Loss of Inhibitory Control in Alcohol Seeking and Dependence: Role of Thalamostriatal Circuitry
酒精寻求和依赖中抑制控制的丧失:丘脑纹状体回路的作用
基本信息
- 批准号:10802977
- 负责人:
- 金额:$ 33.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-25 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAlcohol consumptionAlcohol dependenceAlcoholsBehaviorBehavioralBehavioral AssayBehavioral inhibitionBrainCalciumCharacteristicsChronicCollaborationsComplexConsummatory BehaviorConsumptionDangerousnessDataDependenceDevelopmentDopamine ReceptorEconomicsElectrophysiology (science)EthanolEtiologyFrightGeneticGlutamatesHeadHealthHeavy DrinkingImageIndividualInterneuronsKnowledgeLaboratoriesLearningLiteratureMeasuresModelingMusNeuronsNeurophysiology - biologic functionNucleus AccumbensOdorsParvalbuminsPhysiologyQuinineReporterRewardsRoleSafetySelf AdministrationShapesSliceStimulusStructure of paraventricular nucleus of thalamusSucroseSynapsesTestingThalamic structureTimeWorkalcohol effectalcohol exposurealcohol relapsealcohol researchalcohol seeking behavioralcohol use disorderbehavior testexperimental studyinsightmaladaptive behaviormotivated behaviorneuralneural circuitneuronal circuitrynoveloptogeneticspatch clamppreventreward circuitrysocialstressortargeted treatmenttwo-photonvapor
项目摘要
PROJECT SUMMARY
Maladaptive alcohol seeking, a hallmark of alcohol use disorder (AUD), is thought to be driven not only by
increased function of neural circuitry that drives natural reward seeking, but also by loss of control of circuitry
that serves to suppress behaviors incompatible with safety and survival. The posterior paraventricular thalamus,
(pPVT), and its projections to the nucleus accumbens (NAc), provide feedforward inhibition onto dopamine
receptor-expressing medium spiny neurons (MSNs) which are largely responsible for promoting reward-
motivated behaviors. Stimuli and situations that naturally serve to limit maladaptive behaviors, such as behavioral
threats, have been shown to activate these pPVT®NAc projection neurons and suppress behavior through the
activation of downstream parvalbumin inhibitory interneurons (PV-INs). Our labs have shown that an acute
stressor (TMT predator odor), quinine-adulteration of alcohol and optogenetic activation of pPVT®NAc circuitry
reduces reward- and, of particular importance to this proposal, alcohol-seeking in non-dependent mice.
Furthermore, we show that the ability of this circuit to provoke behavioral inhibition is lost after the induction of
alcohol dependence. These behavioral adaptations parallel reduced synaptic efficacy at pPVT®NAc
glutamatergic synapses onto downstream PV-INs in alcohol-dependent mice. Our data therefore suggest, for
the first time, that pPVT®NAc projection neurons are responsible for the suppression of alcohol-seeking
behavior but are dysregulated by chronic alcohol exposure. We formally test independent components of this
hypothesis in three independent Aims. In Aim 1, using two-photon calcium imaging we will measure and
longitudinally track neuronal ensemble dynamics in both pPVT®NAc projections and NAc PV-INs during alcohol
self-administration, consumption, and tests of behavioral inhibition in non-dependent and dependent mice. Aim
2 will explore the effects of chronic alcohol exposure on intrinsic and synaptic adaptations in pPVT synaptic
inputs to both PV-INs and MSNs in the NAc using slice electrophysiology. Lastly, in Aim 3 we will determine
whether activation of pPVT®NAc inputs and/or activation of PV-INs in the NAc are sufficient to restore
feedforward inhibition and control alcohol-seeking in non-dependent vs. dependent mice. This project will identify
how activity in a principal – but understudied – reward circuit changes from the onset of alcohol use to
dependence and will further determine how this activity influences the expression and suppression of alcohol
seeking.
项目概要
适应不良的饮酒行为是酒精使用障碍 (AUD) 的一个标志,被认为不仅是由以下因素驱动的:
神经回路的功能增强,驱动自然的奖励寻求,但也由于回路控制的丧失
这有助于抑制与安全和生存不相容的行为。后室旁丘脑,
(pPVT) 及其对伏隔核 (NAc) 的投射,提供对多巴胺的前馈抑制
表达受体的中型多棘神经元(MSN)主要负责促进奖赏-
动机行为。自然有助于限制适应不良行为的刺激和情况,例如行为
威胁,已被证明可以激活这些 pPVT®NAc 投射神经元并通过
下游小清蛋白抑制性中间神经元 (PV-IN) 的激活。我们的实验室表明,急性
应激源(TMT 捕食者气味)、酒精奎宁掺假和 pPVT®NAc 电路的光遗传学激活
减少了奖励,并且对于本提议特别重要的是,减少了非依赖性小鼠对酒精的寻求。
此外,我们表明,在诱导
酒精依赖。这些行为适应同时降低了 pPVT®NAc 的突触功效
酒精依赖小鼠的谷氨酸突触下游 PV-IN。因此,我们的数据表明,对于
首次证明 pPVT®NAc 投射神经元负责抑制对酒精的渴求
行为,但因长期接触酒精而失调。我们正式测试这个的独立组件
三个独立目标的假设。在目标 1 中,我们将使用双光子钙成像来测量和
纵向跟踪酒精期间 pPVT®NAc 投影和 NAc PV-IN 中的神经元整体动态
非依赖性和依赖性小鼠的自我给药、消耗和行为抑制测试。目的
2 将探讨慢性酒精暴露对 pPVT 突触内在和突触适应的影响
使用切片电生理学输入到 NAc 中的 PV-IN 和 MSN。最后,在目标 3 中我们将确定
激活 pPVT®NAc 输入和/或激活 NAc 中的 PV-IN 是否足以恢复
前馈抑制和控制非依赖性小鼠与依赖性小鼠的酒精寻求。该项目将确定
主要的(但尚未得到充分研究的)奖励回路的活动从饮酒开始到
依赖性,并将进一步确定该活动如何影响酒精的表达和抑制
寻求。
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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James M Otis其他文献
Noradrenergic Regulation of Fear and Drug-Associated Memory Reconsolidation
去甲肾上腺素能对恐惧和药物相关记忆再巩固的调节
- DOI:
10.1038/npp.2014.243 - 发表时间:
2014-09-12 - 期刊:
- 影响因子:7.100
- 作者:
James M Otis;Craig T Werner;Devin Mueller - 通讯作者:
Devin Mueller
James M Otis的其他文献
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{{ truncateString('James M Otis', 18)}}的其他基金
Thalamostriatal Circuitry in Opioid Seeking
阿片类药物寻求中的丘脑纹状体回路
- 批准号:
10590753 - 财政年份:2022
- 资助金额:
$ 33.78万 - 项目类别:
Thalamostriatal Circuitry in Opioid Seeking
阿片类药物寻求中的丘脑纹状体回路
- 批准号:
10445382 - 财政年份:2022
- 资助金额:
$ 33.78万 - 项目类别:
The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking
去甲肾上腺素能回路对前额神经元整体动力学和线索诱导的海洛因寻求的影响
- 批准号:
10359829 - 财政年份:2021
- 资助金额:
$ 33.78万 - 项目类别:
The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking
去甲肾上腺素能回路对前额神经元整体动力学和线索诱导的海洛因寻求的影响
- 批准号:
10211914 - 财政年份:2021
- 资助金额:
$ 33.78万 - 项目类别:
The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking
去甲肾上腺素能回路对前额神经元整体动力学和线索诱导的海洛因寻求的影响
- 批准号:
10574625 - 财政年份:2021
- 资助金额:
$ 33.78万 - 项目类别:
Evaluating the function and activity dynamics of thalamic inputs for reward seeking and consumption
评估丘脑输入的功能和活动动态以寻求奖励和消费
- 批准号:
9051064 - 财政年份:2016
- 资助金额:
$ 33.78万 - 项目类别:
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