Elucidating cellular activity patterns underlying spinal cord function

阐明脊髓功能背后的细胞活动模式

基本信息

批准号：
9912873
负责人：
Axel Nimmerjahn
金额：
$ 42.09万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912873
关键词：
Acute Affect Anatomy Anesthetics Animal Model Animals Astrocytes Calcium Capsaicin Communication Data Development Electrophysiology (science)Esthesia Exhibits Exposure to Frequencies Functional disorder Genetic Genetic study Goals Image In Vitro Injections Intervention Ligation Measurement Measures Mechanics Mechanoreceptors Methods Molecular Monitor Mus Nervous System Physiology Neuraxis Neuroglia Neurons Neurosciences Nociception Nociceptors Normal Range Opioid Pain Pain management Pathogenesis Pathologic Pattern Peripheral Pharmaceutical Preparations Pharmacology Pharmacology Study Phase Photons Physiological Population Posterior Horn Cells Pre-Clinical Model Process Research Resolution Role Sensory Shapes Skin Spinal Spinal Cord Spinal cord posterior horn Stimulus Technology Testing Time Viral Work animal tissue awake base calcium indicator cell type dorsal horn excitatory neuron experimental study histological studies imaging approach in vivo inhibitory neuron insight miniaturize neural network novel novel strategies optogenetics pain model pain reduction pain relief pain sensitivity prevent relating to nervous system response sciatic nerve sensory stimulus somatosensory two-photon

项目摘要

PROJECT SUMMARY A key unresolved question in neuroscience is how different cell types and their activity patterns contribute to sensory processing in the central nervous system. Anatomical and physiological measurements indicate that computations underlying somatosensation are initiated in the dorsal horn of the spinal cord. Genetic, electrophysiological, and circuit-tracing methods have identified a number of neuronal populations involved in this process, as well as their potential contributions. Likewise, histologic, pharmacologic, and genetic studies have revealed important roles for glial cells in the pathogenesis and resolution of aberrant sensations. However, despite these advances, little is known about the dynamic neuronal and glial activity patterns, or the interactions between them, that underlie the moment-to-moment processing of innocuous and noxious stimuli. The recent development of novel two-photon and miniaturized one-photon imaging approaches has enabled stable measurement of cellular calcium excitation in the spinal dorsal horn of behaving animals. These technologies have provided the first insights into how sensory information from mechanoreceptors and nociceptors in the skin activates dorsal horn neurons and astrocytes. Using cutting-edge imaging, optogenetic, and pharmacological approaches, the objective of this proposal is to define how the activity patterns of different types of dorsal horn neurons shape astrocyte calcium excitation, and how astrocyte excitation influences neuronal spiking under physiological and pathophysiological conditions. The rationale for the proposed research is that by uncovering the bi-directional relationship between neuron and astrocyte activity in the spinal dorsal horn, new strategies for pain relief may be developed. Three specific aims will be pursued: 1) Determine how sensory evoked activity patterns in molecularly defined neurons relate to astrocyte calcium excitation in the spinal dorsal horn of behaving animals; 2) Determine how aberrant neuronal activity patterns in preclinical models of pain relate to astrocyte calcium excitation in the spinal dorsal horn of behaving animals; and 3) Determine how targeted manipulation of astrocyte calcium excitation controls aberrant neuronal activity patterns in the spinal dorsal horn of behaving animals. In summary, this work will reveal how molecularly defined neurons encode different sensory stimuli and how their activity patterns relate to astrocyte calcium excitation. These efforts will also reveal how normal activity patterns are altered in two animal models of pain and how pharmacologic and non-pharmacologic interventions targeting astrocytes affect aberrant neuronal activity and sensory processing.

项目概要神经科学中一个未解决的关键问题是不同的细胞类型及其活动模式如何促进中枢神经系统的感觉处理。解剖学和生理学测量表明躯体感觉的计算是在脊髓背角启动的。遗传，电生理学和电路追踪方法已经确定了许多参与的神经元群这个过程，以及他们的潜在贡献。同样，组织学、药理学和遗传学研究揭示了神经胶质细胞在异常感觉的发病机制和解决中的重要作用。然而，尽管取得了这些进展，但人们对动态神经元和神经胶质活动模式或神经胶质细胞的活动知之甚少。它们之间的相互作用是无害和有害刺激的即时处理的基础。新型双光子和小型化单光子成像方法的最新发展使得行为动物脊髓背角细胞钙激发的稳定测量。这些技术首次提供了关于机械感受器的感觉信息如何皮肤中的伤害感受器激活背角神经元和星形胶质细胞。利用尖端成像、光遗传学、和药理学方法，该提案的目的是定义不同的活性模式背角神经元的类型塑造星形胶质细胞钙兴奋，以及星形胶质细胞兴奋如何影响生理和病理生理条件下的神经元尖峰。拟议的理由研究是通过揭示脊髓中神经元和星形胶质细胞活动之间的双向关系背角，可能会开发出新的缓解疼痛的策略。将追求三个具体目标： 1) 确定分子定义的神经元中的感觉诱发活动模式如何与星形胶质细胞钙兴奋相关行为动物的脊髓背角； 2) 确定临床前异常神经元活动模式如何疼痛模型与行为动物脊髓背角星形胶质细胞钙兴奋有关；和 3) 确定星形胶质细胞钙兴奋的靶向操作如何控制异常神经元活动行为动物脊髓背角的模式。总之，这项工作将揭示分子如何定义的神经元编码不同的感觉刺激以及它们的活动模式与星形胶质细胞钙的关系励磁。这些努力还将揭示两种疼痛动物模型中正常活动模式是如何改变的以及针对星形胶质细胞的药物和非药物干预如何影响异常神经元活动和感觉处理。