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

• 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
• 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

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.

项目摘要 感官体验在产后发展和整个生命的过程中雕刻神经回路。一个关键问题 发育神经生物学是感觉驱动的神经元活动与内在基因表达程序合作的方式 在开发过程中组装功能性神经回路。虽然这个问题在中央神经中相对良好 电路，角色感觉活动在调节原发性感觉神经元中基因表达方面发挥作用。 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，人们已经知道感觉体验对哺乳动物感觉的发展和功能产生深远的影响 视觉和听觉系统等系统。同样，长期以来一直假定感官体验来调节 体感电路的接线和功能，但仅有限的暗示性证据支持这种假设。我们的实验室 已经产生了遗传工具，可以使主要光接触式DRG的可视化和功能操纵 小鼠中的神经元亚型，最近发现破坏感觉活动会改变基因表达程序 这些神经元。但是，感觉活动塑造决定DRG神经元的基因表达程序的方式 开发和功能尚未表征。 AIM 1特征关节染色质RNA单核测序方法描述DRG神经元基因调节 跨发展的景观。 AIM 2结合了相同的测序方法和体感 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。 AIM 3使用小鼠遗传工具以及生理和形态学分析来确定机械敏的作用 DRG感觉神经元功能特性的发展。这些目标在一起将开始揭示感官活动如何 塑造决定DRG神经元发展和功能的基因表达程序，此类发现将告知 周围神经病（例如糖尿病周围神经病）中DRG神经元故障的研究。