Background: There is presently no cure for locomotor deficits after spinal cord injury (SCI). Very few therapies effectively target the brain due to poor understanding of the brain’s role post-SCI. Newly developed tissue clearing techniques have permitted unbiased three-dimensional circuit analysis, opening new opportunities for SCI-related brain interrogation. Methods: We established a novel brain interrogation pipeline by optimizing mouse brain clearing, imaging, and atlas registration. We leveraged a spontaneous recovery lateral hemisection model to analyze whole brain cell activity and connectivity with the lumbar cord using cFos immunolabelling and virus-mediated projection tracing. We identified a functionally and anatomically dynamic region correlating with recovery and interrogated its locomotor role with optogenetics. We assessed deep brain electrical stimulation (DBS) of this region in a more clinically relevant rat contusion SCI using an established bipedal robotic interface. Results: We unexpectedly uncovered the lateral hypothalamus (LH) to functionally and anatomically correlate with recovery. LHVglut2 optogenetic stimulation significantly augmented locomotor function. LH DBS in rats acutely robustly augmented bipedal locomotion post-SCI. Conclusions: This is the first demonstration of the LH’s role in locomotion post-SCI and is a novel DBS target that robustly augmented locomotor function, dependent on LH glutamatergic cells. LH DBS may be a promising intervention in humans.

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P.122 Unbiased whole brain circuit interrogation reveals neurons restoring walking after spinal cord injury

INTRODUCTION: Currently, there is no cure for locomotor deficits after spinal cord injury (SCI). Despite advances in spinal cord modulation with epidural electrical stimulation, there remains a paucity of therapies targeting the brain due to a poor understanding of the brain’s role post-SCI. Recently developed tissue clearing and light sheet imaging techniques have permitted unbiased three-dimensional interrogation of whole brain circuits, which has opened unexplored avenues for SCI-related brain interrogation. METHODS: We established a novel brain interrogation pipeline for SCI by optimizing mouse whole brain clearing, imaging, and atlas registration after a spontaneous recovery lateral hemisection model. We examined both whole brain cell activity and connectivity with the lumbar cord using cFos immunolabelling and virus-mediated projection tracing, respectively, to identify a functionally and anatomically dynamic region correlating with recovery. We interrogated the locomotor role of this region with optogenetics and chemogenetics. In a more clinically relevant rat contusion SCI, we assessed the translatability of deep brain electrical stimulation (DBS) of this region by leveraging an established bipedal robotic interface and rehabilitation paradigm. RESULTS: We unexpectedly uncovered the lateral hypothalamus (LH) to be a functionally and anatomically dynamic region post-SCI correlating with recovery. Optogenetic stimulation of mouse LHVglut2 neurons significantly augmented locomotor function, which required medullary reticular formation (MRF) Vglut2-positive neurons. In line with previously demonstrated sparing of MRF-to-spinal cord projections after contusion SCI, we found that LH DBS in rats post-contusion SCI could acutely robustly augment bipedal rat locomotor function. CONCLUSION: This is the first demonstration of the LH's role in locomotion post-SCI. The LH is a novel DBS target that robustly augmented locomotor function, dependent on LH and brainstem glutamatergic cells.

200 Unbiased Interrogation of Whole Brain Circuits Identifies Neurons That Restore Walking After Spinal Cord Injury

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P.122 Unbiased whole brain circuit interrogation reveals neurons restoring walking after spinal cord injury

200 Unbiased Interrogation of Whole Brain Circuits Identifies Neurons That Restore Walking After Spinal Cord Injury