Measuring and manipulating reward circuit plasticity in opiate addiction models

测量和操纵阿片成瘾模型中的奖励回路可塑性

• 批准号: 9017991
• 负责人: Matthew Carl Hearing
• 金额: $ 15.24万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9017991
• 关键词: Abstinence; Adverse effects; Advisory Committees; Amygdaloid structure; Behavior; Biological Neural Networks; Brain; Brain region; Cells; Chemosensitization; Chronic; Corpus striatum structure; Cues; Data; Disease; Dopamine; Dopamine D1 Receptor; Dorsal; 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; 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 of abuse; drug seeking behavior; experience; glutamatergic signaling; hippocampal pyramidal neuron; in vivo; neuroadaptation; neurochemistry; neurotransmission; novel; opioid abuse; optogenetics; prevent; psychostimulant; receptor; research study; synaptic function; tool

DESCRIPTION: 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 electrophysiologicl 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 viv 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.

描述：阿片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隐秘的方面。在复发之前，吸毒者在接触到毒品或与毒品相关的刺激时往往会经历强烈的渴望。对抗成瘾的一个重要步骤是了解在戒毒很长一段时间后恢复吸毒的神经、化学和细胞机制。伏隔核(NAC)是哺乳动物大脑中成瘾药物的关键靶点，为药物成瘾行为提供了动力。虽然药物诱导的NAc AMPA型谷氨酸受体(AMPAR)的可塑性在精神刺激剂复发中已被广泛研究，但阿片类药物诱导的可塑性的时间和解剖动力学以及这些适应如何促进复发尚不清楚。在这里，我通过将全细胞电生理学方法与病毒介导的光敏视蛋白表达(光遗传学)相结合，以及在给药的可操作模型中的荧光报告小鼠，研究了吗啡诱导的突触强度和皮质纹状体脑回路内谷氨酸相关可塑性的适应。我们实验室的实验数据表明，在连续和非连续使用吗啡戒断(10-14天)后，NAC壳区MSN谷氨酸能突触强度增强。在K99 AIMS中，我建议使用成瘾的扩展通路操作模型来描述含有多巴胺D_1-(D_1-MSN)或D_2-(D_2-MSN)受体亚型的NAc中棘神经元(MSN)亚群中突触强度、谷氨酸受体信号和亚单位组成变化的发展和持续的时间进程。接下来，我建议使用直接传递到NAC的光刺激来选择性地激活MSN上表达视紫红质2通道的皮质或杏仁核传入，以评估通路特异性的可塑性变化。K99阶段的培训将在 在马克·托马斯博士的指导下，他是一位测量奖励回路中谷氨酸能突触功能的专家，他的实验室最近将光遗传学工具用于体外和VIV研究。作为我的顾问委员会的一部分，我们从Tim Ebner博士(光遗传学/导师)、Antonello Bonci博士(光遗传学和行为学)和David Self博士(老鼠药物自我管理)那里招募了更多的专业人员。随着我在K99期间接受的神经网络电生理学和光遗传调制方面的培训，我将使用这些技术来进一步确定持续阿片剂诱导的可塑性在上下文中所起的功能作用--提示-- 以及药物引起的复发。使用体内光遗传刺激来削弱NAC MSN上的皮质和/或边缘传入，我预测，在复发测试之前使用已建立的长期抑郁方案恢复“基本”神经传递将防止随后再次出现阿片类药物寻找。最后，我将使用一个新的模型成瘾模型，该模型最近被证明在一组小鼠中促进了强迫性类药物寻找，以探索内侧前额叶皮质和背侧纹状体的兴奋性和抑制性神经传递神经元的变化，这两个大脑区域在阿片类药物可塑性的研究中通常被忽视。这些实验将为阿片成瘾文献以及减少复发的潜在药物治疗目标提供重要贡献。