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

CREST：钙反应性转录激活剂，连接可卡因相关记忆的关键表观遗传机制

• 批准号: 9397360
• 负责人: Yasaman Alaghband
• 金额: $ 6.1万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397360
• 关键词: Abstinence; Acute; Affect; Behavior; Behavioral; Calcium; Calcium Signaling; Cell physiology; ChIP-seq; Characteristics; Chromatin Structure; Chronic; Cocaine; Complex; Cues; DNA Sequence; Data; Dependovirus; Disease; Drug Addiction; Drug Exposure; Drug usage; Epigenetic Process; Event; FOS gene; Foundations; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic Transcription; Goals; Impairment; Infusion procedures; Intravenous; Lead; Link; Long-Term Depression; Long-Term Potentiation; Memory; Methods; Modeling; Modification; Molecular; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Nucleosomes; Nucleus Accumbens; Pharmaceutical Preparations; Phase; Physical Dependence; Physiology; Property; Relapse; Research; Rewards; Role; Self Administration; Small Interfering RNA; Substance abuse problem; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Time; Trans-Activators; Transcription Coactivator; Transcriptional Regulation; addiction; cocaine exposure; cocaine use; combat; conditioning; craving; drug abstinence; drug maintenance; drug of abuse; drug seeking behavior; experimental study; genome-wide; histone modification; human disease; knock-down; long term memory; mutant; neuropsychiatric disorder; next generation sequencing; novel; preference; programs; therapeutic development; therapy development; training opportunity; transcriptome sequencing

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.

项目总结/文摘