CREST: the calcium-responsive transcriptional activator that links key epigenetic mechanisms underlying cocaine-associated memories

项目总结/摘要 成瘾研究的一个主要目标是了解成瘾的神经解剖学和分子机制， 药物成瘾的发生和持续的基础变化，以及药物成瘾的明显倾向， 在瘾君子中观察到的复发。持久性背后的一个强大机制可能是 表观遗传学表观遗传学（即通过改变染色质发生的基因表达调节 DNA序列本身没有根本变化的结构）已被证明可以建立稳定的 细胞功能的变化。细胞功能的这些持续变化可以引起细胞膜上的显著变化。 突触、分子和行为水平。目前，我们对表观遗传学仍然知之甚少。 机制，可以建立持久性特征的药物寻求行为。一个地方到 开始是获得对表观遗传机制的理解，这些机制是药物与 具体线索的虐待。作为一种神经精神疾病，成瘾的部分特征是 药物暴露的背景线索与药物的奖励性质之间存在强烈关联。 这些线索已被证明是寻求药物行为的强大驱动力，即使在一年后- 长达数十年的戒毒期在长期记忆中，这些药物的持续性 关联和随之而来的药物寻求行为涉及改变基因表达。神经元 特异性核小体重构nBAF（neuronal Brg 1-Associated Factor）复合物是一种重要的调节因子 长期记忆形成和突触可塑性的持久形式所需的转录。一 nBAF复合物的潜在关键亚基是钙应答反式激活因子（CREST）。CREST是一个 令人兴奋的亚基研究，因为它有能力整合可卡因诱导的钙信号， 复杂的表观遗传机制来调节可卡因长期后果所需的基因表达 行动上到目前为止，还不知道CREST在可卡因作用中的作用。目标1的重点是 确定CREST在可卡因作用中的作用。目标2提出测试CREST在可卡因中的作用- 诱导神经元可塑性。最后，在目标3中，我们将探讨CREST影响的机制。 使用下一代测序方法（包括RNA-seq和 ChIP-seq）。从这些实验中获得的结果将阐明CREST在可卡因中的作用。 相关记忆了解CREST如何有助于增强药物相关记忆可能有助于 在开发治疗方法，可以用来帮助打击药物滥用， 问题

Project Summary/Abstract A major goal of addiction research is to gain an understanding of the neuroanatomical and molecular changes that underlie the onset and persistence of drug addiction, as well as the pronounced propensity for relapse observed in addicts. One powerful mechanism that may underlie aspects of persistence is epigenetics. Epigenetics (i.e. modulation of gene expression that occurs through altered chromatin structure without fundamental changes to the DNA sequence itself) has been shown to establish stable changes in cell function. These persistent changes in cell function can give rise to significant changes at the synaptic, molecular, and behavioral level. Currently, we still know very little about the epigenetic mechanisms that could establish the persistence characteristic of drug-seeking behavior. One place to begin is to gain an understanding of the epigenetic mechanisms that underlie the association of drugs of abuse with specific cues. As a neuropsychiatric disease, addiction can be partially characterized by the strong association between the contextual cues of drug exposures and the rewarding properties of the drug. These cues have been shown to be strong drivers of drug-seeking behavior, even following year- to decades-long periods of abstinence from drug use. As in long-term memory, the persistence of these drug associations and the consequent drug-seeking behavior involve altered gene expression. The neuron specific nucleosome remodeling nBAF (neuronal Brg1-Associated Factor) complex is an important regulator of transcription required for long-term memory formation and long-lasting forms of synaptic plasticity. A potentially key subunit of the nBAF complex is Calcium-RESponsive Transactivator (CREST). CREST is an exciting subunit to study because it has the ability to integrate cocaine-induced calcium signaling with complex epigenetic machinery to regulate gene expression required for long-term consequences of cocaine action. To date, there is nothing known about the role of CREST in cocaine action. The focus of Aim 1 is to determine the role of CREST in cocaine action. Aim 2 proposes to test the role of CREST in cocaine- induced neuronal plasticity. Finally, in Aim 3, we will explore the mechanism by which CREST affects cocaine-associated memory formation using next-generation sequencing methods (including RNA-seq and ChIP-seq). The results obtained from these experiments will elucidate the role of CREST in cocaine- associated memories. Understanding how CREST contributes to robust drug-associated memories may aid in the development of therapeutic treatments that could be leveraged to help combat substance abuse problems.