The mechanism underlying the age-related failure of regeneration : new trial for successful neural regeneration

为了研究横断轴突与年龄相关的再生失败机制，我们在成年小鼠和出生后7、14和21天的未成熟小鼠的下丘脑外侧单侧横断黑质纹状体多巴胺能轴突。横断10天后，在出生后第7天横断的小鼠中，酪氨酸羟酶免疫反应性轴突从尾侧到吻侧在病变部位再生，而在出生后第14天或更大的小鼠中，它们停止并且没有延伸到病变部位。在所有年龄的小鼠中，在病变周围观察到含有硫酸软骨素蛋白聚糖的活性星形胶质细胞。然而，在出生后14天或更大的小鼠中，在病变部位一致形成含有IV型胶原免疫反应性沉积物的纤维化疤痕，而在出生后7天的小鼠中则没有形成。在出生后第14天和成年小鼠横断时，在病变部位注射胶原合成抑制剂2,2′-联吡啶，可完全阻止IV型胶原的沉积和纤维化瘢痕的形成，大量酪氨酸羟化酶免疫反应性轴突横过病变，并重新支配纹状体。这些结果表明，在损伤部位形成的纤维化疤痕是成年小鼠上升多巴胺能轴突再生的关键障碍，并表明IV型胶原是成人脑损伤纤维化反应的发展所必需的。

To investigate the mechanism of the age-related failure of regeneration of transected axons, nigrostriatal dopaminergic axons were unilaterally transected in the lateral hypothalamus in adult mice and in immature mice aged postnatal days 7, 14 and 21. Ten days after the transection, tyrosine hydroxylase-immunoreactive axons had regenerated from caudal to rostral across the lesion site in mice transected at postnatal day 7, while they stopped and did not extend across the lesion site in mice transected at postnatal day 14 or older. Reactive astrocytes bearing chondroitin sulfate proteoglycans were observed around the lesion in mice transected at all ages. However, a fibrotic scar containing type IV collagen-immunoreactive deposits which was consistently formed at the lesion site in mice transected at postnatal day 14 or older, was not formed in mice lesioned at postnatal day 7. When 2,2'-dipyridyl, an inhibitor of collagen synthesis, was injected into the lesion site at the time of transection in both postnatal day 14 and adult mice, the deposition of type IV collagen and the formation of a fibrotic scar were completely prevented, and a large number of tyrosine hydroxylase-immunoreactive axons extended across the lesion and reinnervated the striatum. These results imply that the fibrotic scar formed in the lesion site is a crucial impediment to the regeneration of ascending dopaminergic axons in adult mice, and suggest that type IV collagen is required for the development of the fibrotic response to adult brain injury.