title: Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke.
abstract: Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of-function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH.
  
  
  CONCLUSIONS
  The research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use.
authors.affiliation: Department of Neurophysiology and Brain Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan.
authors.forename: Akimasa
authors.identifier: http://orcid.org/0000-0001-6625-3439
authors.initials: A
authors.lastname: Ishida
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Isa
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Umeda
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University, Fukushima, 960-1295, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Section of Viral Vector Development, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan, and Graduate University of Advanced Studies (SOKENDAI), Hayama, 240-0193, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Neurophysiology and Brain Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan.
authors.forename: Hideki
authors.identifier: http://orcid.org/0000-0002-9679-4508
authors.initials: H
authors.lastname: Hida
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan, Graduate University of Advanced Studies (SOKENDAI), Hayama, 240-0193, Japan tisa@nips.ac.jp.
authors.forename: Tadashi
authors.identifier: http://orcid.org/0000-0001-5652-4688
authors.initials: T
authors.lastname: Isa
mesh_terms: D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000150:complications* / Q000534:rehabilitation; D046690:Deep Brain Stimulation; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology*; D007839:Functional Laterality / Q000502:physiology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D020772:Internal Capsule / Q000293:injuries; D008297:Male; D009044:Motor Cortex / Q000502:physiology*; D009048:Motor Skills / Q000502:physiology; D009069:Movement Disorders / Q000209:etiology* / Q000534:rehabilitation*; D009118:Muscimol / Q000494:pharmacology; D009434:Neural Pathways / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D012012:Red Nucleus / Q000502:physiology*
chemical_list: D003911:Dextrans; D058785:GABA-A Receptor Agonists; C076397:biotinylated dextran amine; D009118:Muscimol; D001710:Biotin; D004318:Doxycycline
keywords: forced limb use; intracerebral hemorrhage; red nucleus; rehabilitation; reorganization; use-dependent plasticity