A Critical Period for Functional Motor Recovery After Peripheral Nerve Injury in the Mouse

The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. in his laboratory, for guiding me and supporting my independence in this project, and for providing me with valuable opportunities to present this work and learn from these experiences. Dr. Takao Omura and Dr. Alban Latremolière initially proposed the project, conducted the pilot experiments on the multiple crush experiment, and advised me closely throughout this project. I would like to thank Dr. Omura for his mentorship, which has inspired me to become a surgeon-scientist committed to answering biological questions that will ultimately benefit patient care. I would like to thank Dr. Latremolière for sharing with me his intellectual curiosity and commitment to scientific rigor, which has allowed me to grow as a scientist during this research experience. I would also like to thank the rest of the Woolf Lab for their expertise, friendship, and support. Abstract.. Repair of peripheral nerve injury in humans often results in poor functional motor recovery, depending on the location and the timing of surgery. This deficit in motor recovery has previously been attributed to the failure of axons to regenerate into the target muscle. However, we have recently reported that following sciatic nerve transection and immediate resuture in mice, regenerating axons are observed at the motor end plate even in animals with poor functional recovery. In this model, motor recovery reaches a plateau approximately 35 days post-injury, with no further recovery beyond this period. Based on this, we proposed that following axonal injury, there is a critical period during which the axon must reach the target muscle in order to form a functional neuromuscular junction. To test this, we have developed a mouse model of differential prolonged denervation, in which the proximal sciatic nerve is crushed repeatedly every 3 to 7 days, preventing regenerating axons from reaching the target muscle. This multiple crush model allows us to vary the period of denervation, by modifying the number of crushes. We performed 3, 4, or 5 crushes every 7 days (corresponding to ~24, 31, or 38 days of denervation, respectively) and assessed functional motor recovery using the toe-spreading score and modified sciatic function index. Motor recovery occurs after 3 or 4 multiple crushes (24 or 31 days of denervation) but not after 5 crushes (38 days). Immunostaining for alpha-bungarotoxin and neurofilament demonstrated axonal regeneration reaching the motor end …