Striatal ensemble plasticity in alcohol use disorder

酒精使用障碍中的纹状体整体可塑性

基本信息

  • 批准号:
    10734890
  • 负责人:
  • 金额:
    $ 45.81万
  • 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:
    2023-08-01 至 2028-04-30
  • 项目状态:
    未结题

项目摘要

Relapse is a major clinical challenge in the treatment of alcohol use disorder. Relapse is driven in part by alcohol-induced synaptic plasticity at the corticostriatal circuit. The dorsomedial striatum (DMS) has been implicated in alcohol seeking and relapse. The DMS contains direct-pathway medium spiny neurons (dMSNs) and indirect-pathway MSNs (iMSNs), which positively and negatively regulate alcohol seeking, respectively. Alcohol-associated behaviors such as operant self-administration activate only a relatively small subset of neuronal ensembles in the striatum. Although alcohol-induced plasticity is much studied in bulk tissue, it is unknown whether it is induced in dMSN ensembles. Characterizing synaptic mechanisms of the ensemble neurons is especially vital to reconcile with the decades of evidence for drug-induced synaptic changes detected in bulk tissue analysis. In addition, extinction training yields greater suppression of alcohol seeking relative to abstinence alone, but the mechanism is poorly understood. The absence of alcohol delivery during extinction likely stimulates thalamic inputs to the DMS and reduces striatal dopamine levels, concurrently inducing thalamostriatal long-term potentiation (LTP) in DMS iMSNs; this enhances “NoGo” actions, suppressing alcohol seeking during relapse. LTP in iMSNs is also likely to directly or indirectly suppress dMSN activity by reducing dopaminergic activity. This application aims to elucidate how extinction training reduces alcohol- induced corticostriatal plasticity in the DMS ensembles and thereby persistently reduces relapse, with the long- term objective of determining how such strategies can be used to treat alcohol use disorder. They hypothesize that alcohol-induced corticostriatal plasticity in dMSN ensembles drives relapse and that extinction training promotes thalamostriatal plasticity in iMSN ensembles to directly or indirectly, via counteracting dMSN activity, suppress relapse. Three specific research aims will: 1) test the hypothesis that operant alcohol self- administration causes long-lasting corticostriatal plasticity in DMS dMSN ensembles, promoting relapse; 2) test the hypothesis that extinction-mediated thalamostriatal plasticity in DMS iMSN contributes to reduced relapse to alcohol seeking; and 3) test the hypothesis that extinction training potentiates the inhibitory outputs from iMSNs to dMSNs or the disinhibitory effects of iMSNs on habenula-projecting globus pallidus neurons, suppressing relapse. This application is highly innovative because it applies state-of-the-art approaches, including a combination of ArcTRAP, Cal-Light, and dual-channel optogenetic stimulation, allowing us for the first time to determine how extinguishing alcohol-evoked synaptic plasticity in specific molecularly defined neuronal ensembles alters their activities in vivo and thus persistently decreases relapse behavior; these critical questions cannot be addressed using conventional methodologies. Knowledge generated from this proposal will provide novel strategies for the long-term treatment of alcohol use disorder.
复发是酒精使用障碍治疗中的一大临床挑战。复发在一定程度上是由 通过酒精诱导皮质纹状体环路的突触可塑性。背内侧纹状体(DMS) 与酗酒和旧病复发有关。DMS含有直接通路中棘神经元(DMSN)。 和间接途径MSN(IMSN),它们分别对酒精寻求进行正向和负向调节。 酒精相关的行为,如操作性自我给药,只激活相对较小的子集 纹状体中的神经元团。虽然酒精诱导的可塑性在大块组织中有很多研究,但它是 不知道它是否在dMSN系综中诱导。描述集合的突触机制 神经元对于与数十年来检测到的药物诱导的突触变化的证据相一致尤其重要 在大块组织分析中。此外,消亡训练对酒精寻觅的抑制作用比 仅仅是禁欲,但其机制却鲜为人知。在物种灭绝期间没有酒精输送 可能刺激丘脑对DMS的输入并降低纹状体多巴胺水平,同时诱导 DMS iMSN中的丘脑纹状体长时程增强(LTP);这增强了“NoGo”活动,抑制了 旧病复发期间酗酒。IMSN中的LTP还可能通过以下方式直接或间接抑制dMSN活动 减少多巴胺能活动。这项申请旨在阐明消亡训练是如何减少酒精的- 在DMS群体中诱导皮质纹状体的可塑性,从而持久地减少复发,长期的- 确定这种策略如何用于治疗酒精使用障碍的学期目标。他们的假设是 DMSN群体中酒精诱导的皮质纹状体可塑性导致复发和消退训练 通过对抗dMSN,直接或间接地促进IMSN系综丘脑纹状体的可塑性 活跃,抑制复发。三个具体的研究目标将:1)检验可操作酒精自我调节的假设 给药导致DMS dMSN群体的皮质纹状体长期可塑性,促进复发;2) 验证DMS IMSN中灭绝介导的丘脑-纹状体可塑性有助于减少的假设 再次酗酒;以及3)检验消退训练增强抑制性输出的假设 从iMSN到dMSN或iMSNS对缰核投射苍白球神经元的抑制作用, 抑制复发。该应用程序具有很高的创新性,因为它应用了最先进的方法, 包括ArcTRAP、Cal-Light和双通道光遗传刺激的组合,使我们能够 首次确定如何在特定分子水平上消除酒精诱发的突触可塑性 神经元集合改变了它们在体内的活动,从而持续地减少复发行为;这些关键 这些问题不能用传统的方法解决。从该建议书中获得的知识 将为酒精使用障碍的长期治疗提供新的策略。

项目成果

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Jun Wang其他文献

Spiking Neural Systems with Weights
带权重的尖峰神经系统
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Jun Wang;Hendrik Jan Hoogeboom;Gheorghe Paun;Linqiang Pan
  • 通讯作者:
    Linqiang Pan

Jun Wang的其他文献

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{{ truncateString('Jun Wang', 18)}}的其他基金

Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antivirals
开发针对病毒主要蛋白酶和宿主组织蛋白酶 L 的双重抑制剂作为 SARS-CoV-2 抗病毒药物
  • 批准号:
    10457835
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
High-Resolution Spatial MIST Technology for Functional Proteomic Study of Neuroinflammation in Alzheimer's Disease
高分辨率空间 MIST 技术用于阿尔茨海默病神经炎症的功能蛋白质组学研究
  • 批准号:
    10343115
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
Repurposing of Maraviroc for the treatment of neuropathic pain
重新利用马拉韦罗治疗神经性疼痛
  • 批准号:
    10586296
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
Sex-specific role of CCL5/CCR5 axis in depression and its therapeutic implication
CCL5/CCR5轴在抑郁症中的性别特异性作用及其治疗意义
  • 批准号:
    10364861
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
NanoDiagnotic Technology I-Corps Training
纳米诊断技术 I-Corps 培训
  • 批准号:
    10541690
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antivirals
开发针对病毒主要蛋白酶和宿主组织蛋白酶 L 的双重抑制剂作为 SARS-CoV-2 抗病毒药物
  • 批准号:
    10543633
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antivirals
开发针对病毒主要蛋白酶和宿主组织蛋白酶 L 的双重抑制剂作为 SARS-CoV-2 抗病毒药物
  • 批准号:
    10693823
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
Sex-specific role of CCL5/CCR5 axis in depression and its therapeutic implication
CCL5/CCR5轴在抑郁症中的性别特异性作用及其治疗意义
  • 批准号:
    10653682
  • 财政年份:
    2022
  • 资助金额:
    $ 45.81万
  • 项目类别:
Rapid detection of infectious viral particles by cluster induced exhaustive reaction
通过簇诱导穷举反应快速检测感染性病毒颗粒
  • 批准号:
    10443877
  • 财政年份:
    2021
  • 资助金额:
    $ 45.81万
  • 项目类别:
Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antivirals
开发针对病毒主要蛋白酶和宿主组织蛋白酶 L 的双重抑制剂作为 SARS-CoV-2 抗病毒药物
  • 批准号:
    10191875
  • 财政年份:
    2021
  • 资助金额:
    $ 45.81万
  • 项目类别:

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