Vibhu Sahni and Victoria Abraira, Weill Cornell Medicine, Burke Neurological Institute, White Plains, USA

Developmental genes for molecularly directed corticospinal circuit repair

Funded in: 2020, 2021, 2022

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Problem: Permanent damage of nerve connections between the brain and the spinal cord
Target: Stimulate injured axons for repair by activating growth molecules
Goal: Promote axons growth by re-activating molecules in specific combinations

Introduction: One of the principal causes for paralysis after spinal cord injury is the permanent damage to nerve connections, so-called axons, that relay impulses between the cortex in the brain and the spinal cord. The failure of repair is in part because the mechanisms that once directed the growth of these axons during development are lost in the adult.
Problem Statement: During embryonic and early postnatal life, these axons normally grow and then connect with specific spinal targets. A potential strategy to stimulate these injured axons for repair is by reactivating the same molecules that directed their growth. In earlier work, the research group identified novel molecules that control the targeted growth of these axons to the specific levels of the spinal cord during this developmental period. Their hypothesis is that by re-activating these molecules in specific combinations, the research group can promote axon growth after spinal cord injury and enhance functional recovery.  
Methods and Expected Results: The scientists will test the application of these developmental molecules in two separate models of spinal cord injury in mice. First, they will overexpress these genes to “activate” these neurons in the brains of young mice. These experiments will test whether the initial decline in growth ability, as nerve cells age, is due to a decline in levels of these developmental molecules. In a second set of experiments, the researchers will use adult models of spinal cord injury. This will test whether application of these developmental molecules, in specific combinations, can promote long-distance regeneration. Such regeneration has not been achieved to date with any experimental manipulation.
For these experiments, the scientists will overexpress these genes in nerve cells using ultrasound-guided rodent microsurgery in both normal as well as transgenic mouse lines. They expect that reactivation of these developmental genes will a) prevent the developmental decline in the ability of axons to grow; and b) even enable adult axons to re-grow well after this normal period of growth is over. In both sets of experiments, they will also test the functional recovery using established tests of skilled mouse behavior. In addition, the group will also test the applicability of Mo-seq, a new technique which uses machine vision and artificial intelligence to score mouse behavior. The scientists expect that the enhanced axonal regrowth will result in functional improvement after both neonatal and adult injury.
Potential Application: Activation of key developmental molecules to stimulate axon regeneration is a potential therapeutic strategy that could help reestablish lost connections and improve spinal cord repair and function. While the current work is aimed at acute injury, pending validation, this work can be easily translated and applied to chronic spinal cord injury.