Input-specific mechanisms of drug-evoked synaptic plasticity in the ventral tegmental area

腹侧被盖区药物诱发突触可塑性的输入特异性机制

基本信息

  • 批准号:
    9902381
  • 负责人:
  • 金额:
    $ 34.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-06-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

The mesolimbic dopamine (DA) system is composed of DA neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc). It plays a pivotal role in reinforcement learning and is often considered the center of the brain's reward system. Drugs of abuse such as cocaine, morphine, nicotine and amphetamine have different pharmacological effects, yet they all significantly impact reward and motivation at least in part by activating the mesolimbic DA system. An important research topic over the last decade has been to elucidate how drugs of abuse induce synaptic adaptations of glutamatergic inputs on VTA DA neurons. This body of work has led to the well-accepted theory that addiction is an aberrant form of learning and memory. In particular, a single injection of cocaine induces a strong and long-lasting (> 3 weeks) potentiation of excitatory inputs on DA neurons projecting to NAc medial shell. However, so far the origin of these inputs remains unknown due to major technical limitations. In recent years, state-of-the-art combinations of viral tracing methods and optogenetic tools made it possible to fully map the functional connectivity of the mesolimbic circuitry. As the result of these efforts, the next important step in addiction research is to identify specific inputs to mesolimbic DA neurons that are susceptible to drug-evoked synaptic plasticity. We hypothesize that different inputs to the VTA participate in related but independent circuits that are differentially modulated by drugs of abuse. To assess input-specific effects of cocaine-evoked synaptic potentiation, we will employ a multidisciplinary approach combining synaptic electrophysiology, viral tracing, immunohistochemistry and in vivo and ex vivo optogenetic experiments in mice. Because drug- evoked synaptic plasticity may contribute to addictive behaviors we will also investigate if optogenetic manipulations of specific VTA afferents promote or suppress drug-adaptive behaviors (e.g., cocaine-induced locomotor sensitization, cocaine-induced conditioned place preference). Given that the VTA is a major site of action of addictive drugs, and DA neurons projecting to NAc medial shell are particularly prone to undergo long-lasting drug-evoked synaptic adaptations, selective manipulations of inputs to these cells will provide a more comprehensive understanding of the precise nature of circuit remodeling caused by addictive drugs. Outcomes of this study may reveal important information for the development of more effective treatments of substance abuse and other mental disorders.
中唇多巴胺(DA)系统由腹侧对段区域的DA神经元组成 (VTA)投射到伏隔核(NAC)。它在加强学习中起关键作用 通常被认为是大脑奖励系统的中心。可卡因等滥用药物, 吗啡,尼古丁和苯丙胺具有不同的药理作用,但它们都是 至少部分通过激活中边DA系统,显着影响奖励和动机。 过去十年中,一个重要的研究主题是阐明滥用药物如何诱导 VTA DA神经元上谷氨酸能输入的突触适应。这项工作导致了 被接受的理论是,成瘾是一种异常的学习和记忆形式。 特别是,单一注射可卡因会诱导强烈而持久(> 3周) 投射到NAC内侧外壳的DA神经元上的兴奋性输入的增强。但是,到目前为止 由于主要的技术限制,这些输入的起源仍然未知。最近几年, 病毒追踪方法和光遗传学工具的最新组合使得 充分绘制中唇电路的功能连接性。作为这些努力的结果 成瘾研究的下一个重要步骤是确定中左右DA神经元的特定输入 容易受到药物诱发的突触可塑性的影响。我们假设对 VTA参与相关但独立的电路,这些电路是由 虐待。为了评估可卡因诱发的突触增强的投入特异性影响,我们将采用 多学科方法结合了突触电生理学,病毒追踪, 在小鼠中进行免疫组织化学以及体内和离体光遗传学实验。因为药物 - 诱发的突触可塑性可能会导致成瘾行为,我们还将调查是否 特定VTA传入的光学遗传操作促进或抑制药物自适应行为 (例如,可卡因诱导的运动敏化,可卡因诱导的条件偏好)。 鉴于VTA是成瘾药物的主要作用部位,而DA神经元投射到NAC 内侧外壳特别容易受到持久的药物引起的突触适应, 选择性操纵这些细胞的输入将提供更全面的理解 由成瘾药物引起的电路重塑的确切性质。这项研究的结果可能 揭示开发更有效治疗药物滥用的重要信息 和其他精神障碍。

项目成果

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Stephan Lammel其他文献

Stephan Lammel的其他文献

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{{ truncateString('Stephan Lammel', 18)}}的其他基金

A multi-level investigation into the effects of chronic stress on lateral habenula circuitry
慢性应激对外侧缰核回路影响的多层次研究
  • 批准号:
    9900592
  • 财政年份:
    2017
  • 资助金额:
    $ 34.35万
  • 项目类别:
Input-specific mechanisms of drug-evoked synaptic plasticity in the ventral tegmental area
腹侧被盖区药物诱发突触可塑性的输入特异性机制
  • 批准号:
    9219915
  • 财政年份:
    2017
  • 资助金额:
    $ 34.35万
  • 项目类别:
Circuit-specific mechanisms of reward and aversion in ventral tegmental area dopamine neurons
腹侧被盖区多巴胺神经元奖励和厌恶的电路特异性机制
  • 批准号:
    10585085
  • 财政年份:
    2017
  • 资助金额:
    $ 34.35万
  • 项目类别:
A multi-level investigation into the effects of chronic stress on lateral habenula circuitry
慢性应激对外侧缰核回路影响的多层次研究
  • 批准号:
    9509539
  • 财政年份:
    2017
  • 资助金额:
    $ 34.35万
  • 项目类别:

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