Adult-Born Hippocampal Dentate Granule Cells Undergoing Maturation Modulate Learning and Memory in the Brain

Recovery of progenitor cell proliferation and neurogenesis in the DG after drug withdrawal in Nestin-tk transgenic mice. A, The experimental scheme for B and C. B, C, Representative confocal images of adult DG from wt-GCV and tg-GCV mice labeled by immature neuron marker Dcx (green). Nuclear marker DAPI is in blue. See text for quantifications. D, The experimental scheme for E and F. E, Ki67 cell numbers are similar between tg-GCV and wt-GCV at 1, 3, and 9 weeks after GCV treatment. F, BrdU cell numbers are reduced in tg-GCV at 1, 3, and 9 weeks after GCV treatment. See supplemental Table 1, available at www.jneurosci.org as supplemental material, for statistics for E and F. Scale bar: (in C) B and C, 50 μm. *p < 0.01. Error bars represent ± SEM.

Impaired memory formation in GCV-treated Nestin-tk transgenic mice in the standard version of the hidden platform MWM. A, The experimental scheme. B, Neither latency nor distance swum to reach the hidden platform during training was significantly different between tg-GCV and wt-GCV (latency: ANOVA, F_(1,30) = 2.179, p > 0.15; distance: ANOVA, F_(1,30) = 0.566, p > 0.46; n = 16 for each group). C, Short-term retention from daily probe tests from day 4 to day 8 of training. Notice that tg-GCV mice spent progressively less time in the target quadrant whereas wt-GCV mice spent progressively more time there. D, Long-term retention from the probe test 1 week after training. tg-GCV mice spent equal time in all quadrants whereas wt-GCV mice spent significantly more time in the target quadrant. The red dotted line indicates chance level (15 s). The hidden platform (black square) is located in the northwest quadrant. *p < 0.05 between the target quadrant and all other quadrants; for detailed statistical data for C and D, see supplemental Table 2, available at www.jneurosci.org as supplemental material. Error bars represent ± SEM.

Learning and memory were not impaired in Nestin-tk mice if training started 3.5 or 9 weeks after GCV treatment. A, The experimental scheme. B, C, Acquisition of the water maze task. GCV-treated transgenic mice in both the 3.5-week-delay cohort (B, ANOVA, F_(1,17) = 1.946, p > 0.98, for wt-GCV, n = 9, for tg-GCV, n = 10) and the 9-week-delay cohort (C, ANOVA, F_(1,22) = 0.036, p > 0.85, for wt-GCV, n = 13, for tg-GCV, n = 11) performed similarly to wild-type littermate controls, as indicated by distance moved in the maze. D, Short-term retention from daily probe tests from day 4 to day 8 was similar in GCV-treated transgenic mice and wild-type littermates in the 3.5-week-delay cohort. E, Long-term retention in the probe test 1 week after training was similar in GCV-treated transgenic mice and wild-type littermates in the 3.5-week-delay cohort. F, Short-term retention from daily probe tests from day 4 to day 8 was similar in GCV-treated transgenic mice and wild-type littermates in the 9-week-delay cohort. G, Long-term retention in the probe test 1 week after training was similar in GCV-treated transgenic mice and wild-type littermates in the 9-week-delay cohort. The red dotted line indicates chance level (15 s). The hidden platform (black square) is located in the northwest quadrant. *Statistically significant difference between the target quadrant and all other quadrants. For detailed statistical analysis for D–G, see supplemental Table 2, available at www.jneurosci.org as supplemental material. Error bars represent ± SEM.

Impaired long-term retention in GCV-treated Nestin-tk transgenic mice. A, The experimental scheme for B and C. B, Neither latency nor distance swum to reach the hidden platform during training was significantly different between tg-GCV and wt-GCV (latency: ANOVA, F_(1,19) = 0.184, p > 0.67; distance: ANOVA, F_(1,19) = 0.525, p > 0.47; for tg-GCV, n = 11, for wt-GCV, n = 10). C, GCV-treated transgenic mice were defective in long-term retention on day 15 but not in short-term retention on day 8, as indicated by duration in the target quadrant (duration), frequency of entering the target quadrant (frequency), latency to reach the virtual platform (latency), and frequency of entering the virtual platform (platform crossings) (duration: on day 8, F_(1,19) = 0.018, p > 0.89, on day 15, F_(1,19) = 10.015, p < 0.0051; frequency: on day 8, F_(1,19) = 0.345, p > 0.56, on day 15, F_(1,19) = 18.232, p < 0.0004; latency: on day 8, F_(1,19) = 0.728, p > 0.40, on day 15, F_(1,19) = 0.404, p > 0.067; platform crossings: on day 8, F_(1,19) = 0.834, p > 0.37, on day 15, F_(1,19) = 8.097, p < 0.0103). D, The experimental scheme for E and F. E, Neither latency nor distance swum to reach the hidden platform during training was significantly different between tg-GCV and wt-GCV (latency: ANOVA, F_(1,19) = 0.604, p > 0.44; distance: ANOVA, F_(1,19) = 1.077, p > 0.31; for tg-GCV, n = 11, for wt-GCV, n = 10). F, GCV-treated transgenic mice were defective in long-term retention as indicated by duration (t₍₁₉₎ = 4.170, p < 0.0005), frequency (t₍₁₉₎ = 3.184, p < 0.0049), latency (t₍₁₉₎ = 2.142, p < 0.0454), and platform crossings (t₍₁₉₎ = 2.917, p < 0.0088). The red dotted line indicates chance level (15 s). *Statistically significant difference; ^#nonsignificant increase of latency in tg-GCV. Error bars represent ± SEM.

No enhancement of extinction of spatial memory in GCV-treated Nestin-tk transgenic mice. A, The experimental scheme. B, C, No difference in the latency (B) and distance swum (C) to reach the hidden platform between the tg-GCV and wt-GCV mice during acquisition (latency: ANOVA, F_(1,20) = 0.138, p > 0.71; distance: ANOVA, F_(1,20) = 0.238, p > 0.63; for tg-GCV, n = 12, for wt-GCV, n = 10). D, No difference in the duration in the target quadrants across the four probe trials between tg-GCV and wt-GCV mice (ANOVA, F_(1,20) = 0.0035, p > 0.95). Error bars represent ± SEM.