Characterization of Neuronal Death and Functional Deficits following Nerve Injury during the Early Postnatal Developmental Period in Rats

Abstract

In contrast to adult rat nerve injury models, neonatal sciatic nerve crush leads to massive motor and sensory neuron death. Death of these neurons results from both the loss of functional contact between the nerve terminals and their targets, and the inability of immature Schwann cells in the distal stump of the injured nerve to sustain regeneration. However, current dogma holds that little to no motoneuron death occurs in response to nerve crush at postnatal day 5 (P5). The purpose of the current study was to fully characterize the extent of motor and sensory neuronal death and functional recovery following sciatic nerve crush at mid-thigh level in rats at postnatal days 3-30 (P3-P30), and then compare this to adult injured animals. Following nerve crush at P3, motoneuron numbers were reduced to 35% of that of naïve uninjured animals. Animals in the P5 and P7 group also displayed statistically fewer motoneurons than naïve animals. Animals that were injured at P30 or earlier displayed statistically lower sensory neuron counts in the dorsal root ganglion than naïve controls. Surprisingly, complete behavioral recovery was observed exclusively in the P30 and adult injured groups. Similar results were observed in muscle twitch/tetanic force analysis, motor unit number estimation and wet muscle weights. Rats in both the P5 and P7 injury groups displayed significant neuronal death and impaired functional recovery following injury, challenging current dogma and suggesting that severe deficits persist following nerve injury during this early postnatal developmental period. These findings have important implications concerning the timing of neonatal nerve injury in rats.

Treatment with Riluzole Restores Normal Control of Soleus and Extensor Digitorum Longus Muscles during Locomotion in Adult Rats after Sciatic Nerve Crush at Birth

“…Kemp and colleagues [21] showed that the neuroprotective agent P7C3 enhanced motor and sensory neuron survival and produced a partial recovery of animal performance. Furthermore, it has been reported in rats with SNC at P3-P30 [22] that locomotor recovery, assessed with the SFI in P7 rats, was worse than in naive animals, and a decrease in the number of motor and sensory neurons was seen at P7 and P30 as well as a severe impairment of muscle function observed when SNC was inflicted before P30. Overall, there is a lack of systematic experimental data on the effect of SNC on the neuronal circuits involved in locomotor control and recovery of locomotor function indicating a need for better measures of outcome assessment.…”

Effects of early nerve repair on experimental brachial plexus injury in neonatal rats

“…However, more proximal postganglionic BPI (C7 spinal nerve) results in delayed 20%–30% death of corresponding motoneurons in adult rats (Jivan et al., 2006; Ma et al., 2001). Recent studies assessing the effects of age on motoneuronal survival following sciatic nerve injury in rats also demonstrate that injury at 3–7 days after birth induced greater neuronal loss that injury at age 30 days (Kemp et al., 2015).…”

Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion

“…These results are consistent with earlier observations on the differential expression of c‐JUN and ATF‐3 following proximal or distal axotomy (Herdegen et al ., ; Tsujino et al ., ; Zhou et al ., ; Linda et al ., ). In contrast, peripheral axotomy in neonatal (P3‐30) rats leads to similar motoneuron loss and poor function regeneration, emphasizing the importance of the age of the experimental animals and location of the axotomy (Kemp et al ., ).…”

“…This indicates that atrophy following ventral root avulsion could have been mistaken for motoneuron death (McPhail et al, 2004). Motoneuron loss occurs only following a nerve lesion close to the cell body in adult rats or following peripheral nerve axotomy in neonatal (P3-30) rats (Kemp et al, 2015). The precise biological mechanism which underlies the degeneration of motoneurons is still not fully understood.…”