Elucidating cellular activity patterns underlying spinal cord function

项目总结 神经科学中一个关键的悬而未决的问题是，不同的细胞类型及其活动模式如何对 中枢神经系统中的感觉处理。解剖和生理测量表明 躯体感觉的计算始于脊髓的背角。基因， 电生理学和电路追踪方法已经确定了一些涉及到 这一进程，以及它们的潜在贡献。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，尽管有这些进展，人们对动态神经元和神经胶质活动模式知之甚少，即 它们之间的相互作用，这是无害和有害刺激的时刻到时刻处理的基础。 新的双光子和小型化单光子成像方法的最新发展使 行为动物脊髓背角细胞钙兴奋的稳定测量。这些 技术提供了第一个洞察力，让我们了解机械感受器和 皮肤中的伤害性感受器激活背角神经元和星形胶质细胞。使用尖端成像，光遗传， 和药理学方法，这项提议的目的是定义如何不同的活动模式 背角神经元的类型决定星形胶质细胞的钙兴奋，以及星形胶质细胞的兴奋如何影响 生理和病理生理条件下的神经元放电。建议的理由是 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，可能会开发出新的止痛策略。将追求三个具体目标：1)确定 分子定义神经元的感觉诱发活动模式与星形胶质细胞钙兴奋的关系 行为动物的脊髓背角；2)决定临床前的异常神经元活动模式 疼痛模型与行为动物脊髓背角星形胶质细胞钙兴奋有关； 确定星形胶质细胞钙激发的靶向操作如何控制异常神经元活动 行为动物的脊髓后角的图案。总而言之，这项工作将揭示分子如何 已定义的神经元编码不同的感觉刺激及其活动模式与星形胶质细胞钙的关系 激动人心。这些努力还将揭示两种疼痛动物模型的正常活动模式是如何改变的 以及针对星形胶质细胞的药理学和非药理学干预如何影响异常神经元 活动和感觉处理。

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.