Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice - PubMed (original) (raw)

Comparative Study

Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice

Henriette van Praag et al. J Neurosci. 2007.

Erratum in

Abstract

Diet and exercise have a profound impact on brain function. In particular, natural nutrients found in plants may influence neuronal survival and plasticity. Here, we tested whether consumption of a plant-derived flavanol, (-)epicatechin, enhances cognition in sedentary or wheel-running female C57BL/6 mice. Retention of spatial memory in the water maze was enhanced by ingestion of (-)epicatechin, especially in combination with exercise. Improved spatial memory was associated with increased angiogenesis and neuronal spine density, but not newborn cell survival, in the dentate gyrus of the hippocampus. Moreover, microarray analysis showed upregulation of genes associated with learning and downregulation of markers of neurodegeneration in the hippocampus. Together, our data show that ingestion of a single flavanol improves spatial memory retention in adult mammals.

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Figures

Figure 1.

Figure 1.

Water maze learning in mice fed control or (−)epicatechin food pellets and housed with or without access to a running wheel (2 h per day) for 42 d. Mice were trained for 8 d with two trials per day between days 31 and 38 to find the hidden platform in the Morris water maze. A–C, Latency (A), path length (B), and swim speed (C) did not differ between the groups. D, E, The probe tests (40 s) at 4 h (D) and 24 h (E) after the last trial on day 8 showed that ER mice spent significantly more time in the target quadrant (NW) than any of the other quadrants (*p < 0.05). Error bars indicate SEM. NW, Northwest; NE, northeast; SE, southeast; SW, southwest.

Figure 2.

Figure 2.

Spatial learning in mice that received control (CON) or (−)epicatechin (EPI) food pellets for 14 d. Thereafter, mice were fed control diet for the duration of study. Animals were trained in the water maze with four trials per day over 8 d between days 21 and 28. A, Acquisition of the task did not differ between the groups. B, C, Retention of the task was assessed using probe trials on days 4, 6, and 8 of training, as well as 24 h, 1 week, and 2 weeks after the last training session in mice fed CON (B) or EPI (C) diet. On day 4 of training, only the EPI group (C) showed a significant preference for the platform quadrant (NW; *p < 0.05). On days 6 and 8, the control (B) and (−)epicatechin (C) groups searched the target zone (NW) more than other quadrants (*p < 0.05). At 24 h and 1 week after the last training session, only the EPI mice (C) still preferred the platform quadrant (*p < 0.05). Error bars indicate SEM. NW, Northwest; NE, northeast; SE, southeast; SW, southwest.

Figure 3.

Figure 3.

Dose–response of (−)epicatechin and comparison with memantine: effects on water maze learning. Mice were given (−)epicatechin (0, 3, 15, or 30 mg/d) or memantine (0.6 mg/d) in drinking water for 3 weeks. A, Mice were trained in the Morris water maze with four trials per day for 8 d between days 23 and 30. Acquisition of the task did not differ between control (CON), 3 mg (E3), 15 mg (E15), and 30 mg (E30) of (−)epicatechin or memantine (MEM). B, Retention of the task was significantly improved in the E3 and E15 mice. In the 60 s probe trial on day 8, the E3 and E15 groups spent more time in the target area (NW) than in the other quadrants (p < 0.03), whereas CON, E30, and MEM mice did not show a significant preference for the NW quadrant. Error bars indicate SEM. NW, Northwest; NE, northeast; SE, southeast; SW, southwest.

Figure 4.

Figure 4.

Vasculature in the DG of mice that consumed control or (−)epicatechin diet. Lectin-stained vessels (red) were quantified using imaging software to assign a pseudocolor mask (yellow) to highlight the threshold for brightness and luma. There was a significant increase in vasculature in the DG of flavanol-treated mice (B, D) compared with controls (A, C). The outline of the analyzed area is marked in all panels and includes the DG and molecular layer.

Figure 5.

Figure 5.

DiI labeling of DG granule cells in mice that received control or (−)epicatechin diet under sedentary or running conditions for 6 weeks. A, Representative images of DiI-labeled dendritic fragments in the outer molecular layer of the DG in CS, CR, ES, and ER mice. The arrow indicates a mushroom spine of which the estimated surface area is no less than 0.4 μm2. Scale bar, 5 μm. B, Spine-density quantification showed that neurons from ER mice had more spines than cells from CS (*p < 0.014) or CR (*p < 0.03) animals. Error bars indicate SEM.

Figure 6.

Figure 6.

Two-dimensional representation of gene expression changes resulting from 6 weeks of daily (−)epicatechin consumption with or without running. t statistics and cutoffs (p < 0.005) for ER versus CR (ERvCR; _x_-axis) and ES versus CS (ESvCS; _y_-axis) mice were computed as described in Materials and Methods. Each (x, y) point in the graph represents the t statistic (_t_ER,CR, _t_ES,CS) for a probe set. A–D, Specifically, genes that are depleted (A) or enriched (B) in ER are shown in the horizontal axis; enriched (C) or depleted (D) gene expression with (−)epicatechin alone (ES) is represented in the vertical axis. e, Four genes that are uniquely enriched in both sedentary and running flavanol-treated mice.

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