The role of mechanosensory activity in the transcriptional maturation of primary somatosensory neurons

机械感觉活动在初级体感神经元转录成熟中的作用

基本信息

批准号：
10567984
负责人：
Scott Andrew Shuster
金额：
$ 6.91万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567984
关键词：
Address Affect Afferent Neurons Anatomy Auditory Auditory system Cell physiology Central Nervous System Chromatin Data Development Enhancers Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Ion Channel Joints Life Light Morphology Mus Nature Neurons Pain Peripheral Nervous System Diseases Physiological Physiology Play Property Proteins RNA Regulator Genes Research Rodent Role Sensory Shapes Specific qualifier value Spinal Ganglia Stimulus System Techniques Testing Touch sensation Transcriptional Regulation Vibrissae Visual Visual System Visualization Work developmental genetics developmental neurobiology diabetic experience experimental study in vivo injury recovery insight mouse genetics neural circuit neuron development neuronal growth pleasure postnatal postnatal development programs pup response sensory stimulus sensory system single nucleus RNA-sequencing somatosensory timeline tool

项目摘要

PROJECT SUMMARY Sensory experience sculpts neural circuits over the course of postnatal development and throughout life. A key question in developmental neurobiology is how sensory-driven neuronal activity cooperates with intrinsic gene expression programs to assemble functional neural circuits during development. While this question is relatively well-studied in central neural circuits, the role sensory activity plays in regulating gene expression in primary sensory neurons remains poorly understood. I propose to address this question in the somatosensory neurons of the dorsal root ganglia (DRG). Sensory experience has long been known to exert a profound effect on the development and function of mammalian sensory systems such as the visual and auditory systems. Likewise, sensory experience has long been presumed to regulate the wiring and function of somatosensory circuits, but only limited suggestive evidence supports such presumptions. Our lab has produced genetic tools that enable visualization and functional manipulation of the major light touch-detecting DRG neuron subtypes in the mouse and recently discovered that disrupting sensory activity changes gene expression programs in these neurons. However, the ways in which sensory activity shapes the gene expression programs that dictate DRG neuron development and function have not been characterized. Aim 1 features joint chromatin-RNA single-nucleus sequencing approaches to describe the DRG neuron gene regulatory landscape across development. Aim 2 uses a combination of the same sequencing approaches and a somatosensory stimulation paradigm to describe how sensory activity establishes DRG neuron subtype-specific gene expression programs. Aim 3 uses mouse genetic tools and physiological and morphological analyses to determine the role of mechanosensation in development of DRG sensory neuron functional properties. Together, these aims will begin to reveal how sensory activity shapes the gene expression programs that dictate DRG neuron development and function, and such findings will inform the study of DRG neuron malfunctions in peripheral neuropathies such as diabetic peripheral neuropathy.

项目概要感官体验在出生后发育和一生中塑造神经回路。一个关键问题在发育神经生物学研究的是感觉驱动的神经元活动如何与内在基因表达程序合作在发育过程中组装功能性神经回路。虽然这个问题在中枢神经系统中得到了相对充分的研究尽管神经回路中感觉活动在调节初级感觉神经元基因表达中所起的作用仍然知之甚少。我建议在背根神经节（DRG）的体感神经元中解决这个问题。长期以来，人们都知道感官体验对哺乳动物感觉的发育和功能产生深远的影响系统，例如视觉和听觉系统。同样，长期以来，感官体验一直被认为可以调节体感电路的接线和功能，但只有有限的暗示性证据支持这种假设。我们的实验室已经生产出遗传工具，可以实现主要光触摸检测 DRG 的可视化和功能操作小鼠神经元亚型，最近发现破坏感觉活动会改变小鼠的基因表达程序这些神经元。然而，感觉活动如何塑造决定 DRG 神经元的基因表达程序发育和功能尚未表征。目标 1 采用联合染色质-RNA 单核测序方法来描述 DRG 神经元基因调控发展过程中的景观。目标 2 使用相同的测序方法和体感技术的组合刺激范式描述感觉活动如何建立 DRG 神经元亚型特异性基因表达程序。目标 3 使用小鼠遗传工具以及生理和形态学分析来确定机械感觉的作用 DRG 感觉神经元功能特性的发展。总之，这些目标将开始揭示感官活动如何塑造决定 DRG 神经元发育和功能的基因表达程序，这些发现将为研究周围神经病变（例如糖尿病周围神经病变）中的 DRG 神经元功能障碍。