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 感官体验在出生后的发育过程中和整个生命过程中塑造神经回路。的一个关键问题 发育神经生物学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比较好的研究， 尽管感觉神经元的神经回路中的基因表达与感觉活动密切相关，但对感觉活动在调节初级感觉神经元中的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）的躯体感觉神经元中解决这个问题。 长期以来，人们一直认为感觉经验对哺乳动物感觉神经的发育和功能有着深远的影响。 例如视觉和听觉系统。同样，长期以来，人们一直认为感官体验可以调节大脑的活动。 布线和功能的躯体感觉电路，但只有有限的暗示性证据支持这样的假设。我们实验室 已经产生了遗传工具，使主要的光触摸检测DRG的可视化和功能操作成为可能。 最近发现，干扰感觉活动会改变小鼠神经元亚型的基因表达程序， 这些神经元。然而，感觉活动塑造决定DRG神经元的基因表达程序的方式， 发育和功能尚未确定。 目的1采用联合染色质-RNA单核苷酸测序的方法来描述DRG神经元基因调控 跨越发展的景观。Aim 2使用相同的测序方法和体感 刺激范例来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。 目的3使用小鼠遗传工具以及生理和形态分析来确定机械感觉的作用 在DRG感觉神经元功能特性的发展中。总之，这些目标将开始揭示感官活动是如何 塑造了决定DRG神经元发育和功能的基因表达程序，这些发现将为研究人员提供信息。 周围神经病变如糖尿病周围神经病变中DRG神经元功能障碍的研究。