Synapse-specific interactions between ethanol and opioid receptor-mediated synaptic depression in dorsal striatum

乙醇和阿片受体介导的背侧纹状体突触抑制之间的突触特异性相互作用

基本信息

  • 批准号:
    10488075
  • 负责人:
  • 金额:
    $ 40.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-20 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary There is no doubt that the alcohol use disorders (AUDs) have a significant socioeconomic toll on the United States and the rest of the world. Many current therapeutics are not sufficiently effective, as they do not target the neurobehavioral underpinnings contributing to the development and maintenance of alcohol abuse in many individuals. There is a critical need for novel therapeutic interventions that can undo the negative effects of ethanol on brain circuitry, restoring cognitive control over drinking behavior. A barrier to progress is a lack of understanding of the specific effects that ethanol has on select synapses within parts of the brain known to control alcohol-related behaviors and even the behavioral role of many of these select synapses in the context of the larger function of each brain region. Our preliminary data indicate that ethanol only affects certain forms of opioid receptor-mediated synaptic plasticity at very specific synapses within the dorsal striatum while leaving plasticity at nearby synapses unaffected. One of these synapses is the inputs from the anterior insular cortex (AIC) to the dorsolateral striatum (DLS). The AIC is involved in ethanol interoception and the DLS controls habitual responding for ethanol drinking and seeking behavior. In vivo ethanol exposure in mice disrupts mu opioid long-term synaptic depression (LTD) at this synapse while leaving mu opioid signaling at other synapses unaffected. LTD mediated by kappa and delta opioid receptors occur at unidentified dorsal striatal synapses and ethanol could have similar differential effects on these forms of LTD. Our data also show that LTD at AIC-DLS synapses is likely mediated by altered cAMP signaling and de novo protein synthesis. The objective of this proposal is to determine synapse-specific opioid LTD mechanisms and how ethanol selectively affects some synapses, while leaving others unaffected and to determine the behavioral relevance of opioid LTD at AIC-DLS synapses. Our central hypothesis is that alcohol disrupts dorsal striatal opioid plasticity at specific synapses due to distinct alcohol-sensitive signaling pathways at synapses that modulate alcohol consumption, seeking, and interoception. In Aim 1, we will identify the impact of in vivo ethanol exposure on mu, delta, and kappa opioid receptor-mediated synaptic depression at specific types of dorsal striatal glutamatergic synapses. In Aim 2 we will determine the mechanisms of ethanol-sensitive and insensitive forms of dorsal striatal opioid plasticity to decipher the impact of ethanol on these signaling pathways. In Aim 3 we will decipher the role of mu opioid LTD at AIC-DLS synapses in ethanol consumption, seeking, and interoception. We will use brain slice electrophysiology, in vitro and in vivo optogenetics, transgenic mice, viral vectors, and pharmacological tools to address these three aims. By understanding the synapse-specific effects of ethanol on plasticity mechanisms at behaviorally-defined synapses in the dorsal striatum, we will identify novel therapeutic targets for treating AUDs. This will be a leap forward towards improving the lives of those that suffer from the effects of AUDs.
项目总结

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states.
基底神经节在学习奖励行为和执行先前学习的选择中的作用:健康和疾病状态。
  • DOI:
    10.1371/journal.pone.0228081
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Mulcahy,Garrett;Atwood,Brady;Kuznetsov,Alexey
  • 通讯作者:
    Kuznetsov,Alexey
Synapse-specific expression of mu opioid receptor long-term depression in the dorsomedial striatum.
背内侧纹状体中μ阿片受体长期抑制的突触特异性表达。
  • DOI:
    10.1038/s41598-020-64203-0
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Muñoz,Braulio;Haggerty,DavidL;Atwood,BradyK
  • 通讯作者:
    Atwood,BradyK
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Brady Atwood其他文献

Brady Atwood的其他文献

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{{ truncateString('Brady Atwood', 18)}}的其他基金

A novel proteomics approach to identify alcohol-induced changes in synapse-specific presynaptic protein interactions.
一种新的蛋白质组学方法,用于识别酒精引起的突触特异性突触前蛋白质相互作用的变化。
  • 批准号:
    10651991
  • 财政年份:
    2023
  • 资助金额:
    $ 40.9万
  • 项目类别:
Impact of prenatal opioid exposure on corticostriatal circuits that modulate alcohol-related behaviors
产前阿片类药物暴露对调节酒精相关行为的皮质纹状体回路的影响
  • 批准号:
    10708335
  • 财政年份:
    2023
  • 资助金额:
    $ 40.9万
  • 项目类别:
Synapse-specific interactions between ethanol and opioid receptor-mediated synaptic depression in dorsal striatum
乙醇和阿片受体介导的背侧纹状体突触抑制之间的突触特异性相互作用
  • 批准号:
    10240541
  • 财政年份:
    2018
  • 资助金额:
    $ 40.9万
  • 项目类别:
Dorsal striatal mu opioid receptor function and alcohol use
背侧纹状体 mu 阿片受体功能和饮酒
  • 批准号:
    9260741
  • 财政年份:
    2015
  • 资助金额:
    $ 40.9万
  • 项目类别:
Dorsal striatal mu opioid receptor function and alcohol use
背侧纹状体 mu 阿片受体功能和饮酒
  • 批准号:
    9222263
  • 财政年份:
    2015
  • 资助金额:
    $ 40.9万
  • 项目类别:

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