Modality-specific restoration of somatosensory connections after dorsal root injury

Primary somatosensory axons of the dorsal root (DR axons) relay sensory information of diverse modalities from the periphery to the spinal cord (SC). They are commonly damaged by DR injuries, which cause permanent loss of sensation and coordinated limb movements. The devastating consequences occur because DR axons stop regeneration at the entrance of the SC, the dorsal root entry zone (DREZ), and because there is no therapy that restores sensory connections even for nociception, which does not require long-distance axon regeneration past the DREZ. Importantly, increasing evidences strongly suggest that DR axons prematurely terminate regeneration at the DREZ by forming synapses with oligodendrocyte precursor cells (OPCs). This novel inhibitory mechanism, which we termed ‘synaptic arrest’ by OPCs, raises the intriguing possibility that OPCs act as the major mechanism restricting regeneration not only at the DREZ but also intraspinal regeneration of DR axons, broadly elsewhere in the SC. Furthermore, synapse formation with OPCs may also restrict appropriate synapse formation of sensory axons with correct SC neurons, further hampering modality-specific reinnervation and functional recovery. In this proposal, we will address these clinically significant issues while investigating novel therapeutically applicable strategies to overcome synaptic arrest. In addition, we will use advanced imaging and mouse genetic tools that now permit selective investigations of physiologically distinct DR axons of specific modalities. Aim 1 will determine if specific axon subtypes terminate regeneration primarily by OPC-mediated synaptic arrest at the DREZ. Aim 2 will determine if BRAF/mTOR viral activation of specific axon subtypes overcomes synaptic arrest, enabling modality-specific functional regeneration in the SC. Aim 3 will determine if transient OPC ablation markedly enhances BRAF/mTOR-elicited intraspinal regeneration and/or reinnervation, robustly enhancing modality-specific functional recovery. Multifaceted information gained from these studies will fill significant gaps in current knowledge, moving the field substantially forward. Together with the unprecedented modality-specific investigations, this information could be very useful for developing new clinical therapies to restore specific somatosensory functions after debilitating DR injuries.