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

项目总结 感觉体验塑造了后天发育和整个生命过程中的神经回路。的一个关键问题 发育神经生物学是指感觉驱动的神经元活动如何与固有的基因表达程序合作来 在发育过程中组装功能神经电路。虽然这个问题在中枢神经中研究得比较好 在回路中，感觉活动在调节初级感觉神经元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)的体感神经元中解决这个问题。 长期以来，人们都知道感觉体验对哺乳动物感觉的发展和功能有着深远的影响 视觉和听觉系统等系统。同样，感官体验长期以来一直被认为是调节 躯体感觉回路的连接和功能，但只有有限的提示性证据支持这一假设。我们的实验室 已经开发出基因工具，使主要的光触摸检测DRG可视化和功能操作成为可能 小鼠的神经元亚型，最近发现干扰感觉活动改变了基因表达程序 这些神经元。然而，感觉活动塑造基因表达程序的方式决定了DRG神经元 发展和功能尚未确定。 目的1采用联合染色质-RNA单核测序方法描述DRG神经元基因调控 整个开发过程中的景观。目标2使用了相同的测序方法和体感的组合 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。 Aim 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 在发展背根节感觉神经元的功能特性方面。综合起来，这些目标将开始揭示感官活动 塑造决定DRG神经元发育和功能的基因表达程序，这样的发现将告知 糖尿病周围神经病变等周围神经病变中背根神经节神经元功能障碍的研究

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.