Mechanisms of pathway-specific plasticity in the incubation of craving

渴望孵化过程中路径特异性可塑性的机制

基本信息

批准号：
9318063
负责人：
John F Neumaier
金额：
$ 42.65万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2017-05-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318063
关键词：
Abstinence Affect Animal Model Automobile Driving Behavior Behavioral Brain Brain Diseases Brain region CAV2 gene Cells Cellular Structures Cocaine Cocaine Dependence Complex Corpus striatum structure Data Decision Making Dendrites Drug usage Engineering Event Exposure to Extinction (Psychology)Gases Genetic Transcription Globus Pallidus Glutamates Goals Individual Injectable Knowledge Laboratories LoxP-flanked allele Measures Mediating Messenger RNA Methods MicroRNAs Modeling Molecular Monitor Neurons Nucleus Accumbens Output Pathway Analysis Pathway interactions Pattern Pharmaceutical Preparations Play Polyribosomes Process Protein Biosynthesis Proteins RNA Rattus Relapse Ribosomes Role Second Messenger Systems Self Administration Signal Pathway Signal Transduction Signal Transduction Pathway Specific qualifier value Synapses Synaptic plasticity Synaptosomes Technology Testing Time Training Transgenes Transgenic Organisms Translating Translations Ventral Striatum Ventral Tegmental Area Viral Vector addiction adeno-associated viral vector base cocaine exposure cocaine use combinatorial compulsion craving designer receptors exclusively activated by designer drugs drug relapse experience experimental study innovation intersectionality neurotransmission new therapeutic target novel novel strategies receptor receptor expression response retrograde transport selective expression tool transcriptome sequencing transgene expression treatment strategy

Abstinence Affect Animal Model Automobile Driving Behavior Behavioral Brain Brain Diseases Brain region CAV2 gene Cells Cellular Structures Cocaine Cocaine Dependence Complex Corpus striatum structure Data Decision Making Dendrites Drug usage Engineering Event Exposure to Extinction (Psychology)Gases Genetic Transcription Globus Pallidus Glutamates Goals Individual Injectable Knowledge Laboratories LoxP-flanked allele Measures Mediating Messenger RNA Methods MicroRNAs Modeling Molecular Monitor Neurons Nucleus Accumbens Output Pathway Analysis Pathway interactions Pattern Pharmaceutical Preparations Play Polyribosomes Process Protein Biosynthesis Proteins RNA Rattus Relapse Ribosomes Role Second Messenger Systems Self Administration Signal Pathway Signal Transduction Signal Transduction Pathway Specific qualifier value Synapses Synaptic plasticity Synaptosomes Technology Testing Time Training Transgenes Transgenic Organisms Translating Translations Ventral Striatum Ventral Tegmental Area Viral Vector addiction adeno-associated viral vector base cocaine exposure cocaine use combinatorial compulsion craving designer receptors exclusively activated by designer drugs drug relapse experience experimental study innovation intersectionality neurotransmission new therapeutic target novel novel strategies receptor receptor expression response retrograde transport selective expression tool transcriptome sequencing transgene expression treatment strategy

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项目摘要

Abstract Cocaine addiction involves the loss of control over drug taking so that individuals take more drug over time and can have prolonged vulnerability to relapsing to drug seeking, even after extended periods of abstinence. The progressive molecular and synaptic adaptations in neurons in the CNS that underlie these changes are not well understood, but can be studied using animal models based on extended cocaine self-administration followed by abstinence in rats. These models have shown that the nucleus accumbens core (NAcC), a small but critical brain region in ventral striatum, is implicated in compulsive cocaine taking and relapse to cocaine seeking after extended abstinence. The NAcC receives and integrates afferent information from many different brain regions and has two main output projections, the direct and indirect pathways; these pathways tend to oppose one another functional, and we predict that adaptations in signaling processes within these neurons are critical determinants affecting the relapse to drug seeking. By understanding the adaptations in cell signaling in these NAcC output neurons following extensive cocaine exposure and abstinence, we hope to contribute to novel treatment strategies for reducing the potential for relapse to drug seeking. We propose to investigate the time-dependent increase in drug seeking during abstinence known as the “incubation of craving”. We will use several innovative tools. First, we will use an intersectional viral vector approach to introduce DREADDs and other transgenic proteins to perturb and study direct and indirect pathway neurons selectively during incubation. By injecting AAV vectors with floxed and inverted transgenes into NAcC, we can activate transgene expression selectively in the direct or indirect pathway neurons by injecting the ventral tegmental area or ventral pallidum with CAV2-Cre, which is retrogradely transported to the cell bodies in NAcC. Second, we will use engineered “DREADD” receptors, a technology that we helped to establish for use in rat brain during complex behavioral experiments. DREADDs will allow us to activate Gs or Gi signaling pathways selectively in either direct or indirect pathway neurons during either repeatedly during cocaine taking or during early or late forced abstinence, thereby assessing how these canonical second messenger pathways modulate the plasticity involved in escalation or incubation. Third, we will utilize RiboTag technology to immunopurify polyribosomes selectively from direct or indirect pathway neurons and investigate the changes in RNA translation in these opposing pathways during abstinence and incubation of craving, both in cell bodies and in the synapses where activity dependent changes in local protein translation has been described. By perturbing and measuring signaling pathways in specified neurons, we hope to develop new strategies for ameliorating the adaptations associated with compulsive drug use and relapse to seeking.

抽象的可卡因成瘾涉及失去对药物服用的控制，以便个人随着时间的推移服用更多药物，即使在戒酒长期之后，也可能长时间脆弱地恢复到毒品。这基于这些变化的中枢神经系统中神经元的进行性分子和突触适应不是理解，但可以使用基于扩展可卡因自我管理的动物模型进行研究其次是大鼠的禁欲。这些模型表明，伏隔核核心（NACC）是一个小的但是腹侧纹状体中的关键大脑区域在强迫性可卡因和可卡因缓解中暗示寻求延长的禁欲。 NACC接收并集成了许多不同的传入信息大脑区域有两个主要的输出项目，即直接和间接途径；这些途径往往互相反对功能，我们预测这些神经元内信号传导过程中的适应是关键的决定者，影响了对吸毒的缓解。通过了解细胞中的适应在广泛的可卡因暴露和戒酒后，这些NACC输出神经元中的信号传导，我们希望有助于新的治疗策略，以减少减轻吸毒的潜力。我们建议研究在禁欲期间寻求药物的时间依赖性增加 “渴望孵化”。我们将使用几种创新工具。首先，我们将使用交叉病毒载体介绍可怕和其他转基因蛋白的方法以驱动并研究直接和间接孵育过程中选择性途径神经元。通过注射AAV矢量有floxed and倒翻译进入NACC，我们可以在直接或间接途径神经元中选择性地激活转化表达向腹侧换段区域或腹侧粒子注入Cav2-cre，该cav2-cre逆转到 NACC中的细胞体。其次，我们将使用工程的“ Dreadd”受体，这是我们帮助的技术在复杂的行为实验中建立用于大鼠脑的使用。恐怖将使我们能够激活GS或 gi信号传导途径在两次反复的直接或间接途径神经元中选择性地在可卡因服用或在强迫节制的早期或晚期，从而评估这些规范的第二 Messenger通路调节升级或孵育所涉及的可塑性。第三，我们将使用Ribotag 从直接或间接途径神经元中选择性化多核糖体的免疫性多核糖体并进行调查的技术在禁欲和渴望中，这些相反途径中RNA翻译的变化，既在细胞体和突触中，局部蛋白质翻译的活性变化一直是描述。通过扰动和测量指定神经元中的信号通路，我们希望开发新的改善与强迫毒品使用和救济相关的适应性策略。