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.
项目摘要 适应不良的酒精寻求,酒精使用障碍(AUD)的一个标志,被认为不仅是由 增加神经回路的功能,驱动自然的奖励寻求,但也失去了控制的电路 用来抑制与安全和生存不相容的行为。后室旁丘脑, pPVT及其向丘脑核(NAc)的投射提供了对多巴胺的前馈抑制。 表达受体的中型多刺神经元(MSN),主要负责促进奖励, 动机行为。刺激和情况,自然有助于限制适应不良的行为,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。我们的实验室显示急性 应激源(TMT捕食者气味)、乙醇奎宁掺杂和pPVT®NAc电路的光遗传学激活 减少奖励-以及对该提议特别重要的是,非依赖性小鼠的酒精寻求。 此外,我们发现,这种回路的能力,以挑起行为抑制后,失去了诱导 酒精依赖这些行为适应与pPVT®NAc的突触功效降低平行 酒精依赖小鼠中下游PV-IN上的神经元能突触。我们的数据表明,对于 第一次,pPVT®NAc投射神经元负责抑制酒精寻求 行为,但由于长期酒精暴露而失调。我们正式测试独立的组件, 三个独立的目标。在目标1中,使用双光子钙成像,我们将测量和 纵向跟踪酒精期间pPVT®NAc投射和NAc PV-IN中的神经元系综动力学 在非依赖性和依赖性小鼠中进行自我给药、消耗和行为抑制试验。目的 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, 使用切片电生理学,将输入输入到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与依赖性小鼠中的酒精寻求。该项目将确定 一个主要但未被充分研究的奖励回路的活动是如何从饮酒开始到 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

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似海外基金

The investigation of chronic alcohol consumption enhanced aging colon in elder mice and the mechanism of suppressed on aging colon tissues by sesame lignans continuous intake
长期饮酒促进老年小鼠结肠衰老的研究及持续摄入芝麻木脂素抑制结肠组织衰老的机制
  • 批准号:
    23K10904
  • 财政年份:
    2023
  • 资助金额:
    $ 33.78万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms of carcinogenesis and symptoms associated with alcohol consumption
致癌的分子机制和饮酒相关症状
  • 批准号:
    23K05734
  • 财政年份:
    2023
  • 资助金额:
    $ 33.78万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Internal Sources of Minority Stress and Alcohol Consumption
少数群体压力和饮酒的内部根源
  • 批准号:
    10742318
  • 财政年份:
    2023
  • 资助金额:
    $ 33.78万
  • 项目类别:
Characterizing the Relationship Between Alcohol Consumption and Neuron-Derived Exosomal MicroRNA Cargo in an Adolescent-Young Adult Twin Cohort
青少年双胞胎队列中酒精消耗与神经元衍生的外泌体 MicroRNA 货物之间关系的表征
  • 批准号:
    10452928
  • 财政年份:
    2022
  • 资助金额:
    $ 33.78万
  • 项目类别:
Endocrine regulation of alcohol consumption and fear learning
饮酒和恐惧学习的内分泌调节
  • 批准号:
    10483780
  • 财政年份:
    2022
  • 资助金额:
    $ 33.78万
  • 项目类别:
The impact of friends sharing different modalities of alcohol-related social media content on alcohol consumption: A longitudinal examination of changes in content shared by social networks over time
朋友分享不同形式的酒精相关社交媒体内容对饮酒的影响:对社交网络分享内容随时间变化的纵向研究
  • 批准号:
    10534428
  • 财政年份:
    2022
  • 资助金额:
    $ 33.78万
  • 项目类别:
Cannabis' Impact on Alcohol Consumption: Integrating Laboratory and Ecological Momentary Assessment Methods
大麻对酒精消费的影响:整合实验室和生态瞬时评估方法
  • 批准号:
    10339931
  • 财政年份:
    2022
  • 资助金额:
    $ 33.78万
  • 项目类别:
Chronic alcohol consumption results in elevated Autotaxin levels that suppress anti-tumor immunity
长期饮酒会导致自分泌运动因子水平升高,从而抑制抗肿瘤免疫力
  • 批准号:
    10370159
  • 财政年份:
    2022
  • 资助金额:
    $ 33.78万
  • 项目类别:
Cannabis' Impact on Alcohol Consumption: Integrating Laboratory and Ecological Momentary Assessment Methods
大麻对酒精消费的影响:整合实验室和生态瞬时评估方法
  • 批准号:
    10595096
  • 财政年份:
    2022
  • 资助金额:
    $ 33.78万
  • 项目类别:
Technology-based assessments and intervention to reduce alcohol consumption and improve HIV viral suppression in the Florida Cohort
基于技术的评估和干预,以减少佛罗里达队列的饮酒量并改善艾滋病病毒抑制
  • 批准号:
    10707386
  • 财政年份:
    2022
  • 资助金额:
    $ 33.78万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了