title: Plasticity of intact rubral projections mediates spontaneous recovery of function after corticospinal tract injury.
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.
authors: Department Of Neurology and.
authors: Chad S
authors: http://orcid.org/0000-0002-6580-0477
authors: CS
authors: Siegel
authors: Department Of Neurology and.
authors: Kathren L
authors: KL
authors: Fink
authors: Department Of Neurology and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06520.
authors: Stephen M
authors: http://orcid.org/0000-0001-8188-3092
authors: SM
authors: Strittmatter
authors: Department Of Neurology and william.cafferty@yale.edu.
authors: William B J
authors: http://orcid.org/0000-0001-6263-2167
authors: WB
authors: Cafferty
mesh_terms: D000818:Animals; D015198:Designer Drugs / Q000494:pharmacology; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008124:Locomotion / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053580:Muscle Strength / Q000235:genetics; D009185:Myelin Proteins / Q000172:deficiency / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology*; D000070798:Nogo Proteins; D011596:Psychomotor Disorders / Q000209:etiology; D011712:Pyramidal Tracts / Q000473:pathology*; D011903:Raphe Nuclei / Q000473:pathology*; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology*; D013239:Stereotyped Behavior / Q000502:physiology; D013997:Time Factors
chemical_list: D015198:Designer Drugs; D005904:Glial Fibrillary Acidic Protein; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse
keywords: plasticity; regeneration; spinal cord injury
references: Neurosci Lett. 1996 Aug 23;214(2-3):119-22
references: 8878098
references: J Neurosci. 1998 Jun 15;18(12):4744-57
references: 9614248
references: Behav Brain Res. 1998 Jun;93(1-2):167-83
references: 9659998
references: Behav Brain Res. 1998 Nov;96(1-2):37-46
references: 9821541
references: Eur J Neurosci. 1999 Apr;11(4):1486-90
references: 10103143
references: Science. 2009 Oct 9;326(5950):298-301
references: 19815778
references: Science. 2009 Oct 23;326(5952):592-6
references: 19833921
references: Glia. 2010 Mar;58(4):423-33
references: 19780196
references: Pain. 2010 Feb;148(2):188-97
references: 19632780
references: J Neurosci. 2010 May 19;30(20):6825-37
references: 20484625
references: Mol Ther. 2000 Apr;1(4):376-82
references: 10933956
references: Nat Neurosci. 1998 Jun;1(2):124-31
references: 10195127
references: Behav Brain Res. 1999 Aug;103(1):45-53
references: 10475163
references: Prog Brain Res. 2005;148:259-82
references: 15661196
references: J Neurosci. 2005 Jan 26;25(4):808-22
references: 15673660
references: Exp Neurol. 2005 Oct;195(2):524-39
references: 16051217
references: Annu Rev Neurosci. 2006;29:279-306
references: 16776587
references: Nat Rev Neurosci. 2006 Aug;7(8):617-27
references: 16858390
references: J Neurosci. 2006 Nov 22;26(47):12242-50
references: 17122049
references: Ann Neurol. 2006 Nov;60(5):540-9
references: 16958113
references: J Neurosci. 2007 Feb 28;27(9):2176-85
references: 17329414
references: Eur J Neurosci. 2007 Mar;25(5):1501-10
references: 17425576
references: Nat Med. 2008 Jan;14(1):69-74
references: 18157143
references: Eur J Neurosci. 2008 Jan;27(2):326-33
references: 18215231
references: Science. 2008 Nov 7;322(5903):963-6
references: 18988856
references: Science. 2008 Nov 7;322(5903):967-70
references: 18988857
references: Exp Neurol. 2009 Mar;216(1):193-206
references: 19118552
references: Nat Neurosci. 2009 Oct;12(10):1333-42
references: 19767747
references: J Neurosci. 2000 Sep 1;20(17):6561-9
references: 10964961
references: Nature. 2001 Jan 18;409(6818):341-6
references: 11201742
references: Nat Rev Neurosci. 2001 Apr;2(4):263-73
references: 11283749
references: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6929-34
references: 11381120
references: Nature. 2002 Apr 11;416(6881):636-40
references: 11948352
references: Nat Neurosci. 2010 Sep;13(9):1075-81
references: 20694004
references: Pharmacol Rev. 2011 Jun;63(2):291-315
references: 21415127
references: Annu Rev Neurosci. 2011;34:131-52
references: 21438684
references: Ann Neurol. 2011 Nov;70(5):805-21
references: 22162062
references: Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5063-8
references: 22411787
references: Brain Struct Funct. 2012 Apr;217(2):221-32
references: 21927901
references: Brain. 2012 Apr;135(Pt 4):1253-67
references: 22436236
references: Nat Neurosci. 2012 May;15(5):703-12
references: 22406547
references: Proc Natl Acad Sci U S A. 2012 May 8;109(19):7517-22
references: 22529377
references: Science. 2012 Jun 1;336(6085):1182-5
references: 22654062
references: Eur J Neurosci. 2012 Dec;36(12):3665-78
references: 23061434
references: J Neurosci. 2014 Mar 19;34(12):4432-41
references: 24647962
references: J Neurosci. 2014 Apr 2;34(14):4822-36
references: 24695702
references: Nature. 2014 Apr 17;508(7496):351-6
references: 24487621
references: Drug Discov Today. 2014 Apr;19(4):469-73
references: 24184433
references: Science. 2014 Jun 13;344(6189):1250-5
references: 24926013
references: Exp Neurol. 2014 Nov;261:451-61
references: 25079366
references: Nature. 2002 May 30;417(6888):547-51
references: 12037567
references: Science. 2002 Aug 16;297(5584):1190-3
references: 12089450
references: ILAR J. 2002;43(4):244-58
references: 12391400
references: J Neurosci. 2003 Sep 24;23(25):8682-91
references: 14507967
references: J Chem Neuroanat. 2003 Dec;26(4):331-43
references: 14729135
references: Nat Neurosci. 2004 Mar;7(3):269-77
references: 14966523
references: Curr Gene Ther. 2004 Mar;4(1):15-31
references: 15032611
references: J Biol Chem. 2004 Oct 15;279(42):43780-8
references: 15297463
references: Neuron. 2004 Oct 28;44(3):439-51
references: 15504325
references: Experientia. 1964 Jul 15;20(7):398-9
references: 5856530
references: Neurosci Lett. 1979 Sep;14(1):19-23
references: 530486
references: Neurosci Lett. 1982 Mar 17;29(1):31-4
references: 6280114
references: Brain Res. 1983 Dec 12;288(1-2):33-48
references: 6198030
references: Neurosci Res. 1987 Oct;5(1):39-62
references: 2963243
references: Nature. 1990 Jan 18;343(6255):269-72
references: 2300171
references: Brain Res. 1990 Mar 26;512(1):15-25
references: 2337803
references: J Comp Neurol. 1990 Jul 8;297(2):267-82
references: 2370323
references: Trends Neurosci. 1990 Dec;13(12):474-9
references: 1703677
references: Behav Brain Res. 1993 Jul 30;56(1):59-76
references: 7691077