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Corticospinal tract regeneration after spinal cord injury: Implications for treatment and recovery
Abbreviations
A
adult
C
cervical
ChABC
chondroitinase ABC
CNS
central nervous system
CSPG
chondroitin sulfate proteoglycans
CST
corticospinal tract
E
embryonic
Htt
huntingtin gene
KLF
Krüppel-like factor
MSE
motor synergy encoder
mTOR
mammalian target of rapamycin
NgR
Nogo-A receptor
NPC
neural progenitor cell
NT-3
neurotrophine-3
P
post-natal
PTEN
tumor suppressor phosphatase and tensin homolog
SCI
spinal cord injury
SOCS3
suppressor of cytokine signaling 3
T
thoracic
YA
young adult
Introduction
The corticospinal tract (CST) is an axonal bundle that starts from cortical layer V pyramid neurons and travels through brain and brainstem to terminate in spinal cord. One major characteristics of CST is that the majority of the CST axons cross the midline at the pyramidal decussation, resulting the right side of brain to control the left side of the body and vice versa. The location of CST is different among different species, from ventral dorsal column in rodent to dorsal lateral funiculus in cat, non-human primate, and human ( ). In addition, the CST termination is different among different species, from dorsal to ventral gray matter.
The main function of the CST is to control primary motor activity of the body, especially the voluntary movements. Disruption of CST along with other tracts after spinal cord injury (SCI) definitely interferes with communication between brain and the spinal cord below the injury, resulting in loss of motor, sensory, and autonomic function. Although studies show that CST sprouts after SCI from uninjured or injured axons, especially after genetically manipulation and therapeutic treatments ( ; ; ; ), true regeneration from transected CST is rarely reported until recently from our lab ( ). Regeneration of CST, including sprouting and regenerative sprouting of CST, is vitally important to restore motor function, especially the voluntary skilled motor function, after SCI.
In this chapter, we will review development of CST and its innervation of spinal cord neurons. In addition, we will review injury-induced CST sprouting, and genetical manipulation and therapeutic treatment to promote CST sprouting and regenerative sprouting. Finally, we will discuss our own work for promotion of CST regeneration by transplantation of caudalized neural progenitor cells (NPCs) after SCI.
CST development
CST outgrowth
The corticospinal tract (CST) is a motor pathway in central nervous system (CNS) starting from the cerebral cortex, traveling through internal capsule and brainstem, most of them crossing the midline at the pyramidal decussation, and ending at the spinal cord ( ). In the popular rodent model of CNS development, CST axons reach brainstem at embryonic day 17 (E17), caudal medulla at E19, and cross the middle line and enter the spinal cord around post-natal day 0 (P0). CST axons continue to extend into entire spinal cord, including cervical cord around P1–2, thoracic around P3, and lumbar around P5–7 ( Fig. 1 ) ( ; ). The development of CST in primate most occurs before birth. For example, CST reaches the entire spinal cord at birth in non-human primate ( ) and reach the entire cervical spinal cord at 24 weeks post-conceptional age in human ( ). The growth of CST is leaded by a small number of “pioneer” axons followed by other axons that eventually populated the CST tract ( ). Following the outgrowth of CST, myelination starts around P10 and finishes in the entire spinal cord around 4 weeks in rodent spinal cord ( Fig. 1 ), indicating readiness for electro impulse transmission ( ).
CST location and termination pattern in spinal cord
CST travels in the spinal cord white matter, which just likes other descending systems in the spinal cord. However, the location where CST travels in the spinal cord varies among species ( ). While the crossed main CST locates in the most ventral portion of dorsal column in rodent, it shifts to dorsal lateral funiculus in cat and primates, including human ( Fig. 2 ). The small proportion of uncrossed lateral and ventral CST are in similar location among different species. In addition, the termination pattern of CST into spinal cord gray matter is different among species. In rodent, the CST terminates most in dorsal and intermediate zone, but not directly into motor neurons in the ventral horn ( Fig. 2 A). However, in primates, both crossed main CST tract and uncrossed CST shift their termination ventrally into intermediate zone and ventral horn ( Fig. 2 C and D), indicating direct cortico-motoneuronal connections ( ). Furthermore, our own work demonstrates additional extensive decussation and bilateral termination of CST in cervical region in monkey, nearly twice as many CST axons decussating in the cervical midline ( ).
Precise control of skilled motor functions by defined CST populations
A recent study identifies spatially defined CST populations with distinct spinal projections that control different musculature groups and function in skilled forelimb motor function in mice ( ). They reveal a sequential activation of topographically organized CST neurons during skilled forelimb performance using in vivo calcium imaging with intersectional approach to specifically label and monitor different regions of CST neurons. Manipulation of region-specific CST neurons by ablation of specific population with diphtheria toxin identifies that caudal forelimb area controls reaching while rostral forelimb area controls grasping. The identification of these spatially defined groups of CST neurons that controls different skilled forelimb movements enables us to understand how CST system precisely works and how to repair it after SCI.
Identification of cellular node for CST control of motor function in mice
Since CST terminate mostly in dorsal and intermediate zone in rodent, it is important to identify those segmental interneurons and propriospinal neurons that relay CST signal into motor neurons. identify a neuronal population term “motor synergy encoder (MSE)” in the mouse spinal cord that may function as relay neurons from CST to motor neurons for voluntary motor movement. The MSE directly receive CST inputs in addition to sensory pathways, and have monosynaptic connection to spinal motor neurons. Molecular study reveals three candidate genes, Tfap2b , Satb1 , and Satb2 , that specifically identify MSE. Identification of MSE could direct neural stem cell study to generate these MSE progenitor cells as graft to attract CST regeneration to mimic their relays for CST input into spinal cord motor neurons below SCI.
Spinal cord injury induced spontaneous sprouting of CST
Classical work
Spontaneous sprouting of spared axons may innervate denervated targets and has been regarded as an underlying factor for functional recovery after SCI. In a classical work to investigate anatomical plasticity of CST, unilaterally lesioned CST tracted at medullary pyramids in young hamster from age 5 to 23 days. They injected vulgaris leucoagglutinin (PHA-L) into intact side to label uninjured CST for 2 weeks. Immunohistochemical study reveals that PHA-L labeled CST sprouts into contralaterally denervated spinal cord side 4 weeks post-injury. CST sprouting is maximal in very young age of 5 days and declines with increased ages. Interestingly, the sprouted CST axons keep the same topographical specificity as normal CST arborization. Their results suggest that sprouting occurs in response to local signals which govern the specificity of denervation and induce sprouting similar to those normal development of corticospinal connections.
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