Anatomical, physiological, and behavioral correlates of a C-LTMR circuit

描述（由申请人提供）：我们已经使用分子遗传学来鉴定和表征C-纤维低阈值机械感受器（C-LTMR），这是一种DRG感觉神经元，被认为有助于损伤诱导的触摸超敏反应和触摸的情感或情绪成分。我们建议评估C-LTMRs在成年小鼠体内的功能，它们的形态，以及它们在背角的突触后靶点，试图阐明关键的机械敏感性和伤害性回路。我们建议使用新开发的小鼠分子遗传学工具，以单细胞分辨率来表征这种知之甚少的神经元群体的解剖特征。为了进一步定义C-LTMR电路，我们将这些工具与生理方法相结合，以测试背角板IIiv的PKC 3+中间神经元是C-LTMR的突触后伙伴的假设。最后，我们将产生新的小鼠品系来消融成年C-LTMR，以直接测试C-LTMR是否是机械性异常性疼痛和多毛皮肤柔软触感的关键介质。总之，这项研究将揭示C-LTMR的形态学特性，定义C-LTMR特异性神经回路，并建立C-LTMR在机械感觉和异常性疼痛中的作用。 公共卫生相关性：感觉神经元群体的正确识别和功能表征不仅对我们理解正常触觉如何产生至关重要，而且对我们理解感觉通路如何在损伤诱导的机械超敏反应等疾病中会聚也至关重要。我们的目标是确定和表征电路介导的触觉和可能的机械异常性疼痛的遗传靶向前和后突触的感觉神经元的背角，并阐明其解剖，生理和行为特性。

DESCRIPTION (provided by applicant): We have used molecular genetics to identify and characterize the C-fiber low threshold mechanoreceptor (C- LTMR), a DRG sensory neuron proposed to contribute to injury-induced touch hypersensitivity and the affective, or emotional, component of touch. We propose to assess the in vivo functions of C-LTMRs in adult mice, their morphologies, and their postsynaptic targets in the dorsal horn in an attempt to elucidate key mechanosensitive and nociceptive circuits. We propose to characterize the anatomical features of this poorly understood neuronal population at single cell resolution using newly developed mouse molecular-genetic tools. To further define a C-LTMR circuit we will couple these tools with physiological approaches to test the hypothesis that PKC3+ interneurons of dorsal horn lamina IIiv are post-synaptic partners of C-LTMRs. Finally, we will generate new mouse lines to ablate C-LTMRs in the adult to directly test whether C-LTMRs are key mediators of mechanical allodynia and hairy skin soft touch. Together, this research will reveal the morphological properties of C-LTMRs, define a C-LTMR-specific neural circuit, and establish the role for C- LTMRs in mechanosensation and allodynia. PUBLIC HEALTH RELEVANCE: Proper identification and functional characterization of sensory neuronal populations is central not only to our understating of how normal touch sensations arise, but also how sensory pathways converge in diseases such as injury induced mechanical hypersensitivity. Our goal is to identify and characterize a circuit mediating touch sensation and possibly mechanical allodynia by genetically targeting pre- and post-synaptic sensory neurons of the dorsal horn and elucidating their anatomical, physiological and behavioral properties.