The effects of nerve growth factor on spatial recent memory in aged rats persist after discontinuation of treatment

Abstract

Nerve growth factor (NGF) infusion significantly reduces spatial recent memory deficits in aged rats, an effect that has great relevance to the treatment of memory impairments characteristic of patients with Alzheimer's disease. The present study was designed to examine whether this NGF-induced improvement in spatial recent memory persists after the discontinuation of NGF treatment, an issue of crucial importance for the potential clinical use of this compound. Spatial recent memory was tested in a Morris water maze delayed nonmatch-to-position task. In addition to memory, sensorimotor skills were also examined. Four- and 22-month-old rats were tested preoperatively, infused intraventricularly with recombinant human NGF or vehicle, and tested both during the 4 week infusion period and during the 4 weeks after discontinuation of the infusion. NGF significantly improved spatial recent memory in 22-month-old rats only, during the 4th week of infusion and for up to 4 weeks after discontinuation of the infusion. Although NGF did not affect overall sensorimotor skills during infusion in either age group, sensorimotor skills were significantly improved both 2 and 4 weeks after discontinuation of infusion in 22-month-old rats. These findings demonstrate that the beneficial effects of NGF on spatial recent memory can persist for up to 1 month after discontinuation of infusion and suggest that NGF can be used intermittently for the treatment of age-associated memory dysfunction and Alzheimer's disease.

Fig. 1.

A, Schematic diagram representing the water tank apparatus (1.8 m in diameter) used in the DNMTP task (Markowska et al., 1996). One escape platform, submerged beneath the surface of the water, was placed in each choice section. Each platform could be made unavailable for escape by additional submersion to a greater depth.B, Schematic diagram illustrating the DNMTP procedure (Markowska et al., 1996). Two pretraining procedures were used: straight swim (1 session, 10 trials), which trained the rats to swim to a platform (Markowska et al., 1994), and shaping (2 sessions, 8 trials/session), which trained the rats to swim to the platforms located in either choice section (Markowska et al., 1996). Only one choice section was open during each shaping trial, and the starting point was at the entrance to an open choice section (session 1) or at the start position (session 2). See Materials and Methods for additional details on the DNMTP procedure.

Fig. 2.

Schedule for behavioral testing and surgery.Rest, Period in which no surgical or behavioral procedures occurred; SM, sensorimotor; Surgery 1, pump implantation; Surgery 2, pump replacement. Arrowsindicate the beginning and end of NGF or vehicle infusion.

Fig. 3.

Preoperative choice accuracy for the DNMTP task. The choice accuracy of the 22-month-old group was significantly lower than that of the 4-month-old group during sessions 5, 7, 8, and 10. Each point represents the group mean ± SEM.

Fig. 4.

A, Pre- and postoperative choice accuracy for the DNMTP task. Each bar represents the mean ± SEM choice accuracy for three sessions as follows: PRE, sessions 8–10; POST1, sessions 11–13;POST2, sessions 14–16; POST3, sessions 17–19; POST4, sessions 20–22. The choice accuracy of the 22moNGF group was significantly increased during POST2 relative to PRE, and this increase was maintained during POST3 and POST4.B, Choice accuracy difference scores for each POST period. The difference between POST2–POST4 and PRE in the 22moNGF group was significantly larger than that of the 22moVEH group.

Fig. 5.

Pre- and postoperative sensorimotor Zscores. Positive Z scores indicate above-average performance, and negative Z scores indicate below-average performance. NGF improved overall sensorimotor skills in 22-month-old rats only after discontinuation of infusion (POST3 andPOST4). Each bar represents the mean combined Z score ± SEM for each treatment group during one test period (2 sessions/period).

Fig. 6.

Pre- and postoperative body weight. NGF infusion decreased body weight in 22-month-old rats and inhibited weight gain in 4-month-old rats both during infusion and after the discontinuation of infusion. All groups gained weight during POST3 and POST4, after discontinuation of infusion. Each bar represents the treatment group mean ± SEM for PRE (days 11–15),POST1 (days 16–20), POST2 (days 21–25),POST3, (days 26–30), or POST4 (days 31–35).