Gustilo M C, Markowska A L, Breckler S J, Fleischman C A, Price D L, Koliatsos V E
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Comp Neurol. 1999 Mar 22;405(4):491-507. doi: 10.1002/(sici)1096-9861(19990322)405:4<491::aid-cne4>3.0.co;2-n.
We compared, in 4- and 23-month-old Fischer-344 rats, the effects of nerve growth factor (NGF) on basal forebrain cholinergic neurons with behavioral performance in acetylcholine-dependent memory tasks (recent and reference memory). Noncholinergic monoamine markers in target fields of cholinergic neurons were also investigated. We found that NGF has contrasting effects on recent memory in the two age groups in causing improvement in aged rats and deterioration in young rats. In addition, NGF caused significant increase in the size of cholinergic perikarya in all sectors of the basal nucleus complex (BNC). Higher doses of NGF were required to produce hypertrophy in aged animals, a pattern consistent with a lower sensitivity to NGF of aged cholinergic neurons. Analysis of covariance showed that the behavioral effects of NGF were eliminated after covarying out the hypertrophy of cholinergic perikarya. Therefore, NGF causes hypertrophy of cholinergic perikarya regardless of age, and this neurobiological measure correlates with the effects of NGF on recent memory. Reference memory improved moderately only in old rats. This mild effect covaried with an increase in choline acetyltransferase activity in neocortex. Cortical terminal fields of noradrenergic and serotoninergic pathways were not affected by NGF. Taken together, our results indicate that NGF influences recent memory in an age- and transmitter-specific fashion. We postulate that the direct cause of the effects of NGF on memory is not perikaryal hypertrophy per se but rather an increased density of terminals, which always accompanies perikaryal hypertrophy. Although these results continue to support the use of NGF for the treatment of Alzheimer's disease, they raise questions regarding the therapeutic role of NGF for degeneration of BNC neurons occurring in young age.
我们比较了4月龄和23月龄的Fischer-344大鼠中，神经生长因子（NGF）对基底前脑胆碱能神经元的影响以及在乙酰胆碱依赖性记忆任务（近期记忆和参考记忆）中的行为表现。我们还研究了胆碱能神经元靶区中的非胆碱能单胺标记物。我们发现，NGF对两个年龄组的近期记忆有相反的影响，在老年大鼠中导致改善，而在幼年大鼠中导致恶化。此外，NGF使基底核复合体（BNC）所有区域的胆碱能神经元胞体大小显著增加。在老年动物中需要更高剂量的NGF才能产生肥大，这一模式与老年胆碱能神经元对NGF的较低敏感性一致。协方差分析表明，在排除胆碱能神经元胞体肥大的影响后，NGF的行为效应消失。因此，无论年龄大小，NGF都会导致胆碱能神经元胞体肥大，并且这种神经生物学指标与NGF对近期记忆的影响相关。只有老年大鼠的参考记忆有适度改善。这种轻微效应与新皮质中胆碱乙酰转移酶活性的增加相关。去甲肾上腺素能和5-羟色胺能通路的皮质终末场不受NGF影响。综上所述，我们的结果表明，NGF以年龄和递质特异性的方式影响近期记忆。我们推测，NGF对记忆产生影响的直接原因不是胞体肥大本身，而是终末密度的增加，而终末密度增加总是伴随着胞体肥大。尽管这些结果继续支持使用NGF治疗阿尔茨海默病，但它们也引发了关于NGF对年轻时发生的BNC神经元变性的治疗作用的问题。
