Stenvers K L, Lund P K, Gallagher M
Curriculum in Neurobiology, University of North Carolina, Chapel Hill 27599, USA.
Neuroscience. 1996 May;72(2):505-18. doi: 10.1016/0306-4522(95)00524-2.
Insulin-like growth factor messenger RNAs are expressed in adult rat brain. However, little is known about the effects of aging on the expression of the insulin-like growth factors, their receptors, and their binding proteins in different regions of rat brain. The goal of the current study was to assess whether there is altered expression of the insulin-like growth factor system during normal aging in the hippocampal formation, a region particularly vulnerable to the aging process. A spatial learning task in the Morris water maze was used to assess the cognitive status of young (7-8-month-old) and aged (28-29-month-old) male Long-Evans rats. Sites of expression and abundance of insulin-like growth factor-I, type 1 insulin-like growth factor receptor, and insulin-like growth factor binding protein-4 messenger RNAs were then examined by in situ hybridization histochemistry and solution or northern blot hybridization assays. In situ hybridization histochemistry revealed no qualitative differences in the regional distribution of insulin-like growth factor-I, type 1 receptor, and insulin-like growth factor binding protein-4 messenger RNAs within the hippocampal formation of young and aged rats. However, quantitative analysis of messenger RNA abundance in hippocampal tissue homogenates showed a significant age-related increase in type 1 receptor messenger RNA (n = 25; t = -2.5; P < 0.02). Furthermore, linear regression analysis indicated that type 1 receptor messenger RNA abundance was significantly correlated with spatial learning impairment in the water maze (r = 0.44; P < 0.03) such that greater behavioral impairment was associated with higher type 1 receptor messenger RNA levels in the hippocampal formation. Neither insulin-like growth factor-I nor insulin-like growth factor binding protein-4 messenger RNA abundance was related to age or behavior. However, linear regression revealed a negative correlation between insulin-like growth factor-I messenger RNA abundance and type 1 receptor messenger RNA abundance in aged hippocampus (r = -0.72, P < 0.01). These data indicate that increased hippocampal expression of type 1 receptor messenger RNA is associated with aging and cognitive decline. The correlation between type 1 receptor and insulin-like growth factor-I messenger RNA abundance in the hippocampal formation of aged rats suggests that insulin-like growth factor availability may influence type 1 receptor expression. However, because no overall age difference was found in the amount of insulin-like growth factor-I messenger RNA in the hippocampal formation, decreased insulin-like growth factor from other sources such as the cerebrospinal fluid and the peripheral circulation may be involved in up-regulating type 1 receptor messenger RNA. Alternatively, type 1 receptor messenger RNA regulation may be part of a trophic response to the degenerative and regenerative events that occur within the hippocampal formation during aging.
胰岛素样生长因子信使核糖核酸在成年大鼠脑中表达。然而，关于衰老对大鼠脑不同区域胰岛素样生长因子、其受体及其结合蛋白表达的影响，人们所知甚少。本研究的目的是评估在正常衰老过程中，海马结构（一个特别易受衰老过程影响的区域）中胰岛素样生长因子系统的表达是否发生改变。采用莫里斯水迷宫中的空间学习任务来评估年轻（7 - 8月龄）和老年（28 - 29月龄）雄性Long-Evans大鼠的认知状态。然后通过原位杂交组织化学以及溶液或Northern印迹杂交分析来检测胰岛素样生长因子-I、1型胰岛素样生长因子受体和胰岛素样生长因子结合蛋白-4信使核糖核酸的表达位点及丰度。原位杂交组织化学显示，年轻和老年大鼠海马结构内胰岛素样生长因子-I、1型受体和胰岛素样生长因子结合蛋白-4信使核糖核酸的区域分布没有质的差异。然而，对海马组织匀浆中信使核糖核酸丰度的定量分析表明，1型受体信使核糖核酸有显著的年龄相关增加（n = 25；t = -2.5；P < 0.02）。此外，线性回归分析表明，1型受体信使核糖核酸丰度与水迷宫中的空间学习障碍显著相关（r = 0.44；P < 0.03），即行为障碍越严重，海马结构中1型受体信使核糖核酸水平越高。胰岛素样生长因子-I和胰岛素样生长因子结合蛋白-4信使核糖核酸丰度均与年龄或行为无关。然而，线性回归显示老年海马中胰岛素样生长因子-I信使核糖核酸丰度与1型受体信使核糖核酸丰度呈负相关（r = -0.72，P < 0.01）。这些数据表明，海马中1型受体信使核糖核酸表达增加与衰老和认知衰退有关。老年大鼠海马结构中1型受体与胰岛素样生长因子-I信使核糖核酸丰度之间的相关性表明，胰岛素样生长因子的可利用性可能影响1型受体的表达。然而，由于在海马结构中未发现胰岛素样生长因子-I信使核糖核酸总量存在总体年龄差异，来自脑脊液和外周循环等其他来源的胰岛素样生长因子减少可能参与了1型受体信使核糖核酸的上调。或者，1型受体信使核糖核酸的调节可能是对衰老过程中海马结构内发生的退行性和再生事件的一种营养反应的一部分。
