Endurance factors improve hippocampal neurogenesis and spatial memory in mice

Abstract

Physical activity improves learning and hippocampal neurogenesis. It is unknown whether compounds that increase endurance in muscle also enhance cognition. We investigated the effects of endurance factors, peroxisome proliferator-activated receptor δ agonist GW501516 and AICAR, activator of AMP-activated protein kinase on memory and neurogenesis. Mice were injected with GW for 7 d or AICAR for 7 or 14 d. Two weeks thereafter mice were tested in the Morris water maze. AICAR (7 d) and GW improved spatial memory. Moreover, AICAR significantly, and GW modestly, elevated dentate gyrus neurogenesis. Thus, pharmacological activation of skeletal muscle may mediate cognitive effects.

Figure 1.

Water maze performance and neurogenesis in mice treated with saline (SAL) or AICAR, (500 mg/kg) for 7 (ACR7) or 14 d (ACR14). (A) ACR7 mice were trained for 11 d with two trials per day in the Morris water maze, 2 wk after injections. Latency to the platform did not differ between the groups. (B,C) However, the ACR7 mice performed better than SAL7 mice in probe trials performed 4 h after the last training session on days 8 and 11. (B) In the day 8 probe ACR7 mice showed a significant preference for the target area as compared with SAL7 mice (^#P < 0.05). (C) In the day 11 probe only the ACR7 mice preferred the platform quadrant in comparison to the other quadrants (*P < 0.02). (D,E) Upon training to a new platform location with four trials per day over 5 d, significant retention of platform location was observed (D) 4 h (*P < 0.006) and (E) 24 h (*P < 0.04) after the last training session in ACR7 mice. (G,H) Longer treatment with AICAR over 14 d had no effect on water-maze performance. ACR14 mice were trained with four trials per day for 7 d. (G) There was no difference in acquisition between the groups. (H) ACR14 mice showed no retention of spatial memory in the 4-h probe trial. (I) In addition, there was no effect of ACR14 on BrdU⁺ cell number, whereas (F) ACR7 significantly enhanced new cell survival. (J–O) Photomicrographs of BrdU⁺ cells 1 d (J,K) and 4 wk (L,M) after the last of a daily series of seven BrdU (50 mg/kg) and AICAR (500 mg/kg) injections in SAL7 (J,L) and ACR7 mice (K,M). Scale bar, 50 µm. (N,O) Confocal images of BrdU-positive cells in SAL7 (N) and ACR7 mice (O) 4 wk after the last injection. Sections were immunofluorescent double-labeled for BrdU (green) and NeuN, indicating neuronal phenotype (red). Scale bar, 20 µm. Error bars, SEM.

Figure 2.

The PPARδ agonist GW enhances Morris water-maze performance and new cell genesis. Mice were treated with vehicle (VEH) or GW (5 mg/kg) for 7 d. Two weeks after treatment, mice were trained for 8 d with four trials per day to find the hidden platform. (A) A significant interaction for latency over days was observed between the groups (P < 0.02). Probe trials were carried out 4 h (B) and 48 h (C) after the last training trial. (B) At 4 h, only GW-injected mice showed a significant preference for the target zone as compared with all other quadrants of the pool (P < 0.024). (C) At 48 h, GW mice showed a trend toward a preference for the target area. (D) A trend toward enhanced new cell genesis was observed in GW mice based on both DCX (P = 0.06) and BrdU (P = 0.08) labeling. (E,F) Images of DCX-positive cells in (E) vehicle and (F) GW mice. (G,H) Photomicrographs of BrdU-positive cells 4 wk after the last injection in (G) vehicle and (H) GW mice. Scale bar, 20 μm. Error bars, SEM.