Research Project
10329901
PROJECT SUMMARY/ABSTRACT Neuropathic pain is an important public health issue compromising quality of life, where non- conventional treatments like electrical stimulation, cannabis, or meditation have emerged as promising strategies for chronic pain management. Yet despite attempts to establish standardized regiments, efficiency remains highly variable. It is evident current empirical observation is insufficient for conclusive evaluation of these milder treatments on individualized pain perception, which may be masked by dynamic changes in mental states such as attention and mood. This limitation precipitates the need for identification and leverage of new mechanistic biomarkers. Recent evidence from Drs. Zhigang He and Clifford Woolf at Boston Children's Hospital revealed a key top-down regulator in processing light touch, somatosensory cortex (S1) corticospinal neurons (CSNs), which become sensitized following nerve injury. As one of the most prominent cerebral cortical cells with direct descending axonal projections to the spinal cord, CSNs could be the missing link between mental states and spinal tactile processing. Thus, the objective of this proposal is to investigate S1 CSNs as a biomarker for monitoring tactile sensitivity and their role in pain-reducing strategies. More specifically, we intend to monitor S1 CSN functional activity in parallel with behavioral sensitivity while probing direct corticocortical circuitry or applying neuromodulatory treatments following spared nerve injury, a reproducible neuropathic pain animal model. Preliminary evidence mapping S1 CSN cortical connectivity indicates the existence of both proximal and distal pre-synaptic connections in three discrete regions: primary motor cortex (M1), secondary somatosensory cortex (S2), and retrosplenial cortex (RSC). While M1 and S2 have been linked to tactile sensation, the RSC displays a more broadly documented role in polymodal sensory and cognitive computation. Thus, our proposed aims intend to investigate the functional contribution of 1) proximal inhibitory connections and 2) distal pre-synaptic projections, as well as 3) characterize the impact of epidural electrical stimulation or cannabidiol (CBD) administration on S1 CSN activity and behavioral sensitivity. To address these aims, we will use viral tracers or Cre mouse lines in combination with optogenetic stimulation and functional calcium imaging. Study outcomes will address light touch sensory processing in the cortex and evaluate the potential of S1 CSNs as a biomarker for pain management strategies. In addition, this support will contribute directly to the technical and scientific knowledge development of a next generation neuroscientist, thereby fostering career growth towards independent research.
