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

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.