Synaptic Plasticity, Neurogenesis, and Functional Recovery after Spinal Cord Injury

Spinal cord injury research has greatly expanded in recent years, but our understanding of the mechanisms that underlie the functional recovery that can occur over the weeks and months following the initial injury, is far from complete. To grasp the scope of the problem, it is important to begin by defining the sensorimotor pathways that might be involved by a spinal injury. This is done in the rodent and nonhuman primate, which are two of the most commonly used animal models in basic and translational spinal injury research. Many of the better known experimentally induced models are then reviewed in terms of the pathways they involve and the reorganization and recovery that have been shown to follow. The better understood neuronal mechanisms mediating such post-injury plasticity, including dendritic spine growth and axonal sprouting, are then examined.

[1]  Hirofumi Nakatomi,et al.  Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors , 2002, Cell.

[2]  S. McMahon,et al.  Chondroitinase ABC Promotes Sprouting of Intact and Injured Spinal Systems after Spinal Cord Injury , 2006, The Journal of Neuroscience.

[3]  V. Dietz,et al.  Repair of the Injured Spinal Cord , 2007, Neurodegenerative Diseases.

[4]  Martin E Schwab,et al.  The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats , 2004, Nature Neuroscience.

[5]  R. An Chondroitinase ABC promotes functional recovery after spinal cord injury , 2002 .

[6]  E. Taub,et al.  Progressive Transneuronal Changes in the Brainstem and Thalamus after Long-Term Dorsal Rhizotomies in Adult Macaque Monkeys , 2000, The Journal of Neuroscience.

[7]  C. Sherrington,et al.  VIII. Experiments upon the influence of sensory nerves upon movement and nutrition of the limbs. Preliminary communication , 1985, Proceedings of the Royal Society of London.

[8]  Kozo Nakamura,et al.  Growth Factor Treatment and Genetic Manipulation Stimulate Neurogenesis and Oligodendrogenesis by Endogenous Neural Progenitors in the Injured Adult Spinal Cord , 2006, The Journal of Neuroscience.

[9]  T. Hagg Collateral sprouting as a target for improved function after spinal cord injury. , 2006, Journal of neurotrauma.

[10]  C. Darian‐Smith Plasticity of Somatosensory Function during Learning, Disease and Injury , 2008 .

[11]  G. Raisman,et al.  Sprouts from Cut Corticospinal Axons Persist in the Presence of Astrocytic Scarring in Long-Term Lesions of the Adult Rat Spinal Cord , 1995, Experimental Neurology.

[12]  Long ascending propriospinal projections from lumbosacral to upper cervical spinal cord in the rat , 2006, Brain Research.

[13]  Maurizio Corbetta,et al.  Functional reorganization and stability of somatosensory-motor cortical topography in a tetraplegic subject with late recovery , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Olsson,et al.  Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis , 2006, The European journal of neuroscience.

[15]  C. Darian‐Smith,et al.  Loss and recovery of voluntary hand movements in the macaque following a cervical dorsal rhizotomy , 2005, The Journal of comparative neurology.

[16]  J. Fawcett,et al.  Proteoglycans in the central nervous system: plasticity, regeneration and their stimulation with chondroitinase ABC. , 2008, Restorative neurology and neuroscience.

[17]  A. Blight,et al.  Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. , 2005, Journal of neurotrauma.

[18]  F. R. Clemente,et al.  Dorsal horn synaptosomal content of aspartate, glutamate, glycine and GABA are differentially altered following chronic constriction injury to the rat sciatic nerve , 2002, Neuroscience Letters.

[19]  M. Aoki,et al.  The possible role of collateral sprouting in the functional restitution of corticospinal connections after spinal hemisection , 1986, Neuroscience Research.

[20]  C. Leonard,et al.  Altered precision grasping in stumptail macaques after fasciculus cuneatus lesions. , 1992, Somatosensory & motor research.

[21]  Vernon B. Mountcastle,et al.  The sensory hand : neural mechanisms of somatic sensation , 2005 .

[22]  O. Steward,et al.  Endogenous Neurogenesis Replaces Oligodendrocytes and Astrocytes after Primate Spinal Cord Injury , 2006, The Journal of Neuroscience.

[23]  J. Kaas Sensory loss and cortical reorganization in mature primates. , 2002, Progress in brain research.

[24]  R. Porter,et al.  Corticospinal Function and Voluntary Movement , 1993 .

[25]  A. Todd,et al.  Light microscope study of the coexistence of GABA‐like and glycine‐like immunoreactivities in the spinal cord of the rat , 1990, The Journal of comparative neurology.

[26]  Jon H. Kaas,et al.  Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord , 2008, Experimental Neurology.

[27]  Zhigang He,et al.  Glial inhibition of CNS axon regeneration , 2006, Nature Reviews Neuroscience.

[28]  Chronic changes in the response of cells in adult cat dorsal horn following partial deafferentation; the appearance of responding cells in a previously non-responsive region A.I. Basbaum and P.D. Wall, Brain Res., 116 (1976) 181–204 , 1977, Pain.

[29]  M. Schwab Nogo and axon regeneration , 2004, Current Opinion in Neurobiology.

[30]  K. Fouad,et al.  Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers , 2006, The European journal of neuroscience.

[31]  C. Vierck Comparison of the effects of dorsal rhizotomy or dorsal column transection on motor performance of monkeys , 1982, Experimental Neurology.

[32]  J. Fawcett,et al.  Promoting plasticity in the spinal cord with chondroitinase improves functional recovery after peripheral nerve repair. , 2007, Brain : a journal of neurology.

[33]  R. Lemon,et al.  Comparing the function of the corticospinal system in different species: Organizational differences for motor specialization? , 2005, Muscle & nerve.

[34]  J. Silver,et al.  CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure , 2008, Experimental Neurology.

[35]  R. Coggeshall,et al.  Reorganization of central terminals of myelinated primary afferents in the rat dorsal horn following peripheral axotomy , 1995, The Journal of comparative neurology.

[36]  I. Tavares,et al.  GABA decreases in the spinal cord dorsal horn after peripheral neurectomy , 1993, Brain Research.

[37]  A. Walmsley,et al.  Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. , 2007, Current pharmaceutical design.

[38]  Craig C Garner,et al.  Synaptic Protein Dynamics in Hibernation , 2007, The Journal of Neuroscience.

[39]  Jack M Parent,et al.  Rat forebrain neurogenesis and striatal neuron replacement after focal stroke , 2002, Annals of neurology.

[40]  H. Ralston,et al.  The terminations of corticospinal tract axons in the macaque monkey , 1985, The Journal of comparative neurology.

[41]  Jerry Silver,et al.  Regeneration beyond the glial scar , 2004, Nature Reviews Neuroscience.

[42]  C. Darian‐Smith Monkey models of recovery of voluntary hand movement after spinal cord and dorsal root injury. , 2007, ILAR journal.

[43]  S. Cullheim,et al.  Ultrastructural evidence for a preferential elimination of glutamate‐immunoreactive synaptic terminals from spinal motoneurons after intramedullary axotomy , 2000 .

[44]  K. Fouad,et al.  Adaptive changes in the injured spinal cord and their role in promoting functional recovery , 2008, Neurological research.

[45]  J. Fawcett,et al.  Neurocan Is Upregulated in Injured Brain and in Cytokine-Treated Astrocytes , 2000, The Journal of Neuroscience.

[46]  T. Jones,et al.  Use-dependent growth of pyramidal neurons after neocortical damage , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  L. Maffei,et al.  Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex , 2002, Science.

[48]  H. Dai,et al.  Modulation of dendritic spine remodeling in the motor cortex following spinal cord injury: Effects of environmental enrichment and combinatorial treatment with transplants and neurotrophin‐3 , 2008, The Journal of comparative neurology.

[49]  J. Larson,et al.  Effects of unilateral and bilateral training in a reaching task on dendritic branching of neurons in the rat motor-sensory forelimb cortex. , 1985, Behavioral and neural biology.

[50]  W. Willis,et al.  Ascending sensory tracts and their descending control , 2003 .

[51]  C. Vierck,et al.  Cutaneous texture discrimination following transection of the dorsal spinal column in monkeys. , 1998, Somatosensory & motor research.

[52]  S. Vicini,et al.  Remodeling of synaptic structures in the motor cortex following spinal cord injury , 2006, Experimental Neurology.

[53]  P. Nathan,et al.  Sensory effects in man of lesions of the posterior columns and of some other afferent pathways. , 1986, Brain : a journal of neurology.

[54]  H. Gundersen,et al.  Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator , 1991, The Anatomical record.

[55]  A. Nagano Treatment of brachial plexus injury , 1998, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[56]  Jerry Silver,et al.  Combining an Autologous Peripheral Nervous System “Bridge” and Matrix Modification by Chondroitinase Allows Robust, Functional Regeneration beyond a Hemisection Lesion of the Adult Rat Spinal Cord , 2006, The Journal of Neuroscience.

[57]  R. Yezierski Chapter 21 Pain following spinal cord injury: central mechanisms. , 2006, Handbook of clinical neurology.

[58]  H. Ralston,et al.  Identification of dorsal root synaptic terminals on monkey ventral horn cells by electron microscopic autoradiography , 1979, Journal of neurocytology.

[59]  V Reggie Edgerton,et al.  Extensive spinal decussation and bilateral termination of cervical corticospinal projections in rhesus monkeys , 2009, The Journal of comparative neurology.

[60]  O. Lindvall,et al.  Neuronal replacement from endogenous precursors in the adult brain after stroke , 2002, Nature Medicine.

[61]  M. Eaton,et al.  Changes in GAD- and GABA- immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors , 1998, Journal of Chemical Neuroanatomy.

[62]  C. Vierck,et al.  Physiological changes in primate somatosensory thalamus induced by deafferentation are dependent on the spinal funiculi that are sectioned and time following injury , 2003, Neuroscience.

[63]  J. Wall,et al.  Human brain plasticity: an emerging view of the multiple substrates and mechanisms that cause cortical changes and related sensory dysfunctions after injuries of sensory inputs from the body , 2002, Brain Research Reviews.

[64]  Ming Xu,et al.  Functional Integration of Newly Generated Neurons Into Striatum After Cerebral Ischemia in the Adult Rat Brain , 2008, Stroke.

[65]  Thierry Wannier,et al.  Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans? , 2007, Nature Medicine.

[66]  M. Schwab,et al.  Disinhibition of neurite growth to repair the injured adult CNS: Focusing on Nogo , 2007, Cellular and Molecular Life Sciences.

[67]  R. Lemon,et al.  Striking differences in transmission of corticospinal excitation to upper limb motoneurons in two primate species. , 2000, Journal of neurophysiology.

[68]  F. Gage,et al.  Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. , 2006, Stem cells and development.

[69]  F. Gage,et al.  Proliferation and Differentiation of Progenitor Cells Throughout the Intact Adult Rat Spinal Cord , 2000, The Journal of Neuroscience.

[70]  Blair R. Leavitt,et al.  Induction of neurogenesis in the neocortex of adult mice , 2000, Nature.

[71]  Martin E. Schwab,et al.  Plasticity of motor systems after incomplete spinal cord injury , 2001, Nature Reviews Neuroscience.

[72]  T. Robinson,et al.  Brain Plasticity and Behavior , 2003 .

[73]  Martin E Schwab,et al.  Sprouting, regeneration and circuit formation in the injured spinal cord: factors and activity , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[74]  Jon H. Kaas,et al.  Deactivation and reactivation of somatosensory cortex after dorsal spinal cord injury , 1997, Nature.

[75]  J. Kaas,et al.  Growth of new brainstem connections in adult monkeys with massive sensory loss. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[76]  W. Greenough,et al.  Lateralized effects of monocular training on dendritic branching in adult split-brain rats , 1982, Brain Research.

[77]  William D. Willis,et al.  Sensory Mechanisms of the Spinal Cord , 1979, Springer US.

[78]  W. Alilain,et al.  Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3 , 2008, Experimental Neurology.

[79]  J. Fawcett Novel strategies for protection and repair of the central nervous system. , 2006, Clinical medicine.

[80]  Walmsley Ar,et al.  Targeting the Nogo-A Signalling Pathway to Promote Recovery Following Acute CNS Injury , 2007 .

[81]  C. Darian‐Smith Primary afferent terminal sprouting after a cervical dorsal rootlet section in the macaque monkey , 2004, The Journal of comparative neurology.

[82]  K. Fouad,et al.  Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses , 2001, Current Biology.

[83]  Hiroshi Baba,et al.  Partial Peripheral Nerve Injury Promotes a Selective Loss of GABAergic Inhibition in the Superficial Dorsal Horn of the Spinal Cord , 2002, The Journal of Neuroscience.

[84]  J. Fawcett,et al.  The glial scar and central nervous system repair , 1999, Brain Research Bulletin.

[85]  I. Darian‐Smith,et al.  Multiple corticospinal neuron populations in the macaque monkey are specified by their unique cortical origins, spinal terminations, and connections. , 1994, Cerebral cortex.

[86]  P. Hickmott,et al.  Dendritic Plasticity in the Adult Neocortex , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[87]  Serge Rossignol,et al.  Spinal Cord Injury: Time to Move? , 2007, The Journal of Neuroscience.

[88]  A. Hama,et al.  Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts , 1996, Neuroscience.

[89]  H. Ralston The fine structure of laminae I, II and III of the macaque spinal cord , 1979, The Journal of comparative neurology.

[90]  C. Leonard,et al.  Alterations of natural hand movements after interruption of fasciculus cuneatus in the macaque. , 1992, Somatosensory & motor research.

[91]  R. Lemon Descending pathways in motor control. , 2008, Annual review of neuroscience.

[92]  J. Kellerth,et al.  Transformation of synaptic vesicle phenotype in the intramedullary axonal arbors of cat spinal motoneurons following peripheral nerve injury , 2001, Experimental Brain Research.

[93]  Michael Fisher,et al.  The Sensory Hand , 2005 .

[94]  H. Kuypers,et al.  Anatomy of the Descending Pathways , 2011 .

[95]  D. Gozal,et al.  Motor Neuron Degeneration Promotes Neural Progenitor Cell Proliferation, Migration, and Neurogenesis in the Spinal Cords of Amyotrophic Lateral Sclerosis Mice , 2006, Stem cells.

[96]  P. Rakić,et al.  Transganglionic degenerative atrophy in the substantia gelatinosa of the spinal cord after peripheral nerve transection in rhesus monkeys , 1987, Cell and Tissue Research.

[97]  C. Darian‐Smith,et al.  Cuneate nucleus reorganization following cervical dorsal rhizotomy in the macaque monkey: Its role in the recovery of manual dexterity , 2006, The Journal of comparative neurology.

[98]  Theresa A. Jones,et al.  Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage , 1992, Brain Research.

[99]  J. Kuhtz-Buschbeck,et al.  Ultrastructural characteristics of glutamatergic and GABAergic terminals in cat lamina IX before and after spinal cord injury. , 1997, The journal of spinal cord medicine.

[100]  Dr. Ian Darian-Smith,et al.  The Anatomy of Manual Dexterity , 1996, Advances in Anatomy Embryology and Cell Biology.

[101]  C. Darian‐Smith,et al.  Functional changes at periphery and cortex following dorsal root lesions in adult monkeys , 2000, Nature Neuroscience.

[102]  F. W. Mott,et al.  Experiments on the Influence of Sensory Nerves upon Movement and Nutrition of the Limbs. , 1895 .

[103]  M. Mishkin,et al.  Massive cortical reorganization after sensory deafferentation in adult macaques. , 1991, Science.

[104]  E G Jones,et al.  Thalamic and brainstem contributions to large-scale plasticity of primate somatosensory cortex. , 1998, Science.

[105]  V. Dietz Do human bipeds use quadrupedal coordination? , 2002, Trends in Neurosciences.

[106]  A. Todd,et al.  GABA-like immunoreactivity in type I glomeruli of rat substantia gelatinosa , 1990, Brain Research.

[107]  W. Willis,et al.  Primary afferent neurons and the spinal dorsal horn , 2003 .

[108]  I. Darian‐Smith,et al.  Manual dexterity and corticospinal connectivity following unilateral section of the cervical spinal cord in the macaque monkey , 1997, The Journal of comparative neurology.

[109]  M. Schwab,et al.  Cells of origin, course, and termination patterns of the ventral, uncrossed component of the mature rat corticospinal tract , 1997, The Journal of comparative neurology.

[110]  C. Darian‐Smith,et al.  Adult neurogenesis in primate and rodent spinal cord: comparing a cervical dorsal rhizotomy with a dorsal column transection , 2007, The European journal of neuroscience.

[111]  R. McKay,et al.  Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus , 2001, The Journal of comparative neurology.

[112]  F. Gage,et al.  Neurons born in the adult dentate gyrus form functional synapses with target cells , 2008, Nature Neuroscience.

[113]  M. Tuszynski,et al.  Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury , 2001, Proceedings of the National Academy of Sciences of the United States of America.