Neurogenesis and the spacing effect: learning over time enhances memory and the survival of new neurons

Abstract

Information that is spaced over time is better remembered than the same amount of information massed together. This phenomenon, known as the spacing effect, was explored with respect to its effect on learning and neurogenesis in the adult dentate gyrus of the hippocampal formation. Because the cells are generated over time and because learning enhances their survival, we hypothesized that training with spaced trials would rescue more new neurons from death than the same number of massed trials. In the first experiment, animals trained with spaced trials in the Morris water maze outperformed animals trained with massed trials, but there was not a direct effect of trial spacing on cell survival. Rather, animals that learned well retained more cells than animals that did not learn or learned poorly. Moreover, performance during acquisition correlated with the number of cells remaining in the dentate gyrus after training. In the second experiment, the time between blocks of trials was increased. Consequently, animals trained with spaced trials performed as well as those trained with massed, but remembered the location better two weeks later. The strength of that memory correlated with the number of new cells remaining in the hippocampus. Together, these data indicate that learning, and not mere exposure to training, enhances the survival of cells that are generated 1 wk before training. They also indicate that learning over an extended period of time induces a more persistent memory, which then relates to the number of cells that reside in the hippocampus.

Figure 1.

Learning increases cell survival in the hippocampus. (A) BrdU was injected 1 wk before the start of training. Massed subjects were trained with four consecutive blocks of four trials in 1 d. Spaced subjects were trained with one block of four trials for four consecutive days. Animals from both groups (plus a naïve group with no training) were perfused 11 d after BrdU injection. (B) Mean escape latency for massed (○) and spaced (●) animals across 16 training trials. Animals trained with spaced trials were able to navigate to the platform in less time than animals trained with massed trials. (C) The number of BrdU cells that were observed 1 d after the end of spaced training is shown. Animals that were designated as good learners possessed more new cells in their dentate gyrus than did the poor learners and the naïve controls. (*) P < 0.05.

Figure 2.

Number of BrdU-labeled cells in the dentate gyrus depends on how well the animal learned. An example of an animal trained with massed trials that learned poorly (A), massed trials that learned well (B), spaced trials that learned poorly (C), and spaced trials that learned well (D).

Figure 3.

Majority of BrdU-labeled cells become neurons. Most BrdU-labeled cells had begun to differentiate into neurons 11 d after they were born. Representative cells from the dentate gyrus that express doublecortin (A), BrdU (B), DCX and BrdU (C) are shown. A similar sequence is shown for D–F. (G) Graph depicts percentage of BrdU-labeled cells that expressed DCX in animals trained with massed versus spaced training. No difference was observed. (H) Similarly, there was no difference in the percentage of BrdU-labeled cells that expressed DCX between good and poor learners.

Figure 4.

Memory predicts cell survival. (A) BrdU was injected 1 wk before the beginning of training. Massed subjects were trained with four blocks of four trials in 1 d, with a 1-h intertrial interval between blocks. Spaced subjects were trained with one block of four trials for four consecutive days. Both groups were tested with a single trial 2 d and 2 wk after the end of training. Animals from both groups were perfused 25 d after the one BrdU injection. (B) Escape latency for animals trained with either massed (○) or spaced (●) trials is shown. There was no difference in the time to escape between the two groups. However, 2 wk after the end of training, more animals trained with spaced trials remembered the platform location. (*) P < 0.05. (C) Using Spearman’s rank-order correlation coefficient, the number of BrdU-labeled cells in the dentate gyrus correlated with the performance on the retention test 2 wk later.