酰化。Delta FosB，一种可卡因诱导的转录因子，似乎介导了Cdk5基因的这种调节。此外，调节组蛋白去乙酰化酶活性会改变对可卡因的运动和奖励反应。因此，染色质重塑是可卡因诱导的神经和行为可塑性的重要调控机制。
Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striaturn, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. Delta FosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.