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.

Recruitment of adult-generated neurons into functional hippocampal networks contributes to updating and strengthening of spatial memory

“…As previously reported in rats, our results indicate that spatial learning also promoted long-term survival of newborn neurons in the DG of mice (12)(13)(14)24). At the time of remote memory retrieval, assessed by a probe test given 30 days after acquisition, we found that a small but significant number of new neurons were activated, thereby revealing their functional contribution to relevant hippocampal assemblies that enable spatial navigation to the hidden goal.…”

Female rats learn trace memories better than male rats and consequently retain a greater proportion of new neurons in their hippocampi

“…Nearly 80% of the cells labeled with BrdU also expressed the immature neuronal marker doublecortin (DCX) (16). The percentage of BrdU-labeled cells that coexpressed DCX was similar in males and females, as reported previously (19).…”

“…Secondary antibodies were Rhodamine Red-X anti-goat (Jackson Immunoresearch) and Fluro 488 antimouse (Molecular Probes). The number of cells that expressed both markers was determined using a confocal laser scanning microscope (16). Twenty cells per subject (n ϭ 4) were counted on random sections throughout the hippocampus (See SI Methods for details).…”

“…Double Labeling: BrdU with DCX. Double labeling for BrdU and DCX was performed in separate hippocampal free-floating sections slices, as before (16). Primary antibodies were goat anti-DCX (Santa Cruz Biotechnology), and mouse anti-BrdU (Becton-Dickinson ImmunoSys).…”

“…The vast majority of these surviving cells differentiate into neurons and many are incorporated into the circuitry of the hippocampus (7,12,14,15). However, this effect of training on cell survival only occurs if animals are trained on a relatively difficult task and only if they learn the task well (8,13,16). Learning a trace eyeblink conditioning task is relatively difficult and successful learning ensures the survival of many, if not most, of the new cells that are available for rescue at the time of training (8,(11)(12)(13)17).…”