Genetic Mapping of Somatosensory Neural Networks

描述(申请人提供)：在哺乳动物中，对化学、机械或热性质的刺激的检测是通过由初级和高级感觉神经元组成的复杂网络进行的，这些神经元组成了我们的躯体感觉系统。我们在分子水平上对躯体感觉的理解取得了重大进展，这是因为瞬时受体电位(Trp)通道家族的成员被鉴定为周围神经中热刺激的主要检测器。这些“温度传感器”对不同的温度范围很敏感，在大多数情况下，它们定义了不同的感觉神经元群体。然而，热刺激诱发的信号是如何在高于外周传入的水平上被解释和处理的，以及用于传达这些刺激的神经网络的结构仍然不清楚。该应用程序的目的是开发遗传模型系统，该系统将能够映射涉及特定刺激模式检测的体感神经网络。这些探索性研究将集中在最近克隆的寒冷和薄荷醇受体CMR1或TRPM8上。我们打算使用TRPM8转录启动子在TRPM8+的外周传入神经中特异性地表达一个跨神经元示踪剂，以便定位这些神经元用来集中传递温度的神经网络和突触连接。在这个动物模型建立后，我们将评估TRPM8神经网络在炎性或神经病理性疼痛诱导后可能导致的脊髓组织的变化。我们还将通过建立一个小鼠模型来评估这些感觉神经的生理学相关性，在该模型中，这些细胞可以被有条件地消融。从这些探索性研究中获得的经验将用于未来对其他温度传感器的研究，并将扩大我们对如何检测和区分感觉刺激的理解。

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.