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; 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.

项目摘要/摘要 疼痛是一种令人衰弱的状况，严重影响生活质量。尽管对新治疗的需求越来越 对疼痛的神经回路的不完全理解限制了新型疼痛的发展 疗法。脊髓表面背喇叭通道疼痛信号中的脊柱投影神经元 进入大脑。这些神经元可能是未来疼痛管理策略的可行目标。而实际上 所有介导伤害感受的脊柱输出神经元针对对侧止痛核，子集的子集 这些神经元还投射到其他脊柱上结构，例如同侧副核（Spino-spino-- PBN神经元）或对侧周围灰色（Spino-PAG神经元）。考虑到明显的抵押 这些神经元的模式，我假设Spino-PBN和Spino-Pag神经元具有独特的 伤害感受功能。我将使用解剖学（AIM 1），功能（AIM 2）和行为来检验此假设 （目标3）方法。 AIM 1将表征Spino-Pag和Spino-PBN神经元的投影模式 通过逆行病毒追踪，光学清除和色带扫描共聚焦显微镜。 AIM 2将确定 使用两光子钙成像的Spino-PAG和Spino-PBN神经元的功能响应特性 和天然刺激应用于离体制备。 AIM 3将发现Spino-Pag和Spino-的作用 PBN神经元在使用化学遗传学和伤害感受制的行为测定中介导非分性行为的PBN神经元。这 该提案中描述的实验有可能提高我们对脊柱输出的基本理解 介导伤害感受的电路并有助于确定脊柱投射神经元作为新目标的疗效 临床干预。为了完成这项建议，我将从 专家科学家和临床医师团队。这项培训将使我成为独立的 调查员，让我实现了成为专门从事疼痛的医师科学家的长期目标。