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

基本信息

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
项目类别：
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

项目摘要

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.

阿片成瘾是一个主要的健康问题，其慢性复发性可能是其最阴险的方面。在复发之前，成瘾者在接触药物或与药物相关的药物时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负责在停止吸毒后很长时间恢复吸毒的机制。细胞核伏隔核（NAc）是哺乳动物大脑中成瘾药物的关键目标，并提供了背后的动力看到毒品的行为。尽管药物诱导的 NAc AMPA 型谷氨酸受体 (AMPAR) 具有可塑性在精神兴奋剂复发、阿片类药物引起的时间和解剖动力学方面进行了广泛的研究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）和药物管理操作模型中的荧光报告小鼠。来自我们实验室的试点数据表明禁欲后 MSN 谷氨酸突触强度在 NAc 壳区域增强（10-14 天）来自偶然和非偶然吗啡给药。在K99目标中，我建议描绘出变化的发展和持续的时间过程。 NAc 培养基亚群中的突触强度、谷氨酸受体信号传导和亚基组成含有多巴胺 D1-(D1-MSN) 或 D2-(D2-MSN) 受体亚型的棘神经元 (MSN) 成瘾的扩展访问操作模型。接下来，我建议选择性地激活视紫红质通道2- 使用直接传递到 NAc 的光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 (Mark Thomas) 是测量奖励回路中谷氨酸突触功能的专家，他的实验室最近将光遗传学工具的使用纳入体外和体内研究。我们已经招募了额外的博士的专业知识。 Tim Ebner（光遗传学/指导）、Antonello Bonci（光遗传学和行为）和 David Self（小鼠自我给药）是我的顾问委员会的成员。通过我在神经网络的电生理学和光遗传学调制方面的培训 K99期间，我将运用这些技术来进一步确定持久阿片引起的功能作用可塑性在环境、暗示和药物引起的复发中发挥作用。利用体内光遗传学刺激减弱皮质和/或边缘传入 NAc MSN 的能力，我预测恢复“基础”神经传递在复发之前使用既定的长期抑郁方案进行测试将防止随后复发寻求鸦片剂。最后，我将使用最近展示的一种新颖的成瘾模型来促进类似强迫的行为在小鼠亚群中寻找药物以探索兴奋性和抑制性神经传递的变化内侧前额皮质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。这些实验将为阿片类药物做出重大贡献成瘾文献以及减轻复发的潜在药物治疗目标。