Circuit and epigenetic mechanisms underlying incubation of methamphetamine craving

甲基苯丙胺渴望潜藏的回路和表观遗传机制

• 批准号: 9751825
• 负责人: Xuan Anna Li
• 金额: $ 24.9万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751825
• 关键词: Abstinence; Amygdaloid structure; Area; Binding; Bioinformatics; Brain; ChIP-seq; Cholera Toxin Protomer B; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Cocaine; Corpus striatum structure; Cues; Data; Data Analyses; Development; Dopamine; Dorsal; Drug Addiction; Drug usage; Environment; Enzymes; Epigenetic Process; Exposure to; Family; Future; Gene Targeting; Genomics; Grant; HDAC5 gene; Heroin; Human; Incubated; Institution; Knock-out; Knowledge; Mediating; Mentors; Mentorship; Methamphetamine; Methamphetamine dependence; Methods; Modeling; Neurons; Pharmaceutical Preparations; Phase; Play; Prefrontal Cortex; Protocols documentation; RNA; Rattus; Recording of previous events; Relapse; Research Personnel; Research Proposals; Role; Self Administration; Substantia nigra structure; System; Techniques; Technology; Testing; Thalamic structure; Tracer; Training; Training Support; Transcript; Transcriptional Regulation; Viral; Withdrawal; activity marker; base; brain tissue; career; craving; designer receptors exclusively activated by designer drugs; disorder later incidence prevention; drug craving; drug relapse; drug withdrawal; insight; methamphetamine user; neuromechanism; novel; novel strategies; nuclease; overexpression; professor; receptor; tenure track; therapeutic target; transcriptome sequencing

Cue-induced drug craving progressively increases after withdrawal, a phenomenon termed ‘incubation of drug craving’. During the last decade, mechanistic studies have primarily focused on incubation of cocaine craving. In contrast, very few studies have examined the mechanisms underlying incubation of methamphetamine (Meth) craving. Here, I propose to study circuit and epigenetic mechanisms underlying incubation of Meth craving with a focus on the dorsal striatum (DS) region. The choice of this brain area is based on my preliminary data implicating a critical role of DS neuronal activity and a potential role of DS histone deacetylase 5 (HDAC5, an epigenetic-related enzyme) in incubation of Meth craving. At the circuit level, I will use a retrograde tracing technique (CTb, cholera toxin subunit B) in combination with the neuronal activity marker Fos to identify critical afferent projections to the DS that are activated during incubation of Meth craving. Next, I will use a novel retro-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) method to study the causal role of afferent projections to the DS in incubation of Meth craving. At the epigenetic level, I will combine chromatin immunoprecipitation-sequencing (ChIP-seq) with RNA-sequencing (RNA-seq) to identify downstream gene targets of HDAC5 in DS whose expression is altered after prolonged withdrawal (1 month) from Meth self-administration. I will also use the CRISPR-Cas9 system to examine the causal role of DS HDAC5 in incubation of Meth craving. My proposal will provide new insights on the mechanisms underlying Meth craving and relapse. Additionally, under the mentorship of Drs. Shaham, Nestler, and Cowan the proposal will provide me with an ideal training environment to prepare me for a future independent career as a researcher in an academic setting who explores basic mechanisms of drug addiction.

线索诱导的药物渴求在戒断后逐渐增加，这种现象被称为“潜伏期”