Loss of Inhibitory Control in Alcohol Seeking and Dependence: Role of Thalamostriatal Circuitry
Loss of Inhibitory Control in Alcohol Seeking and Dependence: Role of Thalamostriatal Circuitry
批准号:
10802977
负责人:
James M Otis
金额:
$33.78万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-25 至 2028-05-31
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
中文摘要
项目总结
不适应饮酒是酒精使用障碍(AUD)的一个标志,人们认为不仅是由
驱动自然奖赏寻求的神经回路功能增强,但也通过失去对回路的控制
这有助于抑制与安全和生存不相容的行为。后脑室旁丘脑,
(PPVT)及其向伏核(NAC)的投射对多巴胺具有前馈抑制作用
受体表达的中棘神经元(MSN)主要负责促进奖赏-
有动机的行为。自然地用来限制不良适应行为的刺激和情况,如行为
已经证明,威胁可以激活这些pPVT®NAC投射神经元,并通过
激活下游小白蛋白抑制中间神经元(PV-INS)。我们的实验室表明,一种急性
应激源(TMT捕食者气味)、奎宁掺杂酒精和pPVT®NAC电路的光遗传激活
减少奖赏--尤其重要的是,减少非依赖小鼠的饮酒行为。
此外,我们还表明,在诱发了行为抑制之后,该回路引发行为抑制的能力就丧失了。
酒精依赖。这些行为适应同时降低了pPVT®NAC的突触效能
酒精依赖小鼠中谷氨酸能突触到下游的PV-in。因此,我们的数据表明,
第一次,pPVT®NAC投射神经元负责抑制酒精寻求
但长期饮酒会导致行为失控。我们正式测试了它的独立组件
三个独立目标中的假设。在目标1中,我们将使用双光子钙成像来测量和
酒精过程中pPVT®NAC投射和NAC PV-in的神经元整体动力学的纵向追踪
非依赖和依赖小鼠的自我给药、消耗和行为抑制测试。目标
2将探讨慢性酒精暴露对pPVT突触的内在和突触适应的影响
在NAC中使用切片电生理学对PV-INS和MSN进行输入。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与依赖小鼠的寻酒行为。该项目将确定
主要的但未被研究的奖赏回路中的活动是如何从开始饮酒到
并将进一步确定这种活动如何影响酒精的表达和抑制
寻找。
英文摘要
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.
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依托单位:
海外基金