Elucidating the logic of proprioceptive networks

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Project Summary/Abstract: We interact with our world using precise and controlled movements. Models of motor control incorporate the idea that the body must have a representation of its internal state to generate either a desired trajectory (feedforward) or to compare with for the completed trajectory (feedback). This body map of the internal state is produced using proprioception, the sense of limb and body position, yet it is not well understood how this sense is generated or how other sensory inputs such as cutaneous (touch) information feed into the proprioceptive sense. Loss of primary proprioceptive sensory neurons leads to severe motor defects, indicating that proprioception is essential for motor function, and studies of the loss of cutaneous sensory nerve inputs shows that touch information is needed for complex motor behaviors. Early studies in cats suggest that at least some of the integration of proprioceptive and cutaneous information happens at the level of cerebellar-projecting neurons in the spinal cord (spinocerebellar neurons). These studies describe “proprioceptive” and “exteroceptive” (cutaneous/touch) subdivisions of the dorsal spinocerebellar tract (DSCT) whereby subsets of neurons within this tract respond to either proprioceptive or proprioceptive and cutaneous stimulation. However, at the time, it was difficult to differentiate between different subsets of DSCT neurons. Current molecular lineage tracing technologies in mice are now able to differentiate between different molecular subsets of the DSCT. The goal of this proposal is to understand how proprioceptive and cutaneous information is organized at the level of DSCT neurons in the spinal cord. We hypothesize that discrete molecular subsets of the DSCT have distinct microcircuit connectivity important for their function in generating the proprioceptive sense and we will test this hypothesis through the following Aims. Aim 1 will investigate the molecular and electrophysiological diversity of DSCT neurons using deep sequencing technologies for the mRNA transcripts of different subsets and recordings of specific neuronal subsets in acute spinal cord slices. Aim 2 will test whether different subsets of the DSCT receive cutaneous and/or proprioceptive information using retrograde transsynaptic viral tracing techniques. Aim 3 will examine if there are different spatial axonal trajectories of DSCT neuronal subsets into the cerebellum to understand the spatial logic of their terminations using whole tissue imaging technologies. Altogether, this proposal uses molecular, anatomical, and electrophysiological approaches to elucidate the connectivity of DSCT neurons. This study will form the foundation for our long- term goal of understanding how internal models of the body are constructed. The fundamental knowledge gained from this study will impact the fields of somatosensation, motor control, and robotics as well as provide insights into what kinds of neural circuits need to be regenerated upon spinal cord injury or neurodegenerative disease states, such as Friedrich's ataxia.