Measuring and Manipulating Reward Circuit Plasticity in Opiate Addition Models

测量和操纵阿片添加模型中的奖励电路可塑性

• 批准号: 9520990
• 负责人: Matthew Carl Hearing
• 金额: $ 9.5万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9520990
• 关键词: Abstinence; Adverse effects; Advisory Committees; Amygdaloid structure; Anatomy; Behavior; Behavioral; Biological Neural Networks; Brain; Brain region; Cells; Chemosensitization; Chronic; Corpus striatum structure; Cues; Data; Disease; Dopamine; Dopamine D1 Receptor; Dorsal; Drug Modelings; Drug usage; Electrophysiology (science); Exposure to; Future; Glutamate Receptor; Glutamates; Goals; Health; Human; In Vitro; Ion Channel; Knowledge; Label; Light; Literature; Long-Term Depression; Measures; Medial; Mediating; Mentorship; Modeling; Morphine; Motivation; Mus; Nature; Neurobiology; Neurons; Nucleus Accumbens; Opiate Addiction; Opiates; Opioid; Opsin; Optics; Pain management; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological Adaptation; Play; Prefrontal Cortex; Protocols documentation; Psychostimulant dependence; Public Health; Receptor Signaling; Recruitment Activity; Relapse; Reporter; Research; Rewards; Rodent; Role; Self Administration; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; System; Techniques; Testing; Time; Training; Viral; Whole-Cell Recordings; Work; addiction; base; clinically significant; course development; craving; drug abstinence; drug of abuse; drug seeking behavior; experience; experimental study; glutamatergic signaling; hippocampal pyramidal neuron; in vivo; neuroadaptation; neurochemistry; neurotransmission; novel; opioid abuse; optogenetics; prevent; psychostimulant; receptor; synaptic function; tool

Opiate addiction is a major health concern, and its chronic relapsing nature is perhaps its most insidious aspect. Preceding relapse, addicts often experience intense craving when exposed to drug or drug-associated stimuli. An essential step in confronting addiction is understanding the neurochemical and cellular mechanisms responsible for the resumption of drug use long after cessation of drug use. The nucleus accumbens (NAc) is a key target of addictive drugs in the mammalian brain and provides a motive force behind drug-seeing behavior. Although drug-induced plasticity in NAc AMPA-type glutamate receptors (AMPARs) has been studied extensively in psychostimulant relapse, the temporal and anatomical dynamics of opiate-induced plasticity and how these adaptations function to promote relapse is unknown. Here, I examine morphine-induced adaptations in synaptic strength and glutamate-related plasticity within corticostriatal brain circuits by combining whole-cell electrophysiological approaches with viral-mediated expression of light sensitive opsins (optogenetics), and fluorescent reporter mice in operant models of drug-administration. Pilot data from our lab indicate that MSN glutamatergic synaptic strength is potentiated in the NAc shell region following abstinence (10-14 days) from both contingent and non-contingent morphine administration. In the K99 Aims, I propose to delineate the time course of development and persistence of changes in synaptic strength, glutamate receptor signaling and subunit composition in subpopulations of NAc medium spiny neurons (MSNs) containing either the dopamine D1-(D1-MSN) or D2-(D2-MSN) receptor subtype using an extended-access operant model of addiction. Next, I propose to selectively activate channelrhodopsin2- expressing cortical or amygdalar afferents onto MSNs using optical stimulation delivered directly to the NAc to evaluate pathway-specific alterations in plasticity. Training in the K99 phase will be under the guidance of Dr. Mark Thomas, an expert in measuring glutamatergic synaptic function in reward circuits, whose lab has recently incorporated the use of optogenetics tools for in vitro and in vivo study. We have recruited additional expertise from Drs. Tim Ebner (optogenetics/ mentorship), Antonello Bonci (optogenetics and behavior) and David Self (mouse drug self-administration) as part of my advisory committee. With the training in electrophysiology and optogenetic modulation of neural networks I receive during the K99 period, I will employ these techniques to further determine the functional role persistent opiate-induced plasticity plays in context-, cue-, and drug-induced relapse. Using in vivo optogenetic stimulation to depotentiate cortical and/or limbic afferents onto NAc MSNs, I predict that restoring "basal" neurotransmission prior to relapse testing using an established long-term depression protocol will prevent a subsequent return to opiate-seeking. Finally, I will use a novel model addiction model recently shown to promote compulsive-like drug-seeking in a subpopulation of mice to explore changes in excitatory and inhibitory neurotransmission neurons of the medial prefrontal cortex and dorsal striatum, two brain regions that have generally been overlooked in studies of opiate plasticity. These experiments will provide significant contributions to opiate addiction literature as well as potential pharmacotherapeutic targets to mitigate relapse.

阿片类药物成瘾是一个主要的健康问题，其慢性复发的性质可能是其最阴险的 方面.在复吸之前，当暴露于药物或与药物相关的药物时，成瘾者通常会经历强烈的渴望。 刺激。对抗成瘾的一个重要步骤是了解神经化学和细胞化学， 在停止使用毒品很久之后，重新使用毒品的机制。细胞核 NAc是哺乳动物大脑中成瘾药物的关键靶点， 吸毒行为虽然药物诱导的NAc AMPA型谷氨酸受体（AMPAR）的可塑性， 已经在精神兴奋剂复发中进行了广泛的研究，阿片诱导的时间和解剖动力学 可塑性以及这些适应如何促进复发尚不清楚。在这里，我检查吗啡诱导的 皮质纹状体脑回路内突触强度和谷氨酸相关可塑性的适应 将全细胞电生理学方法与病毒介导的光敏视蛋白表达相结合 （光遗传学）和荧光报告小鼠。我们实验室的试验数据 表明戒断后在NAc壳区MSN突触能突触强度增强 （10-14天）。 在K99目标中，我建议描述发展的时间过程和变化的持续性， NAc中突触强度、谷氨酸受体信号和亚基组成 多刺神经元（MSN）含有多巴胺D1-（D1-MSN）或D2-（D2-MSN）受体亚型， 一种扩展的操作性成瘾模型接下来，我建议选择性激活通道视紫红质2- 使用直接递送到NAc的光学刺激将皮质或杏仁核传入表达到MSN上， 评估可塑性的途径特异性改变。K99阶段的培训将在Dr. 马克·托马斯是测量奖赏回路中突触功能的专家，他的实验室拥有 最近将光遗传学工具用于体外和体内研究。我们招募了更多的 Tim Ebner博士（光遗传学/导师）、Antonello Bonci博士（光遗传学和行为学）和 大卫自我（小鼠药物自我管理）作为我的咨询委员会的一部分。 随着神经网络的电生理学和光遗传学调制的训练，我在 K99期，我将采用这些技术进一步确定持续性阿片诱导的功能作用。 可塑性在情境、线索和药物诱导的复发中起作用。使用体内光遗传学刺激来 去增强皮质和/或边缘系统传入NAc MSNs，我预测恢复“基础”神经传递 在复发测试之前，使用已建立的长期抑郁协议将防止随后的复发。 寻求鸦片最后，我将使用一个新的模型成瘾模型，最近显示，促进强迫样 在小鼠亚群中探索药物寻找，以探索兴奋性和抑制性神经传递的变化 内侧前额叶皮层和背侧纹状体的神经元，这两个大脑区域通常被 在阿片可塑性研究中被忽视了这些实验将为阿片类药物提供重要贡献。 成瘾文献以及潜在的药物靶点，以减轻复发。