Genetic Mapping of Somatosensory Neural Networks

体感神经网络的遗传图谱

• 批准号: 6907025
• 负责人: David D McKemy
• 金额: $ 22.55万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6907025
• 关键词: afferent nerve; agglutinins; artificial chromosomes; behavior test; cell surface receptors; central neural pathway /tract; diphtheria toxin; dorsal horn; gene expression; genetic mapping; genetic models; genetic promoter element; genetically modified animals; green fluorescent proteins; immunocytochemistry; inflammation; laboratory mouse; membrane channels; model design /development; nerve injury; neural information processing; neurogenetics; pain; plant proteins; somesthetic sensory cortex

DESCRIPTION (provided by applicant): In mammals, the detection of stimuli of a chemical, mechanical, or thermal nature occurs through a complex network of primary and higher-order sensory neurons that make up our somatosensory system. A significant advance in our understanding of somatosensation at the molecular level came from the identification of members of the transient receptor potential (TRP) channel family as the primary detectors of thermal stimuli in peripheral nerves. These "thermosensors" are sensitive over distinct temperature ranges and, in most cases, define discrete populations of sensory neurons. However, how signals evoked by thermal stimuli are interpreted and processed at levels higher than the peripheral afferents, as well as the architecture of the neural networks used to communicate these stimuli is still unclear. The aims of this application are to develop genetic model systems that will enable the mapping of somatosensory neural networks involved in the detection of specific stimulus modalities. These exploratory studies will focus on the recently cloned cold and menthol receptor, CMR1 or TRPM8. We intend to use the TRPM8 transcriptional promoter to specifically express a transneuronal tracer in TRPM8+ peripheral afferent nerves in order to map the neural networks and synaptic connections used by these neurons to communicate temperature centrally. After this animal model has been established, we will then assess for changes in spinal organization of TRPM8 neural networks that may result after the induction of inflammatory or neuropathic pain. We will also assess the physiological relevance of this population of sensory nerves by developing a mouse model in which these cells can be conditionally ablated. The experienced gained from these exploratory studies will be used for future investigations of other thermosensors and will expand our understanding of how we detect and discriminate sensory stimuli.

描述（由申请人提供）：在哺乳动物中，化学、机械或热性质的刺激的检测是通过构成我们的体感系统的初级和高阶感觉神经元的复杂网络进行的。我们在分子水平上对体感的理解取得了重大进展，这来自于将瞬时受体电位 (TRP) 通道家族成员识别为周围神经热刺激的主要检测器。这些“热传感器”在不同的温度范围内都很敏感，并且在大多数情况下，定义了离散的感觉神经元群体。然而，如何在高于外周传入神经的水平上解释和处理由热刺激引起的信号，以及用于传达这些刺激的神经网络的架构仍不清楚。该应用程序的目的是开发遗传模型系统，该系统将能够绘制参与特定刺激方式检测的体感神经网络的映射。这些探索性研究将集中于最近克隆的冷和薄荷醇受体 CMR1 或 TRPM8。我们打算使用 TRPM8 转录启动子在 TRPM8+ 周围传入神经中特异性表达跨神经元示踪剂，以便绘制这些神经元用于集中传递温度的神经网络和突触连接。建立该动物模型后，我们将评估在诱导炎症或神经性疼痛后可能导致的 TRPM8 神经网络脊柱组织的变化。我们还将通过开发一种可以有条件地消融这些细胞的小鼠模型来评估这群感觉神经的生理相关性。从这些探索性研究中获得的经验将用于其他热传感器的未来研究，并将扩大我们对如何检测和区分感官刺激的理解。