Chronic neuronal activation increases dynamic microtubules to enhance functional axon regeneration after dorsal root crush injury

Nature Communications, 2020 · DOI: https://doi.org/10.1038/s41467-020-19914-3 · Published: December 3, 2020

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

After a spinal cord injury, sensory axons often fail to regenerate, leading to permanent sensory deficits. This study found that activating dorsal root ganglion (DRG) neurons using chemogenetics can improve axon growth. The researchers repeatedly activated DRG neurons in rats after a dorsal root crush injury. This activation, combined with chondroitinase to modify the inhibitory environment, enhanced axon regeneration across the dorsal root entry zone (DREZ) into the spinal cord. This regeneration led to the formation of functional synapses and improved performance in a sensorimotor task. The key mechanism involves changes in tubulin, indicating highly dynamic microtubules within the distal axon.

Study Duration

12 weeks

Participants

Adult female Wistar Rats

Evidence Level

Not specified

Key Findings

1
Chemogenetic activation of adult DRG neurons enhances neurite growth on CSPG spots in vitro, indicating that activation can help overcome inhibitory signals.
2
Repeated chemogenetic activation of DRG neurons after dorsal root crush improves recovery in a sensorimotor task that requires proprioception, demonstrating a functional benefit.
3
Axon regeneration mediated by neuronal activation is dependent upon dynamic microtubules, suggesting that microtubule dynamics play a crucial role in promoting axon regrowth.

Research Summary

This study investigates whether repeated chemogenetic activation can enhance DRG axon regeneration following dorsal root crush, addressing both intrinsic and extrinsic limitations. The findings demonstrate that chemogenetic activation of adult DRG neurons enhances axon growth on inhibitory substrates and improves regeneration across the DREZ into the dorsal horn. Neuronal activation increases axon regeneration into gray matter after dorsal root crush.

Practical Implications

Therapeutic Strategy

Combining chemogenetic activation with chondroitinase treatment may offer a novel therapeutic strategy for promoting functional sensory axon regeneration into the CNS after injury.

Microtubule Dynamics

Understanding the role of dynamic microtubules in axon regeneration can lead to the development of targeted therapies that enhance microtubule dynamics to promote axon growth.

Functional Integration

Promoting the functional integration of regenerated axons into existing circuits is crucial for achieving meaningful recovery after spinal cord injury, highlighting the importance of activity-dependent mechanisms.

Study Limitations

1
The mCherry reporter only localized to the soma and portions of axons closer to the soma.
2
The optimal pattern of stimulation required to promote growth is still not well understood.
3
ChABC alone promotes plasticity.

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