Functional plasticity of medullary descending motor tracts following spinal cord injury and regenerative stimulation – MedullaryWalk

This project aims to shed light on the neuronal mechanisms allowing motor recovery after spinal cord injury (SCI). More specifically, it will investigate the plasticity and functional relevance for locomotor recovery of specific descending neuronal tracts originating from the medulla.

SCI is an incurable condition caused by the interruption or weakening of the neuronal tracts that interface the brain and the spinal cord. It leads to a highly debilitating loss of motor and sensory functions below the injury which, for paraplegic or quadriplegic patients, includes the ability to walk and stand. Yet, the spinal motor circuits retain much of the capacity to produce a locomotor-like output if activated adequately, even long after the lesion. Equally encouragingly, severed axonal tracts can show an impressive capacity to sprout or even regrow across the lesion. Strategies for promoting further this plasticity are thus considered highly promising. To be clinically-relevant, it is however crucial that these strategies i) be not be blind to the origin (spinal or supra-spinal), molecular identity (neurotransmitter, genetic signature), directionality (ascending or descending) and function (beneficial for locomotion or not) of the targeted axonal tracts, and ii) be shortly applicable to human patients.

One the one hand indeed, studies in non-lesioned animals models, including from ourselves, revealed that the rapid gating of locomotion owes to descending projections from specific subsets of, but not to all, glutamatergic and serotonergic neurons of the caudal medulla. These locomotor-promoting neurons are spatially intermingled with other tracts, and can thus only be manipulated by intersecting somatic location, neurotransmitter phenotype and molecular identity. On the other hand, we recently demonstrated the benefits of repetitive trans-spinal magnetic stimulation (rTSMS), a safe and non-invasive form of focalized CNS stimulation potentially applicable to humans. rTSMS treatment on spinalized mice indeed leads to long-lasting improvements in sensori-motor functions and to enhanced axonal infiltration across and beyond the lesion. In spite of these advances, there is still a stark lack of porosity between the fundamental and pre-clinical fields of motor control. Notably, the locomotor-relevant descending tracts have only seldom been incorporated into the framework of SCI repair and their capacity to sprout or regrow is ill-defined. Furthermore, regeneretive attempts, including rTSMS, are still too often been blind to the origin, nature and function of the axonal tracts whose connectivity is enhanced.

Leveraging from our combined expertise, we will thus examine here the anatomical plasticity and functional contribution, following experimental SCI in mice, of the prime descending pathways for locomotor initiation identified in non-lesioned contexts. We will implement an unprecedented level of selectivity for labelling and manipulating the activity of these discrete descending tracts following a realistic contusive injury model that best replicates the physiopathological processes seen in humans. From this, we will follow 3 main objectives to:
1) characterize the plasticity post-SCI (i.e., sparing, sprouting, regeneration and connectivity below the lesion) of each descending pathway selectively, using conventional microscopy and state-of-the-art volumetric imaging.
2) demonstrate causality between anatomical plasticity and locomotor recovery. For this we will use cell-type specific optogenetic and chemogenetic interfering tools combined with a fine scoring of motor functions.
3) investigate how rTSMS impacts on, and how its benefits are supported by, the plasticity and function of the selected locomotor-relevant descending tracts .

Our combine efforts will thus provide a connectivity hallmark conducive to motor recovery and will specifify the neuronal underpinnings of a promising and clinically-relevant regenerative stimulation.