From the spinal cord to the brain: Neurology of the pain and itch neurons

从脊髓到大脑：疼痛和瘙痒神经元的神经学

• 批准号: 10544425
• 负责人: Allan I. Basbaum
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544425
• 关键词: Ablation; Afferent Neurons; Behavioral; Behavioral Paradigm; Brain; Cell Transplantation; Electrophysiology (science); Heterogeneity; Human; Imaging Techniques; Injury; Interneurons; Knowledge; Lead; Mechanics; Mediating; Molecular; Molecular Genetics; Mus; Neurology; Neurons; Pain; Pain quality; Population; Process; Property; Pruritus; Rabies; Research; Signal Transduction; Simplexvirus; Spinal Cord; Stimulus; Time; Validation; Viral; animal pain; awake; base; cellular imaging; chronic itch; chronic pain; chronic pain management; designer receptors exclusively activated by designer drugs; experience; experimental study; imaging approach; innovation; insight; molecular subtypes; mouse model; multidisciplinary; neuron development; novel; novel strategies; pain perception; programs; response; segregation; virus genetics

Despite tremendous progress in our understanding of the primary sensory neurons and spinal cord interneuronal circuits that respond to and transmit pain and itch-provoking stimuli, how these stimuli are interpreted by the brain to produce the perceptions of pain and itch are still unclear. To a great extent, this gap in our knowledge reflects the much more limited information that we have about the projection neurons that carry the information from the spinal cord to the brain. That gap is critical as it is the signals carried by the projection neurons that are “read” by the brain and that ultimately lead to a perception of pain or itch, and to their various submodalities (heat, cold, mechanical, etc.). Our research program is multidisciplinary, using novel viral, genetic and functional (electrophysiological, behavioral and imaging) approaches to characterize the properties of the projection neurons, the circuits that engage them, their supraspinal targets and the functional consequence of their activity. An important focus of the research program is on the question of convergence or segregation of the circuits that respond to painful or itch-provoking stimuli and the extent to which these circuits are altered in the setting of injury. Our program includes several highly innovative experiments that for the first time will not only determine the molecular heterogeneity of the projection neurons, but will also examine the responses of populations of neurons in the brain to activity in the projection neurons. Defining molecular subtypes of projection neurons and the development of Cre-expressing mice based on these molecular features will permit a host of experiments, including viral-based retrograde (rabies) and anterograde (HSV) tracing of circuits that influence subsets of projection neurons, as well as the behavioral consequence of selective ablation, or DREADD-mediated activation/inhibition of these neurons. Finally, using incredibly powerful Ca2+ imaging techniques that signal the activity of populations of neurons in awake, freely moving mice, we will obtain new information on the behavioral correlates of algogen and pruritogen-evoked supraspinal activity. Using novel behavioral paradigms our program will also provide important insights into the processes through which noxious, and even innocuous stimuli (in the setting of injury), are interpreted as painful. These new approaches will provide information about the quality of the pain that the animal experiences and also offer a powerful validation of the mouse models of chronic pain and itch and their translatability to the human condition.

尽管我们对初级感觉神经元和脊髓的了解取得了巨大的进步 反应和传递疼痛和瘙痒刺激的神经元间电路，这些刺激是如何 被大脑解释为产生疼痛和瘙痒知觉的人仍然不清楚。在很大程度上，这种差距 在我们的知识中反映了我们拥有的关于投射神经元的更有限的信息 将信息从脊髓传递到大脑。这种差距是至关重要的，因为它是由 投射神经元被大脑“读取”，最终导致疼痛或瘙痒的感觉，并 它们的各种子模式(热、冷、机械等)。我们的研究项目是多学科的，使用 新的病毒、遗传和功能(电生理、行为和成像)方法来表征 投射神经元的特性，连接它们的回路，它们的脊髓上靶点和 他们活动的功能后果。研究计划的一个重要焦点是……问题 对疼痛或瘙痒刺激作出反应的回路的汇聚或分离，以及 在受伤的情况下，这些回路会被改变。我们的节目包括几个极具创新性的 这些实验不仅将首次确定投射神经元的分子异质性， 但也将检查大脑中神经元群体对投射神经元活动的反应。 确定投射神经元的分子亚型和表达Cre的小鼠的发育 这些分子特征将允许进行一系列实验，包括基于病毒的逆行(狂犬病)和 顺行(HSV)跟踪影响投射神经元子集的电路以及行为 选择性消融或DREADD介导的这些神经元的激活/抑制的后果。最后，使用 令人难以置信的强大的钙离子成像技术，自由地发出醒着的神经元群体活动的信号 移动小鼠，我们将获得关于过敏原和瘙痒原诱发的行为相关性的新信息 脊椎上活动。使用新的行为范式，我们的程序还将提供对 有害的，甚至无害的刺激(在伤害的背景下)被解释为 很痛苦。这些新的方法将提供关于动物疼痛质量的信息 并提供了对慢性疼痛和瘙痒的小鼠模型以及它们的 对人类条件的可译性。