Endogenous Cannabinoid Control of Reward Substrates
Endogenous Cannabinoid Control of Reward Substrates
批准号:
10436157
负责人:
Joseph F Cheer
金额:
$38.88万
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
未结题
起止时间:
2008-03-01 至 2026-04-30
关键词:
2-arachidonylglycerolAdultAnimalsBehavioralBrainCNR1 geneCell NucleusCell membraneCellsClinicalCrisis InterventionCuesDataDiseaseDisease remissionDisinhibitionDissectionDopamineEducational process of instructingEndocannabinoidsEnvironmentEnzymesFundingGTP-Binding ProteinsGeneticGlobus PallidusHarm ReductionIn VitroInfrastructureKnowledgeLearningLinkMediatingMembraneMessenger RNAMethodologyMidbrain structureMotivationMusNegative ReinforcementsNeuromodulatorNucleus AccumbensOrganismOutcomeOutputPathway interactionsPatternPharmaceutical PreparationsPharmacologyPopulationPopulations at RiskPositive ReinforcementsProbabilityProcessProductionPunishmentRelapseRewardsRoleSignal TransductionSiteStimulusTestingTherapeuticTimeTrainingTransgenic MiceTransgenic ModelVentral Tegmental AreaWorkaddictionbasebehavior influencedopaminergic neurondrug cravingdrug withdrawalendocannabinoid signalingendogenous cannabinoid systemexpectationexperienceexperimental studyinsightlipoprotein lipasemotivated behaviormotivational processesmouse modelneurobiological mechanismoptogeneticspostsynapticreceptorreceptor expressionrecruitrelating to nervous systemsuperior colliculus Corpora quadrigeminatheoriestooltreatment strategy
中文摘要
项目总结
大脑的主要功能之一是计算有机体要做出的最适应的动作
在给定的环境条件下。此过程需要了解
环境预测行为学上的相关性,并随后决定采取哪些行动,给定可能的
这些行动的结果。因此,用于奖励预测的神经底物必须与控制的神经底物相互作用。
行为输出。神经调节剂多巴胺是这种相互作用的关键成分。多巴胺能
中脑中的神经元被当前环境没有预测到的奖励所兴奋。但是,当
刺激可以可靠地预测奖励,它们减少了锁定在奖励上的活动时间,并转移到环境中
预测者本身。因此,多巴胺被认为是一种传播与刺激有关的教学信号
奖励预测。前几个资金周期的数据显示,腹侧的内源性大麻素
在寻找奖赏的过程中,被盖雕刻线索诱导伏隔核多巴胺释放激增。
我们假设,但从未明确证明,这是由于释放
内源性大麻素2AG来自多巴胺神经元本身,从而减轻了它们的抑制程度。这
去抑制机制是高度保守的,因为我们发现它发生在追求无益奖励的过程中
而且在逃避惩罚期间也是如此。然而,腹侧被盖的精确兴奋性输入
负责从多巴胺神经元按需释放2AG的原因尚不清楚。在这里,我们建议
进一步阐明内源性大麻素信号在奖赏相关线索编码中的作用
它在激励方面的作用。首先,我们将使用基因解剖方法评估2AG是否真的是
从多巴胺神经元释放的活动是否符合奖赏预测理论
因果影响行为(目标1)。接下来,我们将确定CB1受体的哪些表达传入
VTA中的多巴胺神经元负责2AG在线索驱动的奖赏中的去抑制作用
寻找。我们将通过研究兴奋性传入对这些问题提供进一步的机械性见解
在追求奖励的过程中产生2AG依赖的多巴胺神经元去抑制(目标2)。因此,我们将
分离内源性大麻素信号调节动机过程所需的不同成分
采用方法学集成的方法,作为2AG产生和CB1受体的特异性遗传控制
表达将允许对当前关于内源性大麻素调节动机行为的假设进行明确的测试。
本提案利用尚未适用于这些问题的工具,就以下问题提出新的见解
治疗动机障碍的治疗策略,如适应不良的药物寻求。
英文摘要
PROJECT SUMMARY
One of the primary functions of the brain is to calculate the most adaptive action for the organism to make
under a given set of environmental conditions. This process requires learning which features in the
environment predict ethological relevance and subsequently deciding which actions to take, given the probable
outcome of those actions. Hence, neural substrates for reward prediction must interact with those controlling
behavioral output. The neuromodulator dopamine is a critical component of this interaction. Dopaminergic
neurons in the midbrain are excited by rewards not predicted by the current environment. However, when
stimuli reliably predict reward, they decrease activity time locked to the reward and shift to the environmental
predictors themselves. Therefore, dopamine is thought of as a teaching signal that broadcasts stimuli-related
reward predictions. Data from the previous funding cycles showed that endocannabinoids in the ventral
tegmentum sculpt cue-induced surges in dopamine release in the nucleus accumbens during reward seeking.
We hypothesized, but never unambiguously demonstrated, that this arises from release of the
endocannabinoid 2AG from dopamine neurons themselves, which lessens their level of inhibition. This
disinhibition mechanism is highly conserved as we found that it occurs during the pursuit of apetitive rewards
but also during the avoidance of punishment. However, the precise excitatory input to the ventral tegmentum
responsible for the on-demand release of 2AG from dopamine neurons is not known. Here, we propose
experiments to further elucidate the role of endocannabinoid signaling in encoding of reward-related cues and
its role in motivation. First, we will assess, using genetic dissection approaches, whether 2AG is indeed
released from dopamine neurons for their activity to conform to reward prediction theories and whether it can
causally influence behavior (aim 1). Next, we will determine which CB1 receptor-expressing afferents to
dopamine neurons in the VTA are responsible for the disinhibitory actions of 2AG during cue-driven reward
seeking. We will provide further mechanistic insight to these questions by studying the excitatory afferents that
give rise to 2AG-dependent dopamine neuron disinhibition during the pursuit of rewards (aim 2). Thus, we will
isolate the different components necessary for endocannabinoid signaling to modulate motivational processes
using a methodologically-integrated approach, as specific genetic control of 2AG production and CB1 receptor
expression will allow explicit tests of current hypotheses of endocannabinoid modulation of motivated behavior.
The present proposal makes use of tools not yet applied to these questions to generate new insights on
therapeutic strategies for the treatment of motivational disorders such as maladaptive drug seeking.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:9472305
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Enduring Consequences of Adolescent Cannabinoid and Methylphenidate Exposure
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财政年份:2016
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依托单位:
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批准号:9294002
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资助金额:$40.72万
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财政年份:2016
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Enduring Consequences of Adolescent Cannabinoid and Methylphenidate Exposure
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批准号:9193888
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资助金额:$39.87万
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财政年份:2016
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依托单位:
Endocannabinoids and the modulation of expectation
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批准号:8495302
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财政年份:2012
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负责人:Joseph F Cheer
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依托单位:
Endocannabinoids and the modulation of expectation
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资助金额:$11.51万
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依托单位:
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依托单位:
海外基金