Plasticity of intact rubral projections mediates spontaneous recovery of function after corticospinal tract injury

J Neurosci. 2015 Jan 28;35(4):1443-57. doi: 10.1523/JNEUROSCI.3713-14.2015.

Abstract

Axons in the adult CNS fail to regenerate after injury, and therefore recovery from spinal cord injury (SCI) is limited. Although full recovery is rare, a modest degree of spontaneous recovery is observed consistently in a broad range of clinical and nonclinical situations. To define the mechanisms mediating spontaneous recovery of function after incomplete SCI, we created bilaterally complete medullary corticospinal tract lesions in adult mice, eliminating a crucial pathway for voluntary skilled movement. Anatomic and pharmacogenetic tools were used to identify the pathways driving spontaneous functional recovery in wild-type and plasticity-sensitized mice lacking Nogo receptor 1. We found that plasticity-sensitized mice recovered 50% of normal skilled locomotor function within 5 weeks of lesion. This significant, yet incomplete, spontaneous recovery was accompanied by extensive sprouting of intact rubrofugal and rubrospinal projections with the emergence of a de novo circuit between the red nucleus and the nucleus raphe magnus. Transient silencing of this rubro-raphe circuit in vivo via activation of the inhibitory DREADD (designer receptor exclusively activated by designer drugs) receptor hM4di abrogated spontaneous functional recovery. These data highlight the pivotal role of uninjured motor circuit plasticity in supporting functional recovery after trauma, and support a focus of experimental strategies on enhancing intact circuit rearrangement to promote functional recovery after SCI.

Keywords: plasticity; regeneration; spinal cord injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Designer Drugs / pharmacology
  • Functional Laterality
  • Gene Expression Regulation / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Locomotion / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Strength / genetics
  • Myelin Proteins / deficiency
  • Myelin Proteins / genetics
  • Neuronal Plasticity / physiology*
  • Nogo Proteins
  • Psychomotor Disorders / etiology
  • Pyramidal Tracts / pathology*
  • Raphe Nuclei / pathology*
  • Recovery of Function / physiology*
  • Spinal Cord Injuries / pathology*
  • Spinal Cord Injuries / physiopathology*
  • Stereotyped Behavior / physiology
  • Time Factors

Substances

  • Designer Drugs
  • Glial Fibrillary Acidic Protein
  • Myelin Proteins
  • Nogo Proteins
  • Rtn4 protein, mouse