Mechanisms of pathway-specific plasticity in the incubation of craving
渴望孵化过程中路径特异性可塑性的机制
基本信息
- 批准号:9318063
- 负责人:
- 金额:$ 42.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAffectAnimal ModelAutomobile DrivingBehaviorBehavioralBrainBrain DiseasesBrain regionCAV2 geneCellsCellular StructuresCocaineCocaine DependenceComplexCorpus striatum structureDataDecision MakingDendritesDrug usageEngineeringEventExposure toExtinction (Psychology)GasesGenetic TranscriptionGlobus PallidusGlutamatesGoalsIndividualInjectableKnowledgeLaboratoriesLoxP-flanked alleleMeasuresMediatingMessenger RNAMethodsMicroRNAsModelingMolecularMonitorNeuronsNucleus AccumbensOutputPathway AnalysisPathway interactionsPatternPharmaceutical PreparationsPlayPolyribosomesProcessProtein BiosynthesisProteinsRNARattusRelapseRibosomesRoleSecond Messenger SystemsSelf AdministrationSignal PathwaySignal TransductionSignal Transduction PathwaySpecific qualifier valueSynapsesSynaptic plasticitySynaptosomesTechnologyTestingTimeTrainingTransgenesTransgenic OrganismsTranslatingTranslationsVentral StriatumVentral Tegmental AreaViral Vectoraddictionadeno-associated viral vectorbasecocaine exposurecocaine usecombinatorialcompulsioncravingdesigner receptors exclusively activated by designer drugsdrug relapseexperienceexperimental studyinnovationintersectionalityneurotransmissionnew therapeutic targetnovelnovel strategiesreceptorreceptor expressionresponseretrograde transportselective expressiontooltranscriptome sequencingtransgene expressiontreatment strategy
项目摘要
Abstract
Cocaine addiction involves the loss of control over drug taking so that individuals take more drug over time and
can have prolonged vulnerability to relapsing to drug seeking, even after extended periods of abstinence. The
progressive molecular and synaptic adaptations in neurons in the CNS that underlie these changes are not
well understood, but can be studied using animal models based on extended cocaine self-administration
followed by abstinence in rats. These models have shown that the nucleus accumbens core (NAcC), a small
but critical brain region in ventral striatum, is implicated in compulsive cocaine taking and relapse to cocaine
seeking after extended abstinence. The NAcC receives and integrates afferent information from many different
brain regions and has two main output projections, the direct and indirect pathways; these pathways tend to
oppose one another functional, and we predict that adaptations in signaling processes within these neurons
are critical determinants affecting the relapse to drug seeking. By understanding the adaptations in cell
signaling in these NAcC output neurons following extensive cocaine exposure and abstinence, we hope to
contribute to novel treatment strategies for reducing the potential for relapse to drug seeking.
We propose to investigate the time-dependent increase in drug seeking during abstinence known as the
“incubation of craving”. We will use several innovative tools. First, we will use an intersectional viral vector
approach to introduce DREADDs and other transgenic proteins to perturb and study direct and indirect
pathway neurons selectively during incubation. By injecting AAV vectors with floxed and inverted transgenes
into NAcC, we can activate transgene expression selectively in the direct or indirect pathway neurons by
injecting the ventral tegmental area or ventral pallidum with CAV2-Cre, which is retrogradely transported to the
cell bodies in NAcC. Second, we will use engineered “DREADD” receptors, a technology that we helped to
establish for use in rat brain during complex behavioral experiments. DREADDs will allow us to activate Gs or
Gi signaling pathways selectively in either direct or indirect pathway neurons during either repeatedly during
cocaine taking or during early or late forced abstinence, thereby assessing how these canonical second
messenger pathways modulate the plasticity involved in escalation or incubation. Third, we will utilize RiboTag
technology to immunopurify polyribosomes selectively from direct or indirect pathway neurons and investigate
the changes in RNA translation in these opposing pathways during abstinence and incubation of craving, both
in cell bodies and in the synapses where activity dependent changes in local protein translation has been
described. By perturbing and measuring signaling pathways in specified neurons, we hope to develop new
strategies for ameliorating the adaptations associated with compulsive drug use and relapse to seeking.
摘要
吸毒成瘾涉及对吸毒的失控,使个人随着时间的推移服用更多的药物,
即使在长时间的禁欲之后,也可能有长期的复吸倾向。的
中枢神经系统中神经元的渐进性分子和突触适应是这些变化的基础,
很好理解,但可以使用基于长期可卡因自我给药的动物模型进行研究
随后在大鼠中进行禁欲。这些模型已经表明,在核内,一个小的
但腹侧纹状体的关键脑区与可卡因的强迫性服用和复发有关
寻求延长禁欲期NAcC接收和整合来自许多不同的传入信息。
大脑区域,有两个主要的输出投射,直接和间接途径;这些途径往往
相反,另一个功能,我们预测,适应信号过程中,这些神经元
是影响重新吸毒的关键决定因素。通过了解细胞的适应性
在这些NAcC输出神经元中的信号传导在广泛的可卡因暴露和戒断后,我们希望
有助于新的治疗策略,以减少潜在的复发药物寻求。
我们建议调查戒毒期间寻求药物的时间依赖性增加,
“渴望的孵化”。我们将使用一些创新的工具。首先,我们将使用一个交叉病毒载体
引入DREADDs和其他转基因蛋白直接和间接干扰和研究的方法
在孵育期间选择性地传递神经元。通过注射带有floxed和inverted转基因的AAV载体,
进入NAcC,我们可以激活转基因表达选择性地在直接或间接途径神经元,
用CAV 2-Cre注射腹侧被盖区或腹侧苍白球,CAV 2-Cre逆行运输到
NAcC中的细胞体。第二,我们将使用工程化的“DREADD”受体,这是一项我们帮助
建立用于复杂行为实验中的大鼠大脑。DREADDs将允许我们激活Gs或
Gi信号通路选择性地在直接或间接通路神经元中重复进行,
可卡因服用或在早期或晚期被迫禁欲,从而评估如何这些典型的第二次
信使途径调节参与升级或孵化的可塑性。第三,我们将利用RiboTag
从直接或间接途径神经元中选择性免疫纯化多聚核糖体技术,并研究
在戒断和渴望的孵化过程中,这些相反的通路中RNA翻译的变化,
在细胞体和突触中,局部蛋白质翻译的活性依赖性变化已经被
介绍了通过干扰和测量特定神经元中的信号通路,我们希望开发新的
改善与强迫性药物使用和寻求复发相关的适应性的策略。
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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John F Neumaier其他文献
Grateful DREADDs: Engineered Receptors Reveal How Neural Circuits Regulate Behavior
感恩性设计受体激动剂:工程化受体揭示神经回路如何调节行为
- DOI:
10.1038/npp.2011.179 - 发表时间:
2011-12-13 - 期刊:
- 影响因子:7.100
- 作者:
Susan M Ferguson;John F Neumaier - 通讯作者:
John F Neumaier
RiboTag: Not Lost in Translation
核糖体标签:在翻译中并未丢失
- DOI:
10.1038/npp.2015.262 - 发表时间:
2015-12-10 - 期刊:
- 影响因子:7.100
- 作者:
Adam J Lesiak;John F Neumaier - 通讯作者:
John F Neumaier
John F Neumaier的其他文献
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{{ truncateString('John F Neumaier', 18)}}的其他基金
Microglia and Opioid Withdrawal: Mechanisms of Negative Reinforcement
小胶质细胞和阿片类药物戒断:负强化机制
- 批准号:
10653870 - 财政年份:2021
- 资助金额:
$ 42.65万 - 项目类别:
The Unfolding Role of Microglia in Alcohol Withdrawal
小胶质细胞在酒精戒断中的作用
- 批准号:
10491273 - 财政年份:2021
- 资助金额:
$ 42.65万 - 项目类别:
The Unfolding Role of Microglia in Alcohol Withdrawal
小胶质细胞在酒精戒断中的作用
- 批准号:
10314628 - 财政年份:2021
- 资助金额:
$ 42.65万 - 项目类别:
Microglia and Opioid Withdrawal: Mechanisms of Negative Reinforcement
小胶质细胞和阿片类药物戒断:负强化机制
- 批准号:
10313923 - 财政年份:2021
- 资助金额:
$ 42.65万 - 项目类别:
Microglia and Opioid Withdrawal: Mechanisms of Negative Reinforcement
小胶质细胞和阿片类药物戒断:负强化机制
- 批准号:
10458741 - 财政年份:2021
- 资助金额:
$ 42.65万 - 项目类别:
Mechanisms of pathway-specific plasticity in the incubation of craving
渴望孵化过程中路径特异性可塑性的机制
- 批准号:
10358255 - 财政年份:2017
- 资助金额:
$ 42.65万 - 项目类别:
UW Psychiatry Resident Research Education Program
华盛顿大学精神病学住院医师研究教育计划
- 批准号:
8933795 - 财政年份:2015
- 资助金额:
$ 42.65万 - 项目类别:
UW Psychiatry Resident Research Education Program
华盛顿大学精神病学住院医师研究教育计划
- 批准号:
9117630 - 财政年份:2015
- 资助金额:
$ 42.65万 - 项目类别:
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