Cellular damage associated with traumatic brain injury (TBI) manifests in motor and cognitive dysfunction following injury. Experimental models of TBI reveal cell death in the granule cell layer (GCL) of the hippocampal dentate gyrus acutely after injury. Adult-born neurons residing in the neurogenic niche of the GCL, the subgranular zone, are particularly vulnerable. Injury-induced proliferation of neural progenitors in the subgranular zone supports recovery of the immature neuron population, but their development and localization may be altered, potentially affecting long-term survival. Here we show that increasing hippocampal levels of insulin-like growth factor-1 (IGF1) is sufficient to promote end-stage maturity of posttrauma-born neurons and improve cognition following TBI. Mice with conditional overexpression of astrocyte-specific IGF1 and wild-type mice received controlled cortical impact or sham injury and bromo-2'-deoxyuridine injections for 7d after injury to label proliferating cells. IGF1 overexpression increased the number of GCL neurons born acutely after trauma that survived 6 weeks to maturity (NeuN+BrdU+), and enhanced their outward migration into the GCL while significantly reducing the proportion localized ectopically to the hilus and molecular layer. IGF1 selectively affected neurons, without increasing the persistence of posttrauma-proliferated glia in the dentate gyrus. IGF1 overexpressing animals performed better during radial arm water maze reversal testing, a neurogenesis-dependent cognitive test. These findings demonstrate the ability of IGF1 to promote the long-term survival and appropriate localization of granule neurons born acutely after a TBI, and suggest these new neurons contribute to improved cognitive function.

中文翻译：

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胰岛素样生长因子 1 的过度表达增加了创伤后出生的海马神经元的长期存活，同时抑制了创伤性脑损伤后的异位迁移。

与创伤性脑损伤 (TBI) 相关的细胞损伤表现为损伤后的运动和认知功能障碍。TBI 的实验模型揭示了损伤后海马齿状回颗粒细胞层 (GCL) 中的细胞死亡。位于 GCL 的神经原性生态位（颗粒下区）中的成年神经元特别脆弱。损伤诱导的颗粒下区神经祖细胞增殖支持未成熟神经元群的恢复，但它们的发育和定位可能会改变，可能影响长期存活。在这里，我们表明增加海马体中胰岛素样生长因子 1 (IGF1) 的水平足以促进创伤后出生的神经元的终末期成熟并改善 TBI 后的认知。条件性过度表达星形胶质细胞特异性 IGF1 的小鼠和野生型小鼠接受受控的皮质撞击或假损伤，并在损伤后 7 天注射溴-2'-脱氧尿苷以标记增殖细胞。IGF1 过表达增加了在创伤后存活 6 周至成熟期（NeuN+BrdU+）的 GCL 神经元的数量，并增强了它们向 GCL 的向外迁移，同时显着降低了异位定位于肺门和分子层的比例。IGF1 选择性地影响神经元，而不会增加齿状回中创伤后增殖神经胶质细胞的持续存在。IGF1 过度表达的动物在桡臂水迷宫逆转测试中表现更好，这是一种依赖于神经发生的认知测试。