Dopamine circuit regulation of morphine reinforcement across the opioid exposure cycle

多巴胺回路对​​阿片类药物暴露周期中吗啡强化的调节

• 批准号: 10282160
• 负责人: Barbara Juarez
• 金额: $ 17.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10282160
• 关键词: Abstinence; Academia; Acute; Advisory Committees; Attenuated; Behavior; Behavioral; Biomedical Research; Brain region; CRISPR/Cas technology; Calcium; Cells; Cholecystokinin; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Computational Technique; Corticotropin-Releasing Hormone Receptors; Coupled; Cues; Data Set; Dependence; Development; Dopamine; Dose; Electrophysiology (science); Exposure to; Fiber; Fiber Optics; Foundations; Genes; Genetic; Glutamates; Goals; Heterogeneity; Implant; Injections; Interneurons; Laboratories; Learning; Link; Machine Learning; Measures; Medial; Mediating; Mentors; Methods; Morphine; Morphine Receptors; Motivation; Mus; Mutagenesis; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Pathologic; Pharmaceutical Preparations; Phase; Photometry; Play; Principal Investigator; Psychological reinforcement; Receptor Gene; Receptor Signaling; Regulation; Relapse; Rewards; Role; Synapses; Training; Ventral Tegmental Area; Viral; Virus; Withdrawal; Work; analytical tool; base; behavioral pharmacology; career development; classical conditioning; combinatorial; conditioned place preference; design; dopamine system; dopaminergic neuron; experience; functional loss; gamma-Aminobutyric Acid; genetic approach; in vivo; mesolimbic system; mu opioid receptors; neural correlate; neuroadaptation; neurophysiology; novel; opioid epidemic; opioid exposure; opioid use; opioid use disorder; opioid withdrawal; programs; recruit; relating to nervous system; response; reward processing; sensor; skills; socioeconomics; virtual

PROJECT SUMMARY Pathological adaptions in the ventral tegmental area (VTA) dopamine system associated with chronic exposure to opioids and opioid withdrawal can dysregulate responsivity to opioids and contextual cue associations. The primary goal of this training proposal is to gain new skills in advanced computational techniques to delineate how functionally diverse subpopulations of VTA dopamine neurons are regulated during morphine exposure and the formation of morphine contextual associations in non-dependent and morphine-dependent mice. Foundational findings have identified the intrinsic and synaptic (glutamatergic and GABAergic) adaptations that VTA dopamine neurons undergo throughout acute and chronic opioid exposure. Yet, few studies have accounted for the functional diversity of VTA dopamine neurons that mediate distinct aspects of cue-reward processing and motivation. Dissociating the potential diversity of VTA dopamine responses in the development of opioid dependence will help unravel the neural basis of the progression of opioid-use disorder. The Zweifel lab has previously used a genetic approach to isolate functionally distinct subpopulations of dopamine neurons that project to discrete regions of the nucleus accumbens (NAc). Corticotrophin releasing hormone receptor 1 (Crhr1)-Cre VTA dopamine neurons were found to selectively project to the NAc Core (VTACore) and cholecystokinin (Cck)-Cre VTA dopamine neurons selectively project to the NAc medial Shell (VTAmShell). I hypothesize that there exist projection-specific neural and behavioral correlates in response to morphine and during the formation of morphine contextual associations in non-dependent and morphine-dependent mice. I will investigate this using a systematic approach across three aims. For Aim 1 (K99), I will use behavioral pharmacology and fiber photometry to determine whether VTACore and VTAmShell dopamine neurons engage in uniform or differential dose-dependent neural activation dynamics in non-dependent and morphine dependent mice. For Aim 2 (K99), I will use my skills in conditioned place preference and in vivo fiber photometry to determine how the VTACore and VTAmShell neurons encode contextual associations to morphine in non-dependent and morphine dependent mice. For Aim 3 (R00), I will determine the basis of these pathological adaptations in VTA dopamine subpopulations by dissecting the role mu-opioid receptor (MOR)- sensitive GABAergic inputs play in morphine contextual associations. During the K99 mentored phase, I will gain new scientific training in Dr. Larry Zweifel’s laboratory, augmented by my advisory committee, in computational analytical tools to analyze complex neurophysiological and behavioral data sets. I will also gain new career development training from Dr. Zweifel, my advisory committee, and the MOSAIC UE5 program that will facilitate my transition into a successful independent principal investigator in academia. Importantly, I will continue my work on increasing representation and equity in the biomedical research workforce.

项目摘要 与慢性暴露相关的腹侧被盖区（VTA）多巴胺系统的病理适应 阿片类药物和阿片类药物戒断可以失调的反应阿片类药物和上下文线索协会。的 本培训计划的主要目标是获得高级计算技术的新技能， 在吗啡暴露期间，腹侧被盖区多巴胺神经元的功能多样性亚群是如何被调节的 以及非依赖和吗啡依赖小鼠中吗啡情境关联的形成。 基础研究发现已经确定了内在和突触（谷氨酸能和GABA能）适应， 腹侧被盖区多巴胺神经元在急性和慢性阿片类药物暴露过程中发生变化。然而，很少有研究 解释了腹侧被盖区多巴胺神经元的功能多样性，这些神经元介导线索奖励的不同方面。 加工和动机。分离腹侧被盖区多巴胺反应在发育中的潜在多样性 阿片类药物依赖的研究将有助于解开阿片类药物使用障碍进展的神经基础。关于Zweifel 一个实验室以前曾用遗传学方法分离出功能不同的多巴胺神经元亚群 投射到脑桥核（NAc）的离散区域。促肾上腺皮质激素释放激素受体1 发现（Crhr 1）-Cre VTA多巴胺神经元选择性投射到NAc核心（VTA CARBON Core）， 胆囊收缩素（Cck）-Cre VTA多巴胺神经元选择性投射到NAc内侧壳（VTA内侧壳）。我 假设在对吗啡反应中存在投射特异性神经和行为相关性， 在非依赖性和吗啡依赖性小鼠中形成吗啡关联的过程中。我 我们将通过三个目标的系统方法对此进行研究。对于目标1（K99），我将使用行为 药理学和纤维光度法，以确定是否VTA的核心和VTA的壳多巴胺神经元 在非依赖性和吗啡依赖性中参与均匀或差异剂量依赖性神经激活动力学 依赖的老鼠对于目标2（K99），我将使用我在条件位置偏好和体内纤维方面的技能 光度测定，以确定VTA神经元核心和VTA神经元外壳如何编码上下文关联， 吗啡在非依赖和吗啡依赖小鼠中的作用。对于目标3（R 00），我将确定这些目标的基础。 通过剖析μ-阿片受体（莫尔）在腹侧被盖区多巴胺亚群中的作用， 敏感的GABA能输入在吗啡关联中起作用。在K99指导阶段，我将 在拉里·茨韦费尔博士的实验室里获得新的科学训练，并得到我的顾问委员会的支持， 计算分析工具来分析复杂的神经生理和行为数据集。我也会得到 我的顾问委员会Zweifel博士和MOSAIC UE 5计划提供的新职业发展培训， 将有助于我成为一名成功的学术界独立首席研究员。重要的是，我会 继续我的工作，增加代表性和公平的生物医学研究劳动力。