Paradoxical influence of hippocampal neurogenesis on working memory

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   Fig. 1.

   Two different methods eliminate hippocampal neurogenesis in adult mice. (A) Targeted exposure of the hippocampal region of the brain to x-rays using stereotaxic positioning of a lead shield. Behavioral testing began 3 months after treatment with three 5-gray x-ray doses. Representative images show doublecortin-positive cells in the dentate gyrus of sham-treated mice and a nearly complete ablation of neurogenesis after hippocampal irradiation. (B) GFAP-TK transgenic mice were treated with GCV through sequential implantation of two s.c. osmotic minipumps, 6 weeks apart. Doublecortin immunoreactivity was significantly reduced in transgenic mice, and the few remaining cells had almost no dendritic processes.

   
   
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   Fig. 2.

   Performance of irradiated mice in two versions of the radial arm maze. (A) Number of errors in a HML/NI working memory task (n = 16 x-ray, 16 sham). Across-phase errors were scored, and no significant effect of irradiation was observed. (B) Score in an LML/HI task (n = 16 x-ray, 13 sham). The same two pairs of arms are used every day for every trial (HI). The number of correct choices was scored. No difference was found between groups during training, but x-ray mice showed enhanced performance when the delay increased to 30 and 50 sec (P = 0.01 and 0.02, respectively).

   
   
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   Fig. 3.

   Performance of irradiated mice in the LML/LI version of the radial arm maze. (A) Schematic diagram of the testing procedure for a single day. (B) Score in LML/LI task (n = 16 x-ray, 14 sham). Only one pair of arms is presented per trial, with six trials/day. Score is plotted as blocks (2 days). Irradiated mice again showed a delay-specific improvement in their performance compared with control subjects (P = 0.05 and 0.02 for 25 and 35 sec, respectively). The improvement was confirmed by using the same delay (35 sec) over 6 consecutive days (3 blocks; P = 0.001). (C) The significant difference in performance between x-ray and sham mice was due to delay-dependent differential processing of intertrial interference. Bar graph represents the average number of correct choices per trial with a delay of 15 (3 last blocks of training) or 35 sec. Each day, six different pairs of arms were presented pseudorandomly. For trials 1–4, four different pairs of arms were used. However, because the maze only has eight arms, the repetition of previously presented arms (interference) occurred during trials 5 and 6. X-ray mice showed a specific enhancement in performance as compared with sham during trials 5 and 6 (with interference; P < 0.0001), but not during trials 1–4 (without interference; P = 0.07) with a delay of 35 sec.

   
   
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   Fig. 4.

   Difference in performance of GFAP-TK transgenic mice during and after GCV treatment in the LML/LI version of the radial arm maze. (A) Experimental timeline. Both control and transgenic mice were treated with GCV for 10 weeks before behavioral testing in the radial maze and retested after a 10-week recovery period. (B) The performance of transgenic mice on GCV (n = 14 GFAP-TK, 12 control) was normal at delays of 35 sec and below but was improved relative to control mice when the delay was 55, 75, and 135 sec (P = 0.039, 0.030, and 0.016, respectively). This effect was confirmed by using the same delay (75 sec) over 6 consecutive days (3 blocks; P = 0.021). After 10 weeks of recovery (GCV Off), performance in both groups of mice was equivalent at all delays. (C) In GCV On mice, the significant difference in performance between GFAP-TK and control mice was due to delay-dependent differential processing of intertrial interference. Bar graph represents the average number of correct choices per trial with a delay of 15 (3 last blocks of training) or 75 sec. Transgenic mice showed a specific enhancement in performance as compared with controls during trials 5 and 6 (with interference; P < 0.011) but not during trials 1–4 (without interference; P = 0.067) with a delay of 75 sec.