Cocaine-induced adaptation in NMDA receptors

可卡因诱导的 NMDA 受体适应

基本信息

  • 批准号:
    10472185
  • 负责人:
  • 金额:
    $ 44.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-01 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

Abstract Treating substance use disorder (SUD) remains an unmet medical need, in part, due to its high relapse rate. During drug abstinence, re-exposure to cues previously associated with drug use triggers robust drug craving and seeking, leading to drug relapse. Rodent studies reveal that the glutamatergic projection from the infralimbic prefrontal cortex (IL) to nucleus accumbens shell (NAcSh) is targeted by cocaine experience to regulate cue-associated reward seeking. IL projections form monosynaptic connections on both of the two subtypes of principal, medium spiny neurons (MSNs) within the NAcSh, one predominantly expressing D1 dopamine receptors and the other expressing D2 receptors. Increasing evidence suggests that the IL-to-D1 vs. IL-to-D2 sub-projections undergo different adaptive changes after cocaine self-administration and differentially contribute to cocaine-associated behaviors. However, it remains poorly understood whether these IL sub-projections are changed through modification of existing synapses without changing the basic circuit connectivity, or through synapse formation or elimination that results in profound rewiring of circuit connectivity. The currently proposed work will address this knowledge gap by focusing on cocaine-generated AMPA receptor (AMPAR)-silent synapses, a type of glutamatergic synapses that contains NMDA receptors without functionally stable AMPARs. Silent synapses can be generated de novo via synaptogenesis and, upon AMPAR insertion and maturation, create and stabilize new network connections. Conversely, silent synapses can also stem from pre-existing synapses through AMPAR internalization, and this initial synaptic weakening may lead to the eventual synapse elimination to reduce network connections. Preliminary studies reveal that cocaine self-administration generated silent synapses in both the IL-to-D1 and IL-to-D2 sub-projections, which anatomically and functionally correlated with synaptogenesis vs. synaptic weakening, respectively. These and other results lead to the central hypothesis that silent synapse-mediated strengthening vs. weakening are simultaneously induced within the IL-to-D1 and IL-to-D2 sub-projections, respectively, after cocaine withdrawal, and the resulting circuit remodeling differentially contributes to cue-induced cocaine seeking. To test this hypothesis, the proposed experiments will (1) characterize the anatomical and electrophysiological consequences of silent synapse-mediated remodeling of IL-to-D1 and IL-to-D2 sub-projections, (2) determine the role of each of the remodeled IL-to-NAcSh sub-projections in formation of neuronal ensembles that potentially encode cue-induced cocaine seeking, and (3) determine how each of the remodeled IL-to-NAcSh sub-projections influences cue-induced cocaine seeking and motivation to obtain cocaine after withdrawal from cocaine. These objectives are highly relevant to the mission of the NIDA, NIH, as the resulting findings will provide novel, circuit-based mechanisms that can be targeted to reduce drug seeking and relapse.
摘要 治疗物质使用障碍(SUD)仍然是一个未满足的医疗需求,部分原因是其高复发率。在药物戒断期间,重新暴露于先前与药物使用相关的线索会引发强烈的药物渴望和寻求,导致药物复发。啮齿类动物的研究表明,从边缘下前额叶皮层(IL)到核壳(NAcSh)的神经元投射是可卡因经验的目标,以调节线索相关的奖励寻求。IL投射在NAcSh内的两种主要的中型多刺神经元(MSN)亚型上形成单突触连接,一种主要表达D1多巴胺受体,另一种表达D2受体。越来越多的证据表明,IL-至-D1与IL-至-D2的子投射在可卡因自我给药后经历了不同的适应性变化,并对可卡因相关行为有不同的贡献。然而,人们仍然很难理解这些IL子投射是否通过修改现有的突触而不改变基本的电路连接,或通过突触形成或消除,导致电路连接的深刻重新布线。目前提出的工作将通过关注可卡因产生的AMPA受体(AMPAR)-沉默突触来解决这一知识缺口,这是一种含有NMDA受体而没有功能稳定的AMPAR的突触。沉默突触可以通过突触发生从头产生,并且在AMPAR插入和成熟时,创建和稳定新的网络连接。相反,沉默突触也可以通过AMPAR内化来自预先存在的突触,并且这种初始突触弱化可能导致最终的突触消除以减少网络连接。初步研究表明,可卡因自我管理产生沉默的突触在IL-到-D1和IL-到-D2的子投射,这在解剖学上和功能上与突触发生与突触弱化,分别。这些和其他结果导致的中心假设,沉默突触介导的加强与减弱同时诱导内IL-至-D1和IL-至-D2的子预测,分别在可卡因戒断后,和由此产生的电路重塑差异有助于线索诱导的可卡因寻求。为了验证这一假设,所提出的实验将(1)表征IL-至-D1和IL-至-D2亚投射的沉默突触介导的重构的解剖学和电生理学结果,(2)确定每个重构的IL-至-NAcSh亚投射在潜在编码线索诱导的可卡因寻求的神经元集合形成中的作用,以及(3)确定每一个重构的IL-至-NAcSh子投射如何影响线索诱导的可卡因寻求和在从可卡因戒断后获得可卡因的动机。这些目标与NIDA、NIH的使命高度相关,因为由此产生的发现将提供新的、基于回路的机制,这些机制可以有针对性地减少药物寻求和复发。

项目成果

期刊论文数量(0)
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Yan Dong其他文献

沙尘、污染、熏烟气溶胶影响下的对流云晶化温度
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    5.2
  • 作者:
    Rosenfeld D;Yan Peng;Xing Yu;Guihua Liu;Xiaohong Xu;Yannian Zhu;Zhiguo Yue;Jin Dai;Zipeng Dong;Yan Dong
  • 通讯作者:
    Yan Dong

Yan Dong的其他文献

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{{ truncateString('Yan Dong', 18)}}的其他基金

A role of FAM3B in suppressing prostate cancer progression
FAM3B 在抑制前列腺癌进展中的作用
  • 批准号:
    9892167
  • 财政年份:
    2020
  • 资助金额:
    $ 44.43万
  • 项目类别:
Interaction of Glutamatergic Inputs to Nucleus Accumbens
谷氨酸能输入与伏隔核的相互作用
  • 批准号:
    10217090
  • 财政年份:
    2020
  • 资助金额:
    $ 44.43万
  • 项目类别:
A role of FAM3B in suppressing prostate cancer progression
FAM3B 在抑制前列腺癌进展中的作用
  • 批准号:
    10454772
  • 财政年份:
    2020
  • 资助金额:
    $ 44.43万
  • 项目类别:
A role of FAM3B in suppressing prostate cancer progression
FAM3B 在抑制前列腺癌进展中的作用
  • 批准号:
    10625388
  • 财政年份:
    2020
  • 资助金额:
    $ 44.43万
  • 项目类别:
Interaction of Glutamatergic Inputs to Nucleus Accumbens
谷氨酸能输入与伏隔核的相互作用
  • 批准号:
    9978349
  • 财政年份:
    2020
  • 资助金额:
    $ 44.43万
  • 项目类别:
Circuitry Progression of Cocaine-induced Cellular Adaptation
可卡因诱导的细胞适应的电路进展
  • 批准号:
    9982846
  • 财政年份:
    2019
  • 资助金额:
    $ 44.43万
  • 项目类别:
Glial-mediated synaptic remodeling in drug addiction
胶质细胞介导的毒瘾突触重塑
  • 批准号:
    10363436
  • 财政年份:
    2016
  • 资助金额:
    $ 44.43万
  • 项目类别:
Glial-mediated synaptic remodeling in drug addiction
胶质细胞介导的毒瘾突触重塑
  • 批准号:
    9001549
  • 财政年份:
    2016
  • 资助金额:
    $ 44.43万
  • 项目类别:
Glial-mediated synaptic remodeling in drug addiction
胶质细胞介导的毒瘾突触重塑
  • 批准号:
    9897513
  • 财政年份:
    2016
  • 资助金额:
    $ 44.43万
  • 项目类别:
Glial-mediated synaptic remodeling in drug addiction
胶质细胞介导的毒瘾突触重塑
  • 批准号:
    10654545
  • 财政年份:
    2016
  • 资助金额:
    $ 44.43万
  • 项目类别:

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