Evidence that nerve growth factor influences recent memory through structural changes in septohippocampal cholinergic neurons

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.