Lichtenwalner R J, Forbes M E, Bennett S A, Lynch C D, Sonntag W E, Riddle D R
Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1010, USA.
Neuroscience. 2001;107(4):603-13. doi: 10.1016/s0306-4522(01)00378-5.
The dentate gyrus of the hippocampus is one of few regions in the adult mammalian brain characterized by ongoing neurogenesis. Significantly, recent studies indicate that the rate of neurogenesis in the hippocampus declines with age, perhaps contributing to age-related cognitive changes. Although a variety of factors may influence the addition of new neurons in the adult dentate gyrus, the mechanisms responsible for the age-related reduction remain to be established. Insulin-like growth factor-I (IGF-I) is one promising candidate to regulate neurogenesis in the adult and aging brain since it influences neuronal production during development and since, like the rate of neurogenesis, it decreases with age. In the current study, we used bromodeoxyuridine labeling and multilabel immunofluorescence to assess age-related changes in neuronal production in the dentate gyrus of adult Brown Norway x Fischer 344 rats. In addition, we investigated the relationship between changes in neurogenesis and the age-dependent reduction in IGF-I by evaluating the effect of i.c.v. infusion of IGF-I on neurogenesis in the senescent dentate gyrus. The analyses revealed an age-dependent reduction in the number of newly generated cells in the adult dentate subgranular proliferative zone and, in addition, a 60% reduction in the differentiation of newborn cells into neurons. Restoration of IGF-I levels in senescent rats significantly restored neurogenesis through an approximately three-fold increase in neuronal production. The results of this study suggest that IGF-I may be an important regulator of neurogenesis in the adult and aging hippocampus and that an age-related decline in IGF-I-dependent neurogenesis could contribute to age-related cognitive changes.
海马体的齿状回是成年哺乳动物大脑中少数以持续神经发生为特征的区域之一。重要的是，最近的研究表明，海马体中的神经发生速率会随着年龄的增长而下降，这可能是导致与年龄相关的认知变化的原因之一。尽管多种因素可能会影响成年齿状回中新神经元的添加，但与年龄相关的减少的机制仍有待确定。胰岛素样生长因子-I（IGF-I）是调节成年和衰老大脑中神经发生的一个有前景的候选因子，因为它在发育过程中影响神经元的产生，而且与神经发生速率一样，它也会随着年龄的增长而下降。在本研究中，我们使用溴脱氧尿苷标记和多标记免疫荧光来评估成年布朗挪威大鼠与费希尔344大鼠杂交后代齿状回中神经元产生的年龄相关变化。此外，我们通过评估脑室内注射IGF-I对衰老齿状回中神经发生的影响，来研究神经发生变化与IGF-I年龄依赖性减少之间的关系。分析显示，成年齿状回颗粒下增殖区新生成细胞的数量存在年龄依赖性减少，此外，新生细胞向神经元的分化减少了60%。衰老大鼠中IGF-I水平的恢复通过神经元产生增加约三倍显著恢复了神经发生。本研究结果表明，IGF-I可能是成年和衰老海马体中神经发生的重要调节因子，并且与年龄相关的IGF-I依赖性神经发生下降可能导致与年龄相关的认知变化。
