Engineering novel spinal circuits to promote recovery after spinal injury.
We have developed an innovative way to establish a functional bridge around a spinal lesion. We disconnected the T13 nerve from its muscle targets, leaving the proximal end intact. The cut end was inserted either into an intact spinal cord, to assess regeneration of T13 axons into the cord and synapse formation with spinal neurons, or caudal to a hemisection at L2/3, to assess restoration of function below the injury. Four to 28 weeks later, anterograde tracers indicated that axons from the inserted T13 nerve regenerated into the ventral horn, the intermediate zone, and dorsal horn base, both in intact and hemisected animals. Antibodies to cholinergic markers showed that many regenerating axons were from T13 motoneurons. Electrical stimulation of the T13 nerve proximal to the insertion site 4 weeks or more after insertion into the intact cord evoked local field potentials in the intermediate zone and ventral horn, which is where T13 axons terminated. Stimulation of T13 in 71% of the animals (8 hemisected, 7 intact) evoked contraction of the back or leg muscles, depending on the level of insertion. Animals in which T13 was inserted caudal to hemisection had significantly less spasticity and muscle wasting and greater mobility at the hip, knee, ankle, and digits in the ipsilateral hindlimb than did animals with a hemisection only. Thus, T13 motor axons form novel synapses with lumbosacral motor circuits. Because the T13 motor neurons retain their connections to the brain, these novel circuits might restore voluntary control to muscles paralyzed below a spinal lesion.
Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA.
Lucas
L
Campos
Zhuo
Z
Meng
Guoli
G
Hu
David T W
DT
Chiu
Richard T
RT
Ambron
John H
JH
Martin
D000818:Animals; D001369:Axons / Q000502:physiology / Q000637:transplantation; D002799:Cholinergic Fibers / Q000502:physiology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D006614:Hindlimb / Q000294:innervation / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D009434:Neural Pathways / Q000503:physiopathology / Q000601:surgery*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology / Q000503:physiopathology / Q000601:surgery; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000601:surgery*; D013900:Thoracic Nerves / Q000601:surgery / Q000637:transplantation*; D016896:Treatment Outcome