Effects of pathway and neuronal aging on the specificity of motor axon regeneration

Youth is a strong predictor of functional recovery after peripheral nerve repair, while adulthood is commonly associated with poor outcome. Identification of the factors responsible for this difference could form the basis for strategies to improve regeneration in adults. Preferential reinnervation of motor pathways by motor axons (PMR) occurs strongly in young rats, but is often absent in older animals, and thus parallels the overall trend for superior resets in young individuals. These experiments evaluate the individual contributions of peripheral nerve age and motoneuron age to the decline in regeneration specificity (PMR) which accompanies the aging process. The femoral nerves of young and old Lewis rats were removed as inverted "Y" grafts from the femoral trunk proximally to the terminal muscle and cutaneous branches distally. These grafts were transferred from (1) old to young, (2) young to old, (3) old to old, and (4) young to young bilaterally in 10 individuals per group. After 8 weeks of regeneration, reinnervation of cutaneous and muscle branches was assessed by dual labeling with HRP and Fluoro-Gold. Motor neuron regeneration was random in old to old (mean muscle branch (M) = 159, mean cutaneous branch (C) = 168), but PMR was seen when young pathways were used in old animals (M = 163, C = 116). PMR was vigorous when either type of graft was used in young animals (young graft, M = 218, C = 134; old graft, M = 204, C = 127). In this model, motoneuron age appears to be the primary determinant of specificity. However, the pathway also makes significant contributions, as shown by the ability of young pathways to generate specificity in old animals. Manipulation of graft Schwann cell behavior might therefore be an appropriate strategy to improve outcome in older individuals.