Molecular genetic dissection of the development and function of spinal somatosensory circuitry

了解功能是如何从发育中的神经元网络中产生的，对于揭示成熟的大脑功能至关重要。为了解决这个问题，它是必不可少的访问定义的功能网络内的单个神经元群体的突触发育。研究回路形成和功能的一个很好的模型系统是躯体感觉系统和其中的神经元回路，它们介导疼痛、瘙痒、温度、触摸和相对肢体/身体位置的感觉。脊髓相对容易在物理上接近，并且今天可以使用强大的遗传工具来识别和操纵成熟神经系统中的相关神经元，尽管在发育过程中解析具有挑战性。躯体感觉系统的中枢是脊髓背角中的感觉神经元，其通过背根神经节（DRG）接收来自外周的信息，并将其传递到大脑。这些背侧中间神经元（dIN）的定义的亚群，包括转录谱和迁移路线的许多早期属性，已经划定。然而，脊髓感觉神经元如何整合到功能回路中，以及哪些子集在成熟阶段服务于每种躯体感觉功能仍然知之甚少。其主要原因是，允许识别个体亚群的遗传标记在早期发育期间瞬时表达，并且不能依赖于随着回路成熟而选择性地识别组成神经元。该项目的目的是开发方法，延长时间，遗传访问一个特定的dIN群体，dI 1，并允许识别和操纵dI 1特定电路从DRG到大脑，使用最先进的跨突触病毒示踪剂，基因表达和活性修饰剂。可视化dI 1细胞和DRG神经元的特定功能类别之间的突触连接，识别这些神经元的中枢靶点和轴突路线，并最终操纵它们的活动，将为脊髓中体感回路的功能组织提供新的见解，而且，这项工作将为我们在疾病，神经性疼痛和脊髓损伤后的治疗提供重要信息。

Understanding how function emerges from developing neuronal networks is critical for unraveling mature brain function. To address this question, it is essential to access the synaptic development of individual neuronal populations within defined functional networks. An excellent model system for studying circuit formation and function is the somatosensory system and the neuronal circuits within, which mediate the sensation of pain, itch, temperature, touch and relative limb/body position. The spinal cord is relatively easy to access physically and powerful genetic tools are available today to identify and manipulate involved neurons in the mature nervous system, although challenging to parse during development. Central to the somatosensory system are sensory neurons in the dorsal horn of the spinal cord that receive information from the periphery, via the dorsal root ganglia (DRG), and relay it to the brain. Many early properties of defined subpopulations of these dorsal interneurons (dINs), including transcriptional profiles and migratory routes, have been delineated. However, how spinal sensory neurons integrate into functional circuits and which subsets serve each somatosensory function in mature stages remain poorly understood. A major reason for this is that genetic markers permitting the identification of individual subpopulations are transiently expressed during early development and cannot be relied on for selective identification of component neurons as the circuitry matures. This project aims to develop methods that extend, temporally, genetic access to one specific population of dINs, the dI1s, and permit identification and manipulation of dI1 specific circuits from DRG to brain, using state of the art trans-synaptic viral tracers, gene expression and activity modifiers. Visualizing the synaptic connections between dI1 cells and specific functional classes of DRG neurons, identifying central targets and the axonal routes of these neurons, and eventually manipulating their activities, will provide novel insights into the functional organization of somatosensory circuits in the spinal cord.Moreover, this work will substantially inform our approaches to treatment in disease, neuropathic pain, and following spinal cord injury.