Identifying the Distinct Intracellular Pathways That Mediate Dopamine-Driven Behaviors
确定介导多巴胺驱动行为的独特细胞内途径
基本信息
- 批准号:10477942
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAntipsychotic AgentsArrestinsAutomobile DrivingAutopsyBehaviorBehavioralBindingBiological AssayBrainBrain regionCategoriesCellsChronicClustered Regularly Interspaced Short Palindromic RepeatsCocaineCollaborationsComplexCorpus striatum structureDRD2 geneDataDevelopmentDiseaseDopamineDopamine ReceptorDopaminergic AgentsDrug abuseEngineeringExhibitsFoodFutureG-Protein-Coupled ReceptorsGTP-Binding ProteinsGene ExpressionGenesHumanInvestigationKnock-outKnockout MiceLearningLocationLocomotionMediatingMediator of activation proteinMolecularMotivationMusNR2B NMDA receptorNeuronsNeurotransmittersNuclearNucleus AccumbensPathologyPathway interactionsPharmaceutical PreparationsPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesProcessProtein Phosphatase 2A Regulatory Subunit PR53ProteinsRNA InterferenceReceptor ActivationRecording of previous eventsResearchRewardsRoleSignal PathwaySignal TransductionSignaling ProteinSurfaceTissuesTreatment EfficacyUp-RegulationWorkarrestin 2beta-arrestinbrain cellcell typecocaine exposurecocaine self-administrationconditioned place preferencedesigndifferential expressiondimerexperimental studyglycogen synthase kinase 3 betahuman subjectinsightnetwork modelsnovelpreferencepreventpsychostimulantputamenreceptorrecruitreward processingscaffoldside effectstimulant dependencestimulant exposuretranscriptometranscriptome sequencingtranscriptomicswillingness
项目摘要
PROJECT SUMMARY/ABSTRACT
Dopamine (DA), a neurotransmitter implicated in learning and motivation, is also a critical player in the
mechanisms of psychostimulant action and the pathology of drug abuse. Dopamine binds five receptors (D1-
D5R), of which D2R carries particular relevance, as it takes on various functional roles in different brain regions
and cells types and is a target of all antipsychotic medications. Dopamine receptors are G protein-coupled
receptors (GPCRs) that activate intracellular G proteins and their downstream signaling cascades. This signal
is terminated upon arrestin binding to the intracellular domain of the receptor. More recently, arrestins have
been found to initiate their own G protein-independent signaling cascades by scaffolding various proteins upon
receptor activation. The functional roles of these distinct intracellular pathways are unclear.
D2R is expressed on striato-pallidal medium spiny neurons (spMSNs) of the nucleus accumbens,
where it functions to mediate many psychostimulant-induced behaviors. Previous research in mice has shown
that in these cells the arrestin pathway is able to mediate locomotion but not motivation, thus indicating that
certain behaviors may be driven by arrestin independently of G protein signaling. GSK-3β, a kinase, is
activated downstream of arrestin and is essential for the expression of certain cocaine-induced behaviors.
Additionally, upon activation, striatal D2Rs dimerize with the NMDA receptor NR2B subunit, a mechanism that
may be GSK-3β-dependent and seems to mediate conditioned place preference (CPP) for cocaine but not
food. In post-mortem striatal sections from psychostimulant dependent humans, the proportion of D2R/NMDAR
heteromers was ~3-fold higher compared to controls despite a substantial decrease of D2R expression. It is
not clear what mediates the formation of these heteromers downstream of D2R.
I hypothesize that, in spMSNs, D2R-driven arrestin and downstream GSK-3β signaling mediate cocaine
but not food reward processing by facilitating D2R-NR2B heteromerization and transcriptomic changes. I will
address this hypothesis through the following Specific Aims: Aim 1 will determine the roles of D2R-driven
arrestin and GSK-3β signaling in cocaine versus food reward processing. I will use CRISPR to knockout β-
arrestin 2 or GSK-3β in spMSNs of adult mice and assay preference for locations associated with, and
willingness to work for, a food reward and cocaine. Aim 2 will use the same knockout strategy to investigate
the molecular and transcriptomic changes mediated by βarr2 and GSK-3β upon chronic psychostimulant
exposure. I will analyze ex vivo NAc tissue for NR2B-D2R heteromerization, as well as GSK-3β and NR2B
phosphorylation, and perform transcriptomic analysis on spMSNs after chronic cocaine exposure using nuclear
RNAseq. Together, the proposed experiments will provide insight into the molecular basis for D2R-driven
behaviors and identify novel avenues for developing drugs for dopamine-related diseases.
项目概要/摘要
多巴胺 (DA) 是一种与学习和动机有关的神经递质,也是
精神兴奋作用机制和药物滥用病理学。多巴胺结合五种受体(D1-
D5R),其中 D2R 具有特殊的相关性,因为它在不同的大脑区域中发挥着不同的功能作用
和细胞类型,是所有抗精神病药物的目标。多巴胺受体是 G 蛋白偶联的
激活细胞内 G 蛋白及其下游信号级联的受体 (GPCR)。这个信号
当抑制蛋白与受体的胞内结构域结合时终止。最近,抑制素已
已发现通过在其上搭建各种蛋白质来启动其自己的不依赖于 G 蛋白的信号级联
受体激活。这些不同的细胞内途径的功能作用尚不清楚。
D2R 在伏隔核的纹状体苍白球中型多棘神经元 (spMSN) 上表达,
它的作用是调节许多精神兴奋剂引起的行为。先前对小鼠的研究表明
在这些细胞中,抑制蛋白途径能够介导运动,但不能介导动机,因此表明
某些行为可能是由抑制蛋白驱动的,与 G 蛋白信号传导无关。 GSK-3β 是一种激酶
抑制蛋白下游被激活,对于某些可卡因诱导行为的表达至关重要。
此外,激活后,纹状体 D2R 与 NMDA 受体 NR2B 亚基形成二聚体,这一机制
可能是 GSK-3β 依赖性的,似乎介导可卡因的条件性位置偏好 (CPP),但不是
食物。在精神兴奋剂依赖性人类的死后纹状体切片中,D2R/NMDAR 的比例
尽管 D2R 表达大幅下降,但异聚体的含量比对照高约 3 倍。这是
尚不清楚是什么介导了 D2R 下游这些异聚体的形成。
我假设,在 spMSN 中,D2R 驱动的抑制蛋白和下游 GSK-3β 信号传导可卡因
但不是通过促进 D2R-NR2B 异聚化和转录组变化来进行食物奖励处理。我会
通过以下具体目标来解决这一假设: 目标 1 将确定 D2R 驱动的角色
可卡因与食物奖励处理中的抑制蛋白和 GSK-3β 信号传导。我将使用 CRISPR 敲除 β-
成年小鼠 spMSN 中的抑制蛋白 2 或 GSK-3β 以及相关位置的测定偏好,以及
愿意为之工作、食物奖励和可卡因。目标2将使用相同的淘汰赛策略进行调查
慢性精神兴奋剂βarr2和GSK-3β介导的分子和转录组变化
接触。我将分析离体 NAc 组织的 NR2B-D2R 异聚化,以及 GSK-3β 和 NR2B
磷酸化,并在慢性可卡因暴露后使用核对 spMSN 进行转录组分析
RNA测序。总之,所提出的实验将深入了解 D2R 驱动的分子基础
行为并确定开发治疗多巴胺相关疾病药物的新途径。
项目成果
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