Nucleus accumbens fast-spiking interneurons regulate opioid reward and addiction

伏隔核快速尖峰中间神经元调节阿片类药物奖励和成瘾

基本信息

批准号：
10369837
负责人：
Emilia M Lefevre
金额：
$ 16.46万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369837
关键词：
Acute Amygdaloid structure Award Behavior Biological Factors Brain region Calcium Cells Chronic Cues Data Dependence Development Electrophysiology (science)Epidemic Female Fentanyl Fiber Foundations Future Goals Image Interneurons Intervention Knowledge Maintenance Mediating Mediator of activation protein Mentors Mentorship Minnesota Mission Modeling Molecular Motivation Mus National Institute of Drug Abuse Neurons Nucleus Accumbens Opiate Addiction Opioid Oxycodone Pathway interactions Pattern Pharmaceutical Preparations Phase Photometry Play Population Postdoctoral Fellow Property Protocols documentation Psychological reinforcement Public Health Publications Relapse Research Rewards Role Self Administration Source Synapses Synaptic plasticity Techniques Testing Thalamic structure Therapeutic Training United States National Institutes of Health Universities Viral addiction attenuation behavioral pharmacology behavioral plasticity career career development combat design designer receptors exclusively activated by designer drugs drug seeking behavior effective intervention experimental study in vivo in vivo monitoring innovation male mu opioid receptors neural circuit neuroregulation novel novel therapeutics opioid abuse opioid epidemic opioid use disorder optogenetics patch clamp post-doctoral training prevent programs public health relevance relating to nervous system response reward circuitry tool translational therapeutics

项目摘要

Project Abstract Opioid addiction is a public health crisis, characterized by compulsive drug seeking and a pervasive vulnerability to relapse, with few therapeutic options available. The nucleus accumbens (NAc) is a central hub within reward circuitry and plays a critical role in the motivational value of drugs and drug-associated cues. Within the heterogeneous neuronal subtypes of the NAc exist the sparsely distributed fast-spiking interneurons (FSIs). The NAc FSIs receive strong excitatory inputs from cortical, thalamic and limbic regions and exert powerful inhibition over the local projection neurons, making them a prime candidate for translational therapeutic strategies to reduce the burden of the opioid abuse epidemic. The overall objectives of this application are to elucidate how NAc FSI circuitry responds to, and mediates, opioid self-administration. Under the primary mentorship of Dr. Patrick Rothwell at the University of Minnesota, Dr. Lefevre has utilized graduate training in molecular and behavioral pharmacology techniques, and post-doctoral training in ex- vivo electrophysiology to study adaptations in NAc circuitry in non-contingent opioid addiction models. This Pathway to Independence Award will provide the opportunity to broaden the candidate’s expertise to include in vivo fiber photometry calcium imaging, and chemogenetics, under the continued mentorship of Dr. Rothwell. To expand career development in addiction research, Dr. Lefevre will receive additional support from co-mentor Dr. Mark Thomas in the implementation of contingent opioid self-administration models in female and male mice. During the mentored (K99) phase of the award, fiber photometry calcium imaging will be used to monitor in vivo activity patterns of NAc FSIs in an Intermittent Access (IntA) fentanyl self-administration protocol to identify how this neural population responds to contingent fentanyl and fentanyl-associated cues. Subsequently, a chemogenetic approach, which will involve targeted expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) by NAc FSIs, will be used to test the hypothesis that these neurons play a functional role in addiction-related behavior. Following fentanyl self-administration, DREADDs will be used to excite or inhibit NAc FSIs prior to progressive ratio and cue-induced reinstatement tests. This innovative combination of tools will be used to test the relationship between NAc FSIs and the manifestation of fentanyl self-administration. The R00 phase of the award will distinguish Dr. Lefevre’s independent research from her mentors and broaden to identifying the role of excitatory synaptic inputs to NAc FSIs. Ex-vivo electrophysiology will be utilized to define input-specific excitatory synaptic plasticity adaptations in NAc FSIs induced by fentanyl self- administration. Additionally, the R00 aims will incorporate electrophysiology, optogenetic and calcium imaging expertise to develop stimulation protocols that restore opioid induced shifts in FSI circuitry and addiction-like behavior. Overall, the aims proposed in this award will identify key FSI circuits in opioid self-administration and provide the foundation for Dr. Lefevre’s independent research program studying the neural circuitry of addiction.

项目摘要阿片类药物成瘾是一场公共卫生危机，其特点是强迫性寻求药物和普遍存在的伏隔核（NAc）是一个中心枢纽，容易复发，几乎没有可用的治疗选择。在奖励回路中，在药物和药物相关线索的激励价值中发挥着关键作用。 NAc 的异质神经元亚型存在稀疏分布的快速尖峰中间神经元 (FSIs)。 NAc FSI 接收来自皮质、丘脑和边缘区域的强烈兴奋性输入，并发挥强大的作用对局部投射神经元的抑制，使它们成为转化治疗的主要候选者减少阿片类药物滥用流行负担的策略本申请的总体目标是阐明 NAc FSI 电路如何响应和介导阿片类药物的自我给药。 Lefevre 博士在明尼苏达大学 Patrick Rothwell 博士的指导下，利用分子和行为药理学技术的研究生培训以及前博士后培训体内电生理学研究非偶然阿片成瘾模型中 NAc 电路的适应性。独立之路奖将提供扩大候选人专业知识的机会，以纳入在 Rothwell To 博士的持续指导下，体内纤维光度法钙成像和化学遗传学。为了扩大成瘾研究的职业发展，Lefevre 博士将得到共同导师 Dr. Lefevre 的额外支持。马克·托马斯（Mark Thomas）在雌性和雄性小鼠中实施偶发阿片类药物自我给药模型。在该奖项的指导（K99）阶段，光纤光度法钙成像将用于监测间歇性获取 (IntA) 芬太尼自我给药方案中 NAc FSI 的体内活性模式，以识别该神经群体如何对偶然的芬太尼和芬太尼相关线索做出反应。化学遗传学方法，其中涉及由以下物质独家激活的设计受体的靶向表达 NAc FSI 的设计药物 (DREADD) 将用于测试这些神经元发挥功能的假设在芬太尼自我给药后，DREADD 将用于兴奋或兴奋。在渐进比率和提示诱导恢复测试之前抑制 NAc FSI 这种创新组合。将使用工具来测试 NAc FSI 与芬太尼自我给药表现之间的关系。该奖项的 R00 阶段将 Lefevre 博士的独立研究与她的导师和将利用离体电生理学来扩大确定兴奋性突触输入对 NAc FSI 的作用。定义由芬太尼自体诱导的 NAc FSI 中输入特异性兴奋性突触可塑性适应此外，R00 的目标将包括电生理学、光遗传学和钙成像。开发刺激方案的专业知识，以恢复阿片类药物引起的 FSI 电路和成瘾样变化总体而言，该奖项提出的目标将确定阿片类药物自我管理和行为中的关键 FSI 回路。为 Lefevre 博士研究成瘾神经回路的独立研究项目提供了基础。