Understanding the functional anatomy of nociceptive spinal output neurons

了解伤害性脊髓输出神经元的功能解剖结构

• 批准号: 10751126
• 负责人: Isabel Bleimeister
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751126
• 关键词: Affect; Affective; Anatomy; Behavior; Behavior monitoring; Behavioral; Behavioral Assay; Bilateral; Biological Assay; Brain; Calcium; Cell Nucleus; Clinical; Contralateral; Data; Development; Future; Genetic; Goals; Image; Intervention; Ipsilateral; Knowledge; Laser Scanning Confocal Microscopy; Mediating; Mentors; Modeling; Neurons; Nociception; Optics; Output; Pain; Pain management; Pathway interactions; Patient-Focused Outcomes; Pattern; Persons; Physicians; Play; Population; Preparation; Property; Quality of life; Research Personnel; Role; Scientist; Side; Signal Transduction; Spinal; Spinal Cord; Stimulus; Structure; Technical Expertise; Testing; Thalamic structure; Therapeutic; Therapeutic Intervention; Training; Vertebral column; Viral; behavioral response; career; cell type; cellular targeting; chronic pain; clinical research site; designer receptors exclusively activated by designer drugs; detector; dorsal horn; efficacy evaluation; experimental study; genetic manipulation; improved outcome; midbrain central gray substance; neural circuit; neuronal patterning; neurotransmission; new therapeutic target; novel; pain signal; parabrachial nucleus; response; somatosensory; tool; transmission process; two-photon; virtual

Project Summary/Abstract Pain is a debilitating condition that severely impacts quality of life. Despite a growing need for new treatments, an incomplete understanding of the neural circuitry underlying pain has limited the development of novel pain therapeutics. Spinal projection neurons in the superficial dorsal horn channel pain signals from the spinal cord into the brain. These neurons may represent a viable target for future pain management strategies. While virtually all the spinal output neurons mediating nociception target the contralateral parabrachial nucleus, subsets of these neurons also project to other supraspinal structures, such as the ipsilateral parabrachial nucleus (spino- PBN neurons) or the contralateral periaqueductal gray (spino-PAG neurons). Given the distinct collateralization patterns of these neurons, I hypothesize that the spino-PBN and spino-PAG neurons have distinct nociceptive functions. I will test this hypothesis using anatomical (Aim 1), functional (Aim 2), and behavioral (Aim 3) approaches. Aim 1 will characterize the projection patterns of the spino-PAG and spino-PBN neurons through retrograde viral tracing, optical clearing, and ribbon scanning confocal microscopy. Aim 2 will determine the functional response properties of the spino-PAG and spino-PBN neurons using two-photon calcium imaging and natural stimuli applied to an ex vivo preparation. Aim 3 will uncover the role of the spino-PAG and spino- PBN neurons in mediating nocifensive behavior using chemogenetics and behavioral assays of nociception. The experiments described in this proposal have the potential to advance our basic understanding of the spinal output circuitry mediating nociception and help determine the efficacy of spinal projection neurons as new targets for clinical intervention. To complete this proposal, I will receive rigorous intellectual and technical training from a team of expert scientist and clinician mentors. This training will enable me to become an independent investigator, allowing me to accomplish my long-term goal of becoming a physician-scientist specializing in pain.

项目概要/摘要 疼痛是一种使人衰弱的疾病，严重影响生活质量。尽管对新疗法的需求不断增长， 对疼痛背后的神经回路的不完全理解限制了新型疼痛的发展 疗法。浅表背角中的脊髓投射神经元传递来自脊髓的疼痛信号 进入大脑。这些神经元可能代表未来疼痛管理策略的可行目标。虽然实际上 所有介导伤害感受的脊髓输出神经元都以对侧臂旁核为目标， 这些神经元还投射到其他脊髓上结构，例如同侧臂旁核（脊髓- PBN 神经元）或对侧导水管周围灰质（spino-PAG 神经元）。鉴于不同的抵押 这些神经元的模式，我假设 spino-PBN 和 spino-PAG 神经元具有不同的 伤害感受功能。我将使用解剖学（目标 1）、功能性（目标 2）和行为学来检验这个假设 （目标 3）逼近。目标 1 将表征 spino-PAG 和 spino-PBN 神经元的投射模式 通过逆行病毒追踪、光学透明和带状扫描共聚焦显微镜。目标 2 将决定 使用双光子钙成像的 spino-PAG 和 spino-PBN 神经元的功能响应特性 以及应用于离体制剂的自然刺激。目标 3 将揭示 spino-PAG 和 spino- 的作用 PBN 神经元利用化学遗传学和伤害感受行为分析来介导伤害行为。这 该提案中描述的实验有可能增进我们对脊髓输出的基本理解 介导伤害感受的电路并有助于确定脊髓投射神经元作为新目标的功效 临床干预。为了完成这个提案，我将接受严格的智力和技术培训 由专家科学家和临床医生导师组成的团队。这次培训将使我成为一个独立的人 研究员，使我能够实现成为一名专门研究疼痛的医师科学家的长期目标。