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
基本信息
- 批准号:9751825
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AbstinenceAmygdaloid structureAreaBindingBioinformaticsBrainChIP-seqCholera Toxin Protomer BChromatinClustered Regularly Interspaced Short Palindromic RepeatsCocaineCorpus striatum structureCuesDataData AnalysesDevelopmentDopamineDorsalDrug AddictionDrug usageEnvironmentEnzymesEpigenetic ProcessExposure toFamilyFutureGene TargetingGenomicsGrantHDAC5 geneHeroinHumanIncubatedInstitutionKnock-outKnowledgeMediatingMentorsMentorshipMethamphetamineMethamphetamine dependenceMethodsModelingNeuronsPharmaceutical PreparationsPhasePlayPrefrontal CortexProtocols documentationRNARattusRecording of previous eventsRelapseResearch PersonnelResearch ProposalsRoleSelf AdministrationSubstantia nigra structureSystemTechniquesTechnologyTestingThalamic structureTracerTrainingTraining SupportTranscriptTranscriptional RegulationViralWithdrawalactivity markerbasebrain tissuecareercravingdesigner receptors exclusively activated by designer drugsdisorder later incidence preventiondrug cravingdrug relapsedrug withdrawalinsightmethamphetamine userneuromechanismnovelnovel strategiesnucleaseoverexpressionprofessorreceptortenure tracktherapeutic targettranscriptome sequencing
项目摘要
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.
戒断后,提示诱发的药物渴望逐渐增加,这种现象被称为“潜伏期”
毒瘾”。在过去的十年中,机制研究主要集中在可卡因的孵化上
渴望。相比之下,很少有研究探讨孵化的机制。
对甲基苯丙胺(Meth)的渴望。在这里,我建议研究潜在的电路和表观遗传机制
冰毒渴望的孵化,重点关注背侧纹状体(DS)区域。这个大脑区域的选择是基于
我的初步数据表明 DS 神经元活动的关键作用和 DS 组蛋白的潜在作用
脱乙酰酶 5(HDAC5,一种表观遗传相关酶)在冰毒渴望的孵化过程中。在电路层面,我将
使用逆行追踪技术(CTb,霍乱毒素 B 亚基)结合神经元活动
标记 Fos 来识别在冰毒渴望孵化期间激活的 DS 的关键传入投射。
接下来,我将使用一种新颖的retro-DREADD(Designer Receptors Exclusively Activated by Designer Drugs)方法来
研究对 DS 的传入投射在冰毒渴望孵化中的因果作用。在表观遗传层面,我会
将染色质免疫沉淀测序 (ChIP-seq) 与 RNA 测序 (RNA-seq) 相结合来鉴定
DS 中 HDAC5 的下游基因靶标,其表达在长期停药后(1 个月)发生改变
来自冰毒自我管理。我还将使用 CRISPR-Cas9 系统来检查 DS HDAC5 的因果作用
正在酝酿对冰毒的渴望。我的建议将为冰毒渴望的潜在机制提供新的见解
并复发。此外,在博士的指导下。 Shaham、Nestler 和 Cowan 该提案将提供
我拥有理想的培训环境,为我未来作为一名研究人员的独立职业做好准备
探索药物成瘾基本机制的学术环境。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Xuan Anna Li其他文献
Xuan Anna Li的其他文献
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{{ truncateString('Xuan Anna Li', 18)}}的其他基金
March5 and Associated Mitochondrial Dynamics in Incubation of Oxycodone Craving
March5 和相关线粒体动力学在羟考酮渴望孵化中的作用
- 批准号:
10724668 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:














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