Circuit-Selective Astroglial Plasticity During Opioid Relapse

阿片类药物复发期间的电路选择性星形胶质细胞可塑性

基本信息

  • 批准号:
    10448889
  • 负责人:
  • 金额:
    $ 19.28万
  • 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:
    2022-08-01 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

Abstract Vulnerability to relapse despite prolonged abstinence is a principal feature of drug addiction. Decades of research have expanded our understanding of the neural basis of relapse, but have yielded few effective treatments that restore top-down control over drug seeking in active and former users. In animal models, repeated drug use, but not repeated exposure to natural rewards, results in excess glutamate transmission within corticofugal projections to the striatum in the presence of reward-associated cues and contexts that drive seeking. This behavioral paradigm has been used to model neural adaptations that trigger relapse, since reactivity to drug-related cues is linked to drug craving in humans. The dysregulation of glutamate transmission after chronic heroin use arises in part from enduring changes in peripheral astrocyte processes that insulate active synapses and express the glutamate transporter GLT-1, consistent with a growing literature that illustrates a prominent role for this cell type in maintaining the integrity of excitatory synaptic transmission. My published data show that astrocytes in the NAcore undergo profound transient morphological plasticity in response to drug- but not sucrose-conditioned cues and that this plasticity serves to attenuate seeking behavior. Heroin-associated cues also stimulate an increase in surface-proximity of GLT-1 on the astroglial membrane, an adaptation expected to limit glutamate spillover during relapse in preclinical models. The goal of this proposal is to explore whether measures of astroglial plasticity that I have discovered are linked to transmitter release from cortical projections within the NAcore and to uncover intracellular signaling events that trigger morphological plasticity in astrocytes during drug-seeking. A final goal of this proposal is to determine whether cue-induced astrocyte adaptations impact different post-synaptic targets, since the two principle neuronal subtypes in the NAcore, D1- and D2-MSNs differentially impact drug seeking behavior. In Aim 1, I will combine confocal microscopy with in vivo fiber photometry in order to identify the time course of astroglial plasticity during a 2-hr reinstatement session. In Aim 2, I will pair optogenetics with confocal microscopy to determine whether glutamate from prelimbic cortical terminals is necessary to drive astrocyte motility and GLT-1 surface diffusion after extinction from heroin self-administration. In Aim 3, I will interfere with the signaling cascade that drives astrocyte process motility during seeking using viral-mediated delivery of shRNAs selectively in astrocytes. Finally, in Aim 4 I will use confocal microscopy in transgenic D1- and D2-Cre rats to determine whether astrocyte processes or surface- proximal GLT-1 are selectively associated with D1- or D2-MSNs during cue-reinstated seeking. These Aims will provide me with comprehensive training in optogenetics as well as with viral tools that will allow me to selectively manipulate protein expression in astrocytes and will link my previous findings with the underlying neural circuitry. The relevance of this work extends beyond relapse to opioids and may have implications for normal synaptic physiology underlying motivated behavior.
摘要 尽管长期戒毒,但容易复发是吸毒成瘾的一个主要特征。几十年来 研究扩大了我们对复发的神经基础的理解,但几乎没有产生有效的结果 恢复现役和既往吸毒者对寻求毒品的自上而下控制的治疗方法。在动物模型中, 反复使用药物,但不反复暴露于自然回报,会导致谷氨酸在体内过度传递 在存在奖赏相关线索和刺激的情况下向纹状体的皮质分离投射 寻找。这种行为范式已经被用来模拟引发复发的神经适应,因为 对毒品相关线索的反应与人类的毒瘾有关。谷氨酸传递的失调 慢性海洛因使用后,部分原因是外周星形胶质细胞突起的持久变化 活跃的突触和表达谷氨酸转运体GLT-1,这与越来越多的文献表明 这种细胞类型在维持兴奋性突触传递的完整性方面起着突出的作用。我出版的 数据显示,NAcore中的星形胶质细胞对药物反应具有深刻的瞬时形态可塑性。 但不是蔗糖条件下的暗示,这种可塑性有助于减弱寻找行为。与海洛因有关 信号还刺激星形胶质细胞膜上GLT-1表面亲和力的增加,这是一种适应 预期在临床前模型中限制复发期间的谷氨酸溢出。这项提案的目标是探索 我所发现的星形胶质可塑性的测量是否与大脑皮层的递质释放有关 NAcore内的投射并揭示触发NAcore形态可塑性的细胞内信号事件 寻找毒品期间的星形胶质细胞。这项提议的最终目标是确定CUE诱导的星形胶质细胞 适应影响不同的突触后靶点,因为NAcore中的两个主要神经元亚型,D1- D2-MSN对寻药行为有不同程度的影响。在目标1中,我将结合共焦显微镜和In 活体纤维光度法,以确定星形胶质细胞在2小时恢复期间可塑性的时间进程 会议。在目标2中,我将把光遗传学与共聚焦显微镜相结合,以确定谷氨酸是否来自 前皮质终末是驱动星形胶质细胞运动和GLT-1消亡后表面扩散所必需的 是海洛因自我注射造成的。在目标3中,我将干扰驱动星形胶质细胞过程的信号级联 利用病毒介导的shRNA在星形胶质细胞中选择性传递寻找过程中的运动性。最后,在《目标4》中,我将 用共聚焦显微镜在转基因的D1Cre和D2Cre大鼠中确定星形胶质细胞突起或表面- 在线索恢复的寻找过程中,近端的GLT-1选择性地与D_1或D_2-MSN相关。这些目标将 为我提供全面的光遗传学培训以及病毒工具,使我能够有选择地 操纵星形胶质细胞中的蛋白质表达,并将我之前的发现与潜在的神经回路联系起来。 这项工作的相关性超出了阿片类药物复发的范围,并可能对正常突触有影响 动机行为的生理基础。

项目成果

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Anna K Kruyer其他文献

Anna K Kruyer的其他文献

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{{ truncateString('Anna K Kruyer', 18)}}的其他基金

Circuit-Selective Astroglial Plasticity During Opioid Relapse
阿片类药物复发期间的电路选择性星形胶质细胞可塑性
  • 批准号:
    10738654
  • 财政年份:
    2023
  • 资助金额:
    $ 19.28万
  • 项目类别:

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