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.

鸦片成瘾是一个主要的健康问题，其慢性复发性质也许是它最阴险的方面。先前的复发，瘾君子在暴露于药物或药物相关时经常感到渴望刺激。面对成瘾的重要步骤是了解神经化学和细胞停止使用药物后很长一段时间，导致药物使用恢复的机制。核伏隔（NAC）是哺乳动物大脑中成瘾药物的关键目标，并在背后提供动力吸毒行为。尽管NAC AMPA型谷氨酸受体（AMPARS）中药物诱导的可塑性具有在精神刺激剂复发，鸦片诱导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性如何促进复发。在这里，我检查了吗啡诱导的通过皮质上的脑电路内的突触强度和与谷氨酸相关的可塑性的适应将全细胞电生理方法与病毒介导的光敏感蛋白的表达相结合（光遗传学）和药物管理操作模型中的荧光记者小鼠。我们实验室的试点数据表明MSN禁欲后，NAC壳区域在NAC壳区域增强了MSN谷氨酸能突触强度（10-14天）来自或非吗啡给药。在K99的目的中，我建议描述开发时间和变化的持续时间 NAC培养基的亚群中的突触强度，谷氨酸受体信号传导和亚基组成使用多巴胺D1-（D1-MSN）或D2-（D2-MSN）受体亚型的刺刺神经元（MSN）成瘾的扩展访问操作模型。接下来，我建议选择性激活ChannelRhodopsin2- 使用直接传递到NAC到NAC的光刺激向MSN表达皮质或杏仁核的传入评估可塑性的特定途径变化。 K99阶段的培训将在Dr.博士的指导下进行。马克·托马斯（Mark Thomas），奖励电路中测量谷氨酸能突触功能的专家，其实验室具有最近，将光遗传学工具用于体外和体内研究。我们招募了其他博士的专业知识。蒂姆·埃伯纳（tim Ebner）（光遗传学/指导），安东内洛·邦奇（Antonello Bonci）（光遗传学和行为）和作为我咨询委员会的一部分，大卫·塞尔（David Self）（老鼠毒品自我管理）。随着我在我接受的神经网络的电生理学和光遗传学调节的培训。 K99时期，我将采用这些技术进一步确定功能作用可塑性在上下文，提示和药物诱导的复发中发挥作用。使用体内光遗传学刺激我预测恢复“基础”神经传递在使用已建立的长期抑郁方案进行复发测试之前，将防止随后返回寻求鸦片。最后，我将使用最近显示的新型模型成瘾模型来促进强迫性样在小鼠亚群中寻求药物，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纹状体的神经元，通常是两个大脑区域在研究鸦片可塑性的研究中被忽略了。这些实验将为鸦片提供重大贡献成瘾文献以及潜在的药物治疗靶标可减轻复发。