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

C-LTMR 回路的解剖学、生理学和行为相关性

基本信息

批准号：
8255102
负责人：
Victoria Eugenia Guadalupe Abraira
金额：
$ 5.13万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-29 至 2014-09-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8255102
关键词：
Ablation Acute Address Adult Affective Afferent Neurons Alkaline Phosphatase Animals Behavior Behavioral Behavioral Paradigm Biological Assay Brain C Fiber Candidate Disease Gene Cells Code Complex Data Development Diphtheria Toxin Disease Emotional Esthesia Exhibits Future Genes Germ-Line Mutation Goals Hair follicle structure Human Hypersensitivity Immunohistochemistry Individual Injection of therapeutic agent Injury Interneurons Knock-out Label Lead Light Mechanics Mechanoreceptors Mediating Mediator of activation protein Modality Molecular Molecular Genetics Morphology Mus Neurons Nociception Pain Pathway interactions Perception Peripheral Physiological Physiology Population Process Property Research Resolution Role Sensory Signal Transduction Skin Slice Stimulus Stretching Surface Synapses Tail Temperature Testing Tissues Touch sensation Tyrosine 3-Monooxygenase allodynia base cell type chronic pain design diphtheria toxin receptor dorsal horn grasp in vivo interdisciplinary approach mature animal mechanical allodynia neural circuit postsynaptic research study response social somatosensory therapeutic target tool vibration

项目摘要

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.

描述（由申请人提供）：我们使用分子遗传学来识别和表征 C 纤维低阈值机械感受器 (C-LTMR)，这是一种 DRG 感觉神经元，被认为有助于损伤引起的触摸超敏反应和情感或情绪成分的触摸。我们建议评估 C-LTMR 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目标，以试图阐明关键的机械敏感和伤害感受回路。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人们知之甚少的神经元群的解剖学特征。为了进一步定义 C-LTMR 回路，我们将这些工具与生理学方法结合起来，以测试背角层 IIiv 的 PKC3+ 中间神经元是 C-LTMR 的突触后伙伴的假设。最后，我们将生成新的小鼠系来消除成人体内的 C-LTMR，以直接测试 C-LTMR 是否是机械性异常性疼痛和毛状皮肤柔软触感的关键介质。总之，这项研究将揭示 C-LTMR 的形态特性，定义 C-LTMR 特异性神经回路，并确定 C-LTMR 在机械感觉和异常性疼痛中的作用。公共健康相关性：感觉神经元群的正确识别和功能表征不仅对于我们理解正常触觉如何产生，而且对于损伤引起的机械超敏反应等疾病中感觉通路如何汇聚至关重要。我们的目标是通过基因靶向背角突触前和突触后感觉神经元并阐明其解剖学、生理学和行为特性，来识别和表征介导触觉和可能的机械异常性疼痛的电路。