Peripheral nerve injury induces adult brain neurogenesis and remodelling.
Unilateral peripheral nerve chronic constriction injury (CCI) has been widely used as a research model of human neuropathic pain. Recently, CCI has been shown to induce spinal cord adult neurogenesis, which may contribute to the chronic increase in nociceptive sensitivity. Here, we show that CCI also induces rapid and profound asymmetrical anatomical rearrangements in the adult rodent cerebellum and pons. This remodelling occurs throughout the hindbrain, and in addition to regions involved in pain processing, also affects other sensory modalities. We demonstrate that these anatomical changes, partially reversible in the long term, result from adult neurogenesis. Neurogenic markers Mash1, Ngn2, doublecortin and Notch3 are widely expressed in the rodent cerebellum and pons, both under normal and injured conditions. CCI-induced hindbrain structural plasticity is absent in Notch3 knockout mice, a strain with impaired neuronal differentiation, demonstrating its dependence on adult neurogenesis. Grey matter and white matter structural changes in human brain, as a result of pain, injury or learned behaviours have been previously detected using non-invasive neuroimaging techniques. Because neurogenesis-mediated structural plasticity is thought to be restricted to the hippocampus and the subventricular zone, such anatomical rearrangements in other parts of the brain have been thought to result from neuronal plasticity or glial hypertrophy. Our findings suggest the presence of extensive neurogenesis-based structural plasticity in the adult mammalian brain, which may maintain a memory of basal sensory levels, and act as an adaptive mechanism to changes in sensory inputs.
MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Gabriel
0000-0002-2811-905X
G
Rusanescu
MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Jianren
J
Mao
D000375:Aging / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D002908:Chronic Disease; D003250:Constriction; D000089662:Doublecortin Protein; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000473:pathology*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley
D015415:Biomarkers; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein
Notch3; Purkinje neurons; adult neurogenesis; cerebellum; chronic pain; cross-modal perception; proprioception; structural plasticity
Neuroimage. 2014 Sep;98 :203-15
24799136
J Comp Neurol. 2006 Dec 20;499(6):953-64
17072831
Neuroreport. 1994 Dec 20;5(18):2593-7
7696611
Brain Res Rev. 2010 Oct 5;65(1):14-27
20553761
Neuron. 1995 Dec;15(6):1287-98
8845153
Neuron. 2013 Oct 30;80(3):807-15
24183029
J Neurophysiol. 2009 Jul;102(1):181-91
19403748
Cerebellum. 2014 Feb;13(1):151-77
23996631
Cerebellum. 2007;6(3):254-67
17786822
J Neurosci. 2009 Dec 2;29(48):15245-57
19955377
Restor Neurol Neurosci. 2011;29(3):153-65
21586822
J Physiol. 1987 May;386:529-38
3681718
Neuroimage. 2013 Jul 1;74:352-8
23485849
J Comp Neurol. 2003 Dec 1;467(1):1-10
14574675
Trends Neurosci. 2007 Jan;30(1):1-8
17116335
Physiol Rev. 2007 Oct;87(4):1215-84
17928584
Annu Rev Genet. 1994;28:373-93
7893132
J Neurosci Methods. 2008 Feb 15;168(1):42-7
17961663
Nat Rev Neurosci. 2002 Jul;3(7):517-30
12094208
Cell. 1999 Jun 11;97(6):703-16
10380923
Prog Neurobiol. 2013 Oct;109:42-63
23981535
Science. 2000 Feb 25;287(5457):1433-8
10688783
Restor Neurol Neurosci. 2014;32(5):663-73
25096973
Mol Cell Neurosci. 2003 Nov;24(3):603-13
14664811
Neuron. 2002 Aug 29;35(5):997-1010
12372292
Dev Biol. 2006 Jun 1;294(1):168-80
16581058
Physiol Rev. 2012 Oct;92(4):1651-97
23073629
Nat Rev Neurosci. 2002 Sep;3(9):715-27
12209120
Trends Cogn Sci. 2011 Oct;15(10):475-82
21906988
J Cell Mol Med. 2014 Oct;18(10 ):2103-16
25164209
Nat Rev Neurosci. 2013 Jun;14(6):429-42
23686172
Eur J Neurosci. 2006 May;23(10):2657-68
16817868
Curr Opin Neurobiol. 2014 Apr;25:38-46
24709599
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2074-7
8446631
Science. 2001 Dec 7;294(5549):2127-30
11739948
Biochem Biophys Res Commun. 2014 Jul 18;450(1):378-83
24944019
Trends Cogn Sci. 2014 Jun;18(6):319-27
24751359
Brain Res. 1990 Jul 2;522(1):144-6
2224508
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4398-403
10716738
Bull Exp Biol Med. 2012 Sep;153(5):746-9
23113275
Brain Res Brain Res Rev. 2003 Apr;42(1):85-95
12668291
Nat Neurosci. 1999 Mar;2(3):260-5
10195219
Eur J Neurosci. 2007 Jan;25(1):47-58
17241266
Proc Natl Acad Sci U S A. 1988 Nov;85(22):8722-6
3186755
J Neurosci. 2010 Jun 23;30(25):8613-23
20573907
Science. 1977 Jul 8;197(4299):183-6
301658
Cold Spring Harb Perspect Biol. 2015 Jul 01;7(7):a018994
26134318
Neuroreport. 2005 Dec 19;16(18):2037-40
16317350
J Comp Neurol. 1969 Jul;136(3):269-93
5788129
Nature. 1995 Jun 8;375(6531):482-4
7777055
Trends Cogn Sci. 2015 Mar;19(3):151-61
25715908
J Cell Mol Med. 2015 Oct;19(10):2352-64
26223362
J Comp Neurol. 1981 Jan 10;195(2):323-38
7251929
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2415-20
18272492
Pain. 1988 Apr;33(1):87-107
2837713
Nat Neurosci. 2002 Jul;5(7):688-94
12068300
Nat Rev Neurosci. 2007 Jun;8(6):481-8
17514200
Arthritis Rheum. 2013 Dec;65(12):3293-303
23982850
J Neurocytol. 1979 Feb;8(1):1-18
438867
Nat Med. 2010 Nov;16(11):1267-76
20948535
Nature. 2000 Jun 22;405(6789):951-5
10879536
Science. 1977 Sep 9;197(4308):1092-4
887941
Curr Opin Neurobiol. 1992 Apr;2(2):212-6
1638157
Open Biol. 2015 Jul;5(7):150056
26136256
PLoS One. 2011;6(6):e21660
21738757
J Neurol. 2016 Apr;263 Suppl 1:S45-53
27083884
Nat Rev Neurosci. 2008 Apr;9(4):304-13
18319727
J Biol Chem. 2013 Mar 22;288(12):8053-60
23344953