Brachial plexus injury (BPI) leads to significant impairment of upper limb motor function, primarily due to progressive atrophy of denervated muscles resulting from the slow rate of axonal regeneration. Therefore, identifying strategies to accelerate axon extension is of critical importance.

In this study, we first established a mouse model of brachial plexus injury and employed chemogenetic approaches to specifically activate C6 spinal motoneurons. We then assessed axonal regeneration and motor function recovery in the injured mice through behavioral tests, morphological analyses, and electrophysiological detection.

We found that the AAV9-hM3Dq virus efficiently transduced motoneurons, and CNO administration robustly activated mature hM3Dq+ motoneurons in vivo. Chronic chemogenetic activation significantly enhanced the regeneration of spinal motoneurons injured by ventral root crush, accelerated axon extension, and improved axonal remyelination, resulting in increased axon size. This activation also facilitated the formation of new neuromuscular junctions (NMJs) in adult motoneurons and reduced muscle atrophy. Furthermore, it promoted electrophysiological recovery of the motor unit and improved overall motor function.

Chemogenetic activation of adult motoneurons can robustly enhances axon growth and mediate better behavioral recovery. These findings highlight the therapeutic potential of chemogenetic neuronal activation in promoting functional recovery following nerve injury.

We have established a chronic chemogenetic method to activate hM3Dq+ motor neurons after brachial plexus injury, which accelerates axonal regeneration and enhances functional recovery. This strategy holds promise as a clinical therapeutic approach for treating nervous system injuries.

Chemogenetic activation

Spinal motoneurons

Brachial plexus injury

Motor repair

© 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Speaking Orthopaedic Society.