title: Re-Establishment of Cortical Motor Output Maps and Spontaneous Functional Recovery via Spared Dorsolaterally Projecting Corticospinal Neurons after Dorsal Column Spinal Cord Injury in Adult Mice.
abstract: Motor cortical plasticity contributes to spontaneous recovery after incomplete spinal cord injury (SCI), but the pathways underlying this remain poorly understood. We performed optogenetic mapping of motor cortex in channelrhodopsin-2 expressing mice to assess the capacity of the cortex to re-establish motor output longitudinally after a C3/C4 dorsal column SCI that bilaterally ablated the dorsal corticospinal tract (CST) containing ∼96% of corticospinal fibers but spared ∼3% of CST fibers that project via the dorsolateral funiculus. Optogenetic mapping revealed extensive early deficits, but eventual reestablishment of motor cortical output maps to the limbs at the same latency as preoperatively by 4 weeks after injury. Analysis of skilled locomotion on the horizontal ladder revealed early deficits followed by partial spontaneous recovery by 6 weeks after injury. To dissociate between the contributions of injured dorsal projecting versus spared dorsolateral projecting corticospinal neurons, we established a transient silencing approach to inactivate spared dorsolaterally projecting corticospinal neurons specifically by injecting adeno-associated virus (AAV)-expressing Cre-dependent DREADD (designer receptor exclusively activated by designer drug) receptor hM4Di in sensorimotor cortex and AAV-expressing Cre in C7/C8 dorsolateral funiculus. Transient silencing uninjured dorsolaterally projecting corticospinal neurons via activation of the inhibitory DREADD receptor hM4Di abrogated spontaneous recovery and resulted in a greater change in skilled locomotion than in control uninjured mice using the same silencing approach. These data demonstrate the pivotal role of a minor dorsolateral corticospinal pathway in mediating spontaneous recovery after SCI and support a focus on spared corticospinal neurons as a target for therapy.
  
  
  CONCLUSIONS
  Spontaneous recovery can occur after incomplete spinal cord injury (SCI), but the pathways underlying this remain poorly understood. We performed optogenetic mapping of motor cortex after a cervical SCI that interrupts most corticospinal transmission but results in partial recovery on a horizontal ladder task of sensorimotor function. We demonstrate that the motor cortex can reestablish output to the limbs longitudinally. To dissociate the roles of injured and uninjured corticospinal neurons in mediating recovery, we transiently silenced the minor dorsolateral corticospinal pathway spared by our injury. This abrogated spontaneous recovery and resulted in a greater change in skilled locomotion than in uninjured mice using the same approach. Therefore, uninjured corticospinal neurons substantiate remarkable motor cortical plasticity and partial recovery after SCI.
authors.affiliation: International Collaboration on Repair Discoveries, Department of Zoology.
authors.forename: Brett J
authors.identifier: http://orcid.org/0000-0003-2813-2294
authors.initials: BJ
authors.lastname: Hilton
authors.affiliation: Department of Psychiatry, and Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Eitan
authors.identifier: http://orcid.org/0000-0002-1579-0506
authors.initials: E
authors.lastname: Anenberg
authors.affiliation: Department of Psychiatry, and Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Thomas C
authors.identifier: http://orcid.org/0000-0002-8744-4645
authors.initials: TC
authors.lastname: Harrison
authors.affiliation: Department of Psychiatry, and Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Boyd
authors.affiliation: Department of Psychiatry, and Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada thmurphy@mail.ubc.ca tetzlaff@icord.org.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Murphy
authors.affiliation: International Collaboration on Repair Discoveries, Department of Zoology, Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada thmurphy@mail.ubc.ca tetzlaff@icord.org.
authors.forename: Wolfram
authors.identifier: http://orcid.org/0000-0003-3462-1676
authors.initials: W
authors.lastname: Tetzlaff
mesh_terms: D000818:Animals; D001931:Brain Mapping; D004525:Efferent Pathways / Q000254:growth & development / Q000473:pathology; D007150:Immunohistochemistry; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D009044:Motor Cortex / Q000473:pathology*; D009473:Neuronal Plasticity; D062308:Optogenetics; D011712:Pyramidal Tracts / Q000473:pathology*; D020127:Recovery of Function; D066191:Sensorimotor Cortex / Q000473:pathology; D013119:Spinal Cord Injuries / Q000473:pathology*
keywords: corticospinal; motor cortex; optogenetics; plasticity; recovery; spinal cord injury