Axon regeneration and circuit reorganization after complete spinal cord injury
First human trials involving neuroprosthetic rehabilitation demonstrated recently that significant
functional benefits can be achieved with lumbosacral neuromodulation and reorganized
spared projections. However, complete spinal cord injuries (SCI) wholly isolate infralesional
circuits from any supraspinal control, leading to irreversible motor deficits that neuroprosthetics
still fails to address. As axons fail to regrow across the lesion site, neuroregenerative
research after SCI has been dogmatically focusing attention on minimizing the environmental
inhibitions to axon regeneration. In the present work, we demonstrate that spontaneous axon
regeneration failure can be reversed, and that propriospinal axons are able to grow across
complete non-neural lesion cores when the required facilitators are provided. We identified
three mechanisms needed for propriospinal regrowth : i) enhancing neuronal intrinsic growth
capacities using viral technologies, ii) remodeling the lesion core with growth factors, in order
to densify permissive substrates, and iii) guiding axons chemically across the SCI site.
Propriospinal neurons - that coordinate different spinal segments in healthy conditions - are
known to support recovery of locomotion in incomplete models of spinal cord injury. However,
restoring a robust descending bridge of propriospinal axons does not by itself promote any
functional benefit. We hypothesize that a lack of somatosensory feedback to the motor cortex
(M1), together with insufficient descending motor control, may prevent coherent exchange
of information between lumbosacral and cortical motor centers. Therefore, we explored the
neuroregenerative potential of reticulospinal axons - which are projected from the brainstem
to the spinal cord - as a second relay for the descending motor cortical command. Together
with axon guidance and lesion remodeling, our viral manipulation of intrinsic growth programs
induced limited yet significant reticulospinal regeneration into the lesion core. In order to
enhance this reticulospinal regrowth, we explored activity-dependent mechanisms of neurite
growth control. As we observed that activity does not recruit growth programs after SCI,
we revealed a possible divergence between the mechanisms that underly reticulospinal axon
regrowth and neurite sprouting. In the mean time, we are developing a somatosensory interface
that aims at restoring sensory feedback to the motor cortex after complete SCI. Based on
hindlimb electromyographic activity, we linked locomotion to optogenetic neuromodulation
of the motor thalamus, and were able to evoke responses in M1 by selectively activating
thalamocortical projections, both before and after complete spinal lesion. Such technology
enables a direct recruitment of thalamic nuclei that gate motor learning and motor planning
at a cortical level. Coming experiments will test wether a strategy combining propriospinal
regeneration with locomotion-dependent thalamocortical modulation is sufficient to restore
voluntary stepping after complete SCI.
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