200 Unbiased Interrogation of Whole Brain Circuits Identifies Neurons That Restore Walking After Spinal Cord Injury. (1st April 2022)

• Record Type: Journal Article
• Authors: Cho, Newton; Squair, Jordan W.; James, Nicholas; Baud, Laetitia; Leonhartsberger, Anna; Sveistyte, Kristina; Galan, Katia; Barraud, Quentin; Goubran, Maged; Batti, Laura; Pagès, Stéphane; Gautier, Matthieu; Hutson, Thomas; Kathe, Claudia; Bichat, Arnaud; Rizzo, Olivier; Hodara, Michael; Bloch, Jocelyne; Courtine, Grégoire
• Is Part Of: Neurosurgery. Volume 68(2022)Supplement 1
• Page Start: 61
• Page End: 61
• Publication Date: 2022-04-01
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1227/NEU.0000000000001880_200
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract : 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.