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

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。

项目成果

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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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