Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol
对乙醇厌恶特性长期耐受的神经生物学机制
基本信息
- 批准号:10866700
- 负责人:
- 金额:$ 7.75万
- 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:2021-06-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:Alcohol consumptionAlcoholsAttenuatedAutomobile DrivingAversive StimulusBehaviorBrainCalcium SignalingCell NucleusCellsChronicConsumptionDataDendritic SpinesDependenceDevelopmentElectrophysiology (science)EquilibriumEthanolExperimental DesignsExposure toExtinctionFeedbackFiberFrightHealthHumanImpairmentIndividualIntoxicationLearningLinkMeasuresMedialMediatingMidbrain structureMorphologyNeuronal PlasticityNeuronsPhotometryPlayPrefrontal CortexPropertyPublic HealthRattusRewardsRoleSignal TransductionSliceStimulusSynapsesSynaptic plasticityTaste aversionTestingViralWorkalcohol abuse therapyalcohol exposurealcohol responsealcohol rewardalcohol use disorderavoidance behaviorbehavioral extinctionbehavioral responsedensitydesigndrinkingexperienceexperimental studyin vivoinnovationinsightloss of functionneural circuitneuroadaptationneurobiological mechanismneuromechanismneuron lossnew therapeutic targetoptogeneticspatch clampresponse
项目摘要
PROJECT SUMMARY
Chronic alcohol exposure is associated with the development of tolerance to alcohol’s aversive properties, which
serve to limit drinking. In contrast, the response to alcohol’s rewarding properties, which promote drinking, remain
unchanged. The brain undergoes a host of neuroadaptive changes as a result of chronic alcohol exposure but
the neural mechanisms underlying this tolerance are unknown. Impaired signaling in circuits encoding aversion
is a likely candidate mechanism. The rostromedial tegmental nucleus (RMTg) is characterized for its involvement
in aversion including signaling the aversive properties of ethanol. The prelimbic (PL) medial prefrontal cortex
(mPFC) shares important functional similarities with the RMTg including facilitation of aversion learning and
regulating the behavioral response to aversive stimuli. The neighboring infralimbic (IL) subregion of the mPFC
exerts opposing effects to PL mPFC by facilitating extinction of aversive responding. Our work has uncovered a
dense projection from the mPFC to the RMTg that spans both PL and IL subregions. Our findings from
experiments investigating the function mPFC inputs to the RMTg support a role for these circuits in regulating
aversive responding. These data lead us to hypothesize that subregion- and circuit-specific dependence-induced
plasticity in RMTg-projecting mPFC neurons facilitates chronic tolerance to ethanol’s aversive properties. The
aims described in the current proposal will use innovative, circuit-specific strategies to test this hypothesis. Aim
1 will use in vivo fiber photometry to measure changes in calcium signal in RMTg-projecting PL and IL mPFC
inputs during the development of tolerance. Aim 2 will use closed-loop in vivo optogenetics to dissect the effects
of bidirectional manipulation of PL and IL mPFC inputs to the RMTg on measures of chronic tolerance to
ethanol’s aversive properties. Aim 3 will use whole-cell patch-clamp slice electrophysiology and a virally-
mediated intersectional approach to identify dependence-induced changes in synaptic and structural plasticity
underlying tolerance to ethanol’s aversive properties. The results of these studies will provide crucial insight into
the circuit-specific neural mechanisms that contribute to uncontrolled alcohol drinking. In doing so, our findings
have the potential to uncover new therapeutic targets for the treatment of alcohol use disorder.
项目总结
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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Elizabeth J Glover其他文献
Elizabeth J Glover的其他文献
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{{ truncateString('Elizabeth J Glover', 18)}}的其他基金
Role of RMTg afferents in mechanisms of withdrawal from chronic ethanol exposure
RMTg 传入神经在慢性乙醇暴露戒断机制中的作用
- 批准号:
10717194 - 财政年份:2023
- 资助金额:
$ 7.75万 - 项目类别:
Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol
对乙醇厌恶特性长期耐受的神经生物学机制
- 批准号:
10626758 - 财政年份:2021
- 资助金额:
$ 7.75万 - 项目类别:
Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol
对乙醇厌恶特性长期耐受的神经生物学机制
- 批准号:
10428482 - 财政年份:2021
- 资助金额:
$ 7.75万 - 项目类别:
Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol
对乙醇厌恶特性长期耐受的神经生物学机制
- 批准号:
10180231 - 财政年份:2021
- 资助金额:
$ 7.75万 - 项目类别:
Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol
对乙醇厌恶特性长期耐受的神经生物学机制
- 批准号:
10616956 - 财政年份:2021
- 资助金额:
$ 7.75万 - 项目类别:
Chronic alcohol and the neurocircuitry of aversion
慢性酒精与厌恶的神经回路
- 批准号:
9914829 - 财政年份:2018
- 资助金额:
$ 7.75万 - 项目类别:
Chronic Alcohol and the Neurocircuitry of Aversion
慢性酒精与厌恶的神经回路
- 批准号:
9253343 - 财政年份:2016
- 资助金额:
$ 7.75万 - 项目类别:
Understanding the Neurobiological Correlates of Ethanol's Aversive Actions
了解乙醇厌恶行为的神经生物学相关性
- 批准号:
8649445 - 财政年份:2013
- 资助金额:
$ 7.75万 - 项目类别:
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