Transplants of embryonic spinal cord can improve locomotor function after experimental spinal cord injuries. To study the responsible mechanisms we propose experiments that will investigate Clarke's nucleus (CN) and vestibulospinal neurons. These neurons form the afferent and efferent limbs of circuits that are crucial for posture and gait stability and important for coordination between forelimbs and hindlimbs during locomotion. Our previous studies with embryonic CNS tissues suggest that the neurotrophic factor Neurotrophin-3 (NT-3) can rescue axotomized CN neurons from retrograde cell death. One series of studies will determine whether the exogenous administration of NT-3 by genetically modified cells rescues axotomized CN neurons. Cell lines have the additional potential to promote axon regeneration in the adult CNS (Specific Aim 1). Axotomized neurons may contribute to recovery through collateral axons. This capacity would be enhanced if stripping of preterminal synapses (desynapsis) which ordinarily accompanies axotomy were prevented or reversed. A second series of experiments will examine whether transplants of embryonic spinal cord can prevent or reverse desynapsis in axotomized CN neurons (Specific Aim 2). Transplant-mediated improvement in locomotor function has not been related to specific axon pathways. A third series of studies will determine whether transplants can mediate recovery of VST function after spinal cord injury. interruption of the vestibulospinal tract (VST) produces obvious and quantifiable behavioral deficits (Specific Aim 3). Relating recover to tahe actions of this pathway will be an important step in understanding recovery and for devising strategies to enhance recovery.
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