CRF and Stress Modulation of Phasic Dopamine Release and Behavior
CRF 和阶段性多巴胺释放和行为的压力调节
基本信息
- 批准号:9043016
- 负责人:
- 金额:$ 23.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmygdaloid structureAttenuatedAwardBasic ScienceBehaviorBehavioralBrain regionCatecholaminesCellsCocaineComplexConsultCorticotropin-Releasing HormoneCuesDataDevelopment PlansDopamineDoseDrug AddictionDrug ExposureDrug abuseExperimental DesignsExposure toFoodFoundationsFutureGoalsImplanted ElectrodesIncidenceIndividualInfusion proceduresIntakeJointsMedialMediatingMental disordersMentorsMonitorMotivationNeural PathwaysNeuronsNeuropeptidesNeurosciences ResearchNorepinephrineNucleus AccumbensPathway interactionsPatternPeptidesPharmaceutical PreparationsPhasePhysiologyPrefrontal CortexRattusRecording of previous eventsReinforcement ScheduleRelapseReportingResearchResearch DesignResearch PersonnelRewardsRodentRodent ModelRoleScanningScientistSelf AdministrationSignal TransductionStimulusStressStressful EventSynapsesTestingTrainingUniversitiesVentral Tegmental AreaWashingtonWorkaddictionbasebehavioral responsecareercareer developmentdesigndopamine systemdopaminergic neuronexperiencein vivolecturesmeetingsmotivated behaviorneural circuitneuroadaptationneuromechanismneurotransmitter releaseplanetary Atmospherereinforcerresearch studyresponsesymposiumtenure tracktransmission process
项目摘要
Project Summary
One of the more daunting problems associated with treating drug addiction is the high incidence of relapse,
which has been reported to occur in up to 90% of addicted individuals. Relapse is often precipitated by
exposure to stressful events; thus highlighting the need for basic science research to characterize the neural
circuits by which stress affects motivated behavior. Previous studies suggest that the dopamine cells of the
ventral tegmental area (VTA) are well situated to mediate the interaction between stress and motivation, but to
date this has not been directly tested. Therefore, the primary goal of the research plan in this K99/R00
'Pathway to Independence Award' proposal is to assess how stress-related peptides, aversive cues, and
stressful stimuli directly affect phasic dopamine release, which is the pattern of dopamine release directly
associated with promoting motivated behavior. To address this goal, fast-scan cyclic voltammetry will be
utilized to monitor phasic dopamine release in combination with brain-region specific pharmacological
manipulations in rats performing operant tasks that assess motivation. During the mentored phase of the
award, the candidate will examine how the stress-released neuropeptide corticotropin-releasing factor (CRF)
acts in the VTA to affect motivated behavior and phasic dopamine release in the nucleus accumbens to
reward-related stimuli for natural (Aim 1) and drug (Aim 2a) reinforcers. Because drug exposure induces
synaptic changes within the dopamine system, including how CRF interacts with dopamine neurons, the
candidate will next assess how prior drug intake influences CRF's effect on motivated behavior for natural
reinforcers (Aim 2b). With this foundation of how a stress-related neuropeptide affects phasic dopamine
release and behavior, subsequent experiments during the independent phase of the award will directly
examine how stress (escapable and inescapable) and stress-associated cues affect behavior and phasic
dopamine release in the nucleus accumbens (Aim 3a). Emerging evidence suggests that catecholamine
(dopamine and norepinephrine) release in the prefrontal cortex and amygdala are also involved with mediating
the response to stress, so the candidate will also address how phasic catecholamine release in these brain
regions is affected by stress and stress-associated cues (Aim 3b).
The findings from the proposed work will not only be of great importance to addiction research by yielding
valuable findings on the interaction between stress, motivation, and phasic catecholamine release, but will also
lay a foundation for future experimentation. The research designed in this project is a logical extension and
synergistic amalgamation of the candidate's previous (cellular level analysis of CRF modulating dopamine
neuron firing rate) and current work (examining phasic catecholamine release during motivated behavior). The
candidate will become proficent in performing drug self-administration studies under the advising of his mentor
Dr. Paul Phillips, and consulting with Dr. Jeansok Kim will add to the candidate's experimental repitoire by
incorporating voltammetry recordings during stress manipulations. The proposed career development plan is
designed to afford the candidate the best opportunity of achieving his long-term goal of becoming an
independent tenure-track investigator conducting neuroscience research focused on examining the role of
catecholamines during behavior. Specifically, the candidate will strive toward this long-term goal by performing
the proposed research, attending various scientific seminars at the University of Washington, presenting at
scientific conferences, giving lectures to graduate level classes about drug abuse and addiction, and taking
classes to enhance his scientific intellect. The candidate will receive career development advising and will be
evaluated on his progress in his monthly joint meetings with his primary mentor, Dr. Phillips and co-mentor, Dr.
Charles Chavkin. Dr. Phillips pioneered voltammetry recordings using chronically implanted electrodes that
remain viable for months, and as such provides an excellent enviroment to perform these experiments.
Furthermore, the atmosphere at the University of Washington and through the Center for Drug Addiction
Research is conducive for developing young scientists, as evidenced by the recent awardees of the K99/R00
whom have transitioned to independent scientific careers.
项目摘要
与治疗毒瘾相关的一个更令人望而生畏的问题是复吸率高,
据报道,高达90%的上瘾者会发生这种情况。复发通常是由以下原因引起的
暴露在应激事件中;从而突出了基础科学研究的必要性,以确定神经的特征
压力影响动机行为的回路。先前的研究表明,大脑中的多巴胺细胞
腹侧被盖区(VTA)很好地调节了压力和动机之间的相互作用,但
日期:这还没有直接测试过。因此,这项K99/R00研究计划的主要目标是
“独立之路奖”的建议是评估与压力相关的多肽、厌恶线索和
应激刺激直接影响多巴胺的时相释放,这是多巴胺直接释放的方式。
与促进有动机的行为有关。为了实现这一目标,快速扫描循环伏安法将
结合脑区特定药理用于监测时相性多巴胺释放
在执行评估动机的可操作性任务的大鼠中的操纵。在指导阶段,
候选人将研究释放压力的神经肽促肾上腺皮质激素释放因子(CRF)是如何
影响伏隔核动机行为和时相多巴胺释放的ACTs
天然(目标1)和药物(目标2a)增强剂的奖励相关刺激。因为接触毒品会导致
多巴胺系统内的突触变化,包括CRF如何与多巴胺神经元相互作用,
候选人接下来将评估先前的药物摄入如何影响CRF对自然动机行为的影响
增强剂(目标2b)。有了应激相关神经肽如何影响时相多巴胺的基础
释放和行为,后续实验将在独立阶段直接获奖
研究压力(逃避和不可避免)和与压力相关的线索如何影响行为和阶段
伏核中的多巴胺释放(目标3a)。新出现的证据表明,儿茶酚胺
(多巴胺和去甲肾上腺素)在前额叶皮质和杏仁核的释放也参与了
对压力的反应,所以候选人还将阐述如何在这些大脑中释放儿茶酚胺
区域受压力和与压力相关的线索的影响(目标3b)。
这项拟议中的工作的发现不仅对成瘾研究具有重要意义,而且
关于压力、动机和儿茶酚胺释放时相性之间相互作用的有价值的发现,但也将
为以后的实验奠定了基础。本项目设计的研究是一个合乎逻辑的延伸和
候选人先前(CRF调节多巴胺的细胞水平分析)的协同融合
神经元放电率)和当前的工作(检查激发行为时相儿茶酚胺的释放)。这个
候选人将在他的导师的建议下,在进行药物自我管理研究方面有所裨益
Paul Phillips博士和Jeansok Kim博士的咨询将通过以下方式增加候选人的实验报告
结合应力处理过程中的伏安记录。拟议的职业发展计划是
旨在为候选人提供最佳机会,实现他成为一名
独立终身教职跟踪调查员进行神经科学研究,重点检查
在行为过程中产生儿茶酚胺。具体地说,候选人将通过以下方式努力实现这一长期目标
拟议的研究,在华盛顿大学参加各种科学研讨会,在
科学会议,给研究生级别的课程讲课,关于药物滥用和成瘾,以及服用
来提高他的科学智商。应聘者将接受职业发展咨询,并将
在每月与他的主要导师菲利普斯博士和共同导师菲利普斯博士举行的联合会议上,对他的进展进行了评估。
查尔斯·查夫金。菲利普斯博士率先使用长期植入的电极进行伏安法记录
保持存活数月,因此为进行这些实验提供了一个极好的环境。
此外,华盛顿大学和吸毒成瘾中心的氛围
研究有利于培养年轻科学家,最近K99/R00奖的获得者证明了这一点
他们已经过渡到独立的科学生涯。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Pattern of dopamine signaling during aversive events predicts active avoidance learning.
厌恶事件期间的多巴胺信号传导模式预测主动回避学习。
- DOI:10.1073/pnas.1904249116
- 发表时间:2019
- 期刊:
- 影响因子:11.1
- 作者:Stelly,ClaireE;Haug,GrahamC;Fonzi,KaitlynM;Garcia,MiriamA;Tritley,SeanC;Magnon,AlexaP;Ramos,MariaAliciaP;Wanat,MatthewJ
- 通讯作者:Wanat,MatthewJ
Operant Costs Modulate Dopamine Release to Self-Administered Cocaine.
操作成本调节自我管理的可卡因的多巴胺释放。
- DOI:10.1523/jneurosci.1721-18.2018
- 发表时间:2019
- 期刊:
- 影响因子:0
- 作者:Oliva,Idaira;Wanat,MatthewJ
- 通讯作者:Wanat,MatthewJ
Ventral Tegmental Area Afferents and Drug-Dependent Behaviors.
- DOI:10.3389/fpsyt.2016.00030
- 发表时间:2016
- 期刊:
- 影响因子:4.7
- 作者:Oliva I;Wanat MJ
- 通讯作者:Wanat MJ
Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain.
可卡因体验消除了中脑腹侧 CRF 的动机抑制作用。
- DOI:10.1111/adb.12837
- 发表时间:2021
- 期刊:
- 影响因子:3.4
- 作者:Oliva,Idaira;Donate,MelissaM;Lefner,MerrideeJ;Wanat,MatthewJ
- 通讯作者:Wanat,MatthewJ
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Matthew J. Wanat其他文献
Estrous cycle stage gates the effect of stress on reward learning
发情周期阶段限制了应激对奖赏学习的影响
- DOI:
10.1038/s41386-025-02170-8 - 发表时间:
2025-07-16 - 期刊:
- 影响因子:7.100
- 作者:
Morgan P. Johnston;Brandon I. Garcia-Castañeda;Leonor G. Cedillo;Sachi K. Patel;Victoria S. Vargas;Matthew J. Wanat - 通讯作者:
Matthew J. Wanat
Matthew J. Wanat的其他文献
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{{ truncateString('Matthew J. Wanat', 18)}}的其他基金
Midbrain astrocytes controlling active avoidance learning
中脑星形胶质细胞控制主动回避学习
- 批准号:
10419855 - 财政年份:2022
- 资助金额:
$ 23.59万 - 项目类别:
Midbrain astrocytes controlling active avoidance learning
中脑星形胶质细胞控制主动回避学习
- 批准号:
10621234 - 财政年份:2022
- 资助金额:
$ 23.59万 - 项目类别:
Midbrain astrocyte energy metabolism regulating drug-evoked dopamine release and behavior
中脑星形胶质细胞能量代谢调节药物诱发的多巴胺释放和行为
- 批准号:
10396967 - 财政年份:2021
- 资助金额:
$ 23.59万 - 项目类别:
CRF and Stress Modulation of Phasic Dopamine Release and Behavior
CRF 和阶段性多巴胺释放和行为的压力调节
- 批准号:
8508006 - 财政年份:2013
- 资助金额:
$ 23.59万 - 项目类别:
CRF and Stress Modulation of Phasic Dopamine Release and Behavior
CRF 和阶段性多巴胺释放和行为的压力调节
- 批准号:
8796749 - 财政年份:2013
- 资助金额:
$ 23.59万 - 项目类别:
The role of phasic dopamine release in cue-evoked motivated behaviors
阶段性多巴胺释放在提示诱发的动机行为中的作用
- 批准号:
7806792 - 财政年份:2010
- 资助金额:
$ 23.59万 - 项目类别:
Stress-related neuropeptides and VTA dopamine neurons
压力相关神经肽和 VTA 多巴胺神经元
- 批准号:
7111941 - 财政年份:2006
- 资助金额:
$ 23.59万 - 项目类别:
Stress-related neuropeptides and VTA dopamine neurons
压力相关神经肽和 VTA 多巴胺神经元
- 批准号:
7238862 - 财政年份:2006
- 资助金额:
$ 23.59万 - 项目类别:
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