Strain differences in neurogenesis and activation of new neurons in the dentate gyrus in response to spatial learning.

Adult neurogenesis continues throughout life in the mammalian hippocampus and evidence suggests that adult neurogenesis is involved in hippocampus-dependent learning and memory. Numerous studies have demonstrated that spatial learning enhances neurogenesis in the hippocampus but few studies have examined whether enhanced neurogenesis is related to enhanced activation of new neurons in response to spatial learning. Furthermore, the majority of these studies have utilized Sprague-Dawley (SD) rats. However, Long-Evans and Sprague-Dawley rats have been reported to have different learning abilities. In order to determine whether these strains exhibit a similar enhancement of neurogenesis and new neuronal activation in response to spatial learning we tested both strains in a hippocampus-dependent or hippocampus-independent version of the Morris water task (MWT) and then compared levels of neurogenesis and activation of these new cells in the hippocampus. Here we show that despite equivalent performance in the MWT, spatial learning produced a different effect on neurogenesis in each strain. Spatial learning increased cell survival and the number of immature neurons in SD rats compared to cage control and cue-trained rats. In Long-Evans (LE) rats however, spatial learning increased cell survival (BrdU-labeling) but did not increase the number of immature neurons (doublecortin-labeling). Furthermore, we report here an intriguing difference in the activation of new neurons (using the immediate early gene product zif268) in SD versus LE rats. In SD rats we show that spatial learning increases the percentage of doublecortin-labeled cells that are activated during a probe trial. Conversely, in LE rats spatial learning increased the activation of BrdU-labeled but not doublecortin-labeled cells. This interesting difference suggests that different ages or maturational stages of cells are recruited by spatial learning in the two strains. These findings may lead to a better understanding of how and why neurogenesis is regulated by spatial learning.

Epp JR ，Scott NA ，Galea LA 《-》

Activation and survival of immature neurons in the dentate gyrus with spatial memory is dependent on time of exposure to spatial learning and age of cells at examination.

Neurogenesis continues to occur throughout life in the dentate gyrus of the hippocampus and may be related to hippocampus-dependent learning. We have recently reported that there is an enhancement of neurogenesis in the hippocampus only when BrdU is administered 6 days prior to starting spatial training but not when training started either 1 day or 11 days following BrdU administration. In that study, all rats were perfused on day 16 after BrdU injection in order to compare cells of the same age (i.e. 16 day old cells) and thus the survival time after learning was different between groups. This study was designed to address whether the amount of time that passed following training could also contribute to the effects of spatial learning on hippocampal neurogenesis and whether there was differential new neuron activation in response to spatial learning that depended on the age of new cells at the time of spatial learning. Here we tested whether a survival period of 5 days following spatial learning at either 1-5, 6-10 or 11-15 days following BrdU administration would alter cell survival and/or activation of new neurons. Our results indicate that 5 days after training in the Morris water task cell survival is unaltered by training on days 1-5, increased by training at days 6-10 and decreased when training occurs on days 11-15. Furthermore spatial learners trained on days 6-10 or 11-15 show greater activation of new neurons compared to cue-trained rats during a probe trial 5 days after training. In addition, rats trained on the spatial task on days 11-15 had a greater number of activated new neurons compared to rats trained on the spatial task on days 6-10. These results suggest there is a gradual removal of older BrdU-labeled new neurons following spatial learning perhaps due to a competitive interaction with a population of younger BrdU-labeled new neurons.

Epp JR ，Haack AK ，Galea LA 《-》

Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation.

Epp JR ，Spritzer MD ，Galea LA 《NEUROSCIENCE》

Task difficulty in the Morris water task influences the survival of new neurons in the dentate gyrus.

Adult neurogenesis continues throughout life in the mammalian hippocampus. The precise function of the adult generated neurons remains uncertain although there is growing evidence that they are involved in hippocampus-dependent learning and memory. Training rats on a hidden platform version of the Morris water task has been shown to increase or decrease the survival of newly produced cells in the dentate gyrus (DG) compared to training on a visible platform version. Here we investigated whether the difficulty of the task is related to the degree or direction of the change in neurogenesis. We trained rats on either a visible platform version of the Morris water task or one of three different hidden platform paradigms: four training trials per session version, two training trials per session, and reduced-cue (a version in which the majority of the distal cues were removed from the room). BrdU was administered 6 days prior to training and rats were perfused 24 h after the last training session. As expected, training on the four trial hidden platform version increased cell survival compared to training on the visible platform version. However, training on the more difficult reduced-cue hidden platform version resulted in a decrease in cell survival. Rats that received fewer trials per session did not differ in terms of cell survival in comparison to rats trained on the visible platform version. These findings demonstrate that altering the difficulty of the spatial task has an impact on the corresponding change in cell survival. The lack of obvious distal cues likely changed the strategy used by the rats to determine the location of the platform and resulted in a decrease, instead of an increase in cell survival in the hippocampus. In conclusion, different types of hippocampus-dependent learning can differentially impact cell survival.

Epp JR ，Haack AK ，Galea LA 《-》

17β-Estradiol, but not estrone, increases the survival and activation of new neurons in the hippocampus in response to spatial memory in adult female rats.

Estrogens fluctuate across the lifespan in women, with circulating 17β-estradiol levels higher pre-menopause than estrone and circulating estrone levels higher postmenopause than 17β-estradiol. Estrone is a common component of hormone replacement therapies, but research shows that 17β-estradiol may have a greater positive impact on cognition. Previous studies show that acute estrone and 17β-estradiol impact hippocampus-dependent learning and cell proliferation in the dentate gyrus in a dose-dependent manner in adult female rats. The current study explores how chronic treatment with estrone and 17β-estradiol differentially influences spatial learning, hippocampal neurogenesis and activation of new neurons in response to spatial memory. Adult female rats received daily injections of vehicle (sesame oil), or a 10 μg dose of either 17β-estradiol or estrone for 20 days. One day following the first hormone injection all rats were injected with the DNA synthesis marker, bromodeoxyuridine. On days 11-15 after BrdU injection rats were trained on a spatial reference version of the Morris water maze, and five days later (day 20 of estrogens treatment) were given a probe trial to assess memory retention. Cell proliferation was assessed by the endogenous cell cycle marker, Ki67, cell survival was assessed by counting the number and density of BrdU-ir cells in the dentate gyrus and cell activation was assessed by the percentage of BrdU-ir cells that were co-labelled with the immediate early gene product zif268. There were no significant differences between groups in acquisition or retention of Morris water maze. However, the 17β-estradiol group had significantly higher, while the estrone group had significantly lower, levels of cell survival (BrdU-ir cells) in the dentate gyrus compared to controls. Furthermore, rats injected with 17β-estradiol showed significantly higher levels of activation of new neurons in response to spatial memory compared to controls. These results provide insight into how estrogens differentially influence the brain and behavior, and may provide insight into the development of hormone replacement therapies for women.

McClure RE ，Barha CK ，Galea LA 《-》