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. 2015 Jan 28;5:8075.
doi: 10.1038/srep08075.

Resveratrol Prevents Age-Related Memory and Mood Dysfunction With Increased Hippocampal Neurogenesis and Microvasculature, and Reduced Glial Activation

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Free PMC article

Resveratrol Prevents Age-Related Memory and Mood Dysfunction With Increased Hippocampal Neurogenesis and Microvasculature, and Reduced Glial Activation

Maheedhar Kodali et al. Sci Rep. .
Free PMC article

Abstract

Greatly waned neurogenesis, diminished microvasculature, astrocyte hypertrophy and activated microglia are among the most conspicuous structural changes in the aged hippocampus. Because these alterations can contribute to age-related memory and mood impairments, strategies efficacious for mitigating these changes may preserve cognitive and mood function in old age. Resveratrol, a phytoalexin found in the skin of red grapes having angiogenic and antiinflammatory properties, appears ideal for easing these age-related changes. Hence, we examined the efficacy of resveratrol for counteracting age-related memory and mood impairments and the associated detrimental changes in the hippocampus. Two groups of male F344 rats in late middle-age having similar learning and memory abilities were chosen and treated with resveratrol or vehicle for four weeks. Analyses at ~25 months of age uncovered improved learning, memory and mood function in resveratrol-treated animals but impairments in vehicle-treated animals. Resveratrol-treated animals also displayed increased net neurogenesis and microvasculature, and diminished astrocyte hypertrophy and microglial activation in the hippocampus. These results provide novel evidence that resveratrol treatment in late middle age is efficacious for improving memory and mood function in old age. Modulation of the hippocampus plasticity and suppression of chronic low-level inflammation appear to underlie the functional benefits mediated by resveratrol.

Figures

Figure 1
Figure 1. A cartoon depicting the time-line of various experiments.
A cohort of 21-months old rats was examined using a water maze test (WMT) and animals with normal spatial learning and memory function were chosen and divided into two groups. One of the groups then received vehicle (VEH, n = 7) and the other group received resveratrol (RESV, n = 8) for four weeks. Animals in both groups also received 5′-bromodeoxyuridine (BrdU) in the last week of VEH or RESV treatment to facilitate the labeling and quantification of newly born cells and neurons. Both groups underwent a second WMT four weeks after the termination of VEH or RESV treatment followed by a forced swim test (FST). Animals were next euthanized via intracardiac perfusions and brain tissues processed for immunohistochemical staining and various quantifications.
Figure 2
Figure 2. Spatial learning and memory performance comparison between the two 21-months old animal groups chosen for vehicle (VEH, n = 7) or resveratrol (RESV, n = 8) treatment.
There were no differences between the two groups for swim speed (A1; p > 0.05, two-way ANOVA), latencies to reach the platform (A2; p > 0.05) or swim path efficiency (A3; p > 0.05) in different learning sessions. Probe test conducted 24 hours after the last learning session revealed similar results (B1–B3). Both groups chosen for VEH (B2) or RESV (B3) treatment showed greater affinity for the platform quadrant, in comparison to the other three quadrants of the pool (one-way ANOVA, p < 0.05–0.001). Additional parameters of memory retrieval ability such as the dwell time in the platform quadrant (C1), platform area crossings (C2) and dwell time in platform area (C3) were also comparable between the two groups (p > 0.05). PQ (NE-Q), platform quadrant (northeast quadrant); SE-Q, southeast quadrant; SW-Q, southwest quadrant; and NW-Q, northwest quadrant. *, p < 0.05, **; p < 0.01; ***; p < 0.001.
Figure 3
Figure 3. Spatial learning and memory performance comparison between the vehicle (VEH, n = 7) treated and resveratrol (RESV, n = 8) treated animal groups, in the second water maze test performed four weeks after the termination of VEH or RESV treatment.
Swim speeds were comparable between the two groups (A1; p > 0.05, two-way ANOVA) and both groups displayed ability for spatial learning (A2; p < 0.0001, repeated measures ANOVA). However, RESV treated rats displayed much superior learning than VEH treated rats (A2; p < 0.0001, two-way ANOVA) and this was also revealed through much improved swim path efficiency values in RESV treated animals (A3; p < 0.001). B1 and B2 illustrate swim paths of representative rats from VEH (B1) and RESV (B2) groups in a single-trial probe test conducted 24 hours after the last learning session whereas, figure B3 shows the position of four quadrants, the platform area and the target area in the water maze pool during the probe test. Note that, VEH treated rats showed almost equal affinity for all four quadrants (B1 and C1; p > 0.05, one-way ANOVA), implying memory retrieval dysfunction in these rats. In contrast, RESV treated rats exhibited a clear affinity for the platform quadrant over all other quadrants (B2, C2; p < 0.001). This difference is also apparent from a direct comparison of the dwell time in the platform quadrant across the two groups (C3; p < 0.001, two-tailed, unpaired Student's t-test). PQ (SW-Q), platform quadrant (southwest quadrant); NW-Q, northwest quadrant; NE-Q, northeast quadrant; SE-Q, southeast quadrant. ***, p < 0.001.
Figure 4
Figure 4. Pre- and post-treatment spatial learning and memory performance comparison in vehicle (VEH, n = 7) and resveratrol (RESV, n = 8) treated aged rats.
Rats treated with VEH retain the ability for spatial learning at pre-treatment levels, which is evident from their learning curves (A1; p > 0.05, two-way ANOVA) and swim path efficiency values (A2; p > 0.05). However, they exhibit memory retrieval dysfunction (A3; p < 0.05). In contrast, RESV treated rats display improved ability for spatial learning and memory retention in comparison to their pre-treatment performance. This is obvious from comparison of pre- and post-RESV treatment learning curves (B1, p < 0.0001), swim path efficiency values (B2; p < 0.01) and dwell time in the platform quadrant (B3; p < 0.01). (C1–C3): Comparison of depressive-like behavior in a forced swim test between VEH treated and resveratrol (RESV) treated aged rats. Note that, RESV treated aged rats displayed reduced depressive-like behavior, in comparison to VEH treated aged rats. The differences in floating time (or immobility) during the test were significant for the first five minutes of the test (C1; p < 0.05) as well as for the entire duration of the test (C3; p < 0.05) but not significant for the last 5 minutes of the test (C2; p > 0.05, two-tailed, unpaired Student's t-test). *, p < 0.05, **; p < 0.01.
Figure 5
Figure 5
Examples of newly born cells expressing 5′-bromodeoxyuridine (BrdU) in the subgranular zone-granule cell layer (SGZ-GCL) of the hippocampus from a rat that received vehicle (VEH) treatment (A1) and a rat that received resveratrol (RESV) treatment (B1). (B1 and B2) are magnified views of regions from A1 and B1. Figures (C1–D3) show examples of BrdU+ newly born cells that mature and express neuron specific nuclear antigen (NeuN). Bar charts compare numbers of newly born (BrdU+) cells (E), percentages of newly born cells expressing NeuN (F) and net hippocampal neurogenesis (G) between VEH and RESV treated groups (n = 6/group). Note that, both numbers of newly born cells and net hippocampal neurogenesis are greater in RESV treated rats than VEH treated rats (p < 0.05–0.01, two-tailed, unpaired, Student's t-test). *, p < 0.05, **; p < 0.01. Scale bar, A1 and B1, 100 μm; A2 and B2, 50 μm; C1–D3, 10 μm.
Figure 6
Figure 6
Newly born neurons expressing doublecortin (DCX) in the subgranular zone-granule cell layer (SGZ–GCL) of rats treated with vehicle (VEH; A1) or resveratrol (RESV; B1, C1). (A2, B2 and C2) are magnified views of regions from (A1, B1 and C1). Comparison of numbers of DCX+ newly born neurons between VEH and RESV treated groups (bar chart in D, n = 6/group) revealed greatly enhanced production of newly born neurons in RESV treated aged animals (p < 0.001, two-tailed, unpaired Student's t-test). DH, dentate hilus; ML, molecular layer. Scale bar, (A1, B1 and C1), 100 μm; (A2, B2 and C2), 50 μm. ***, p < 0.001.
Figure 7
Figure 7. Distribution of rat endothelial cell antigen-1 (RECA-1)-positive microvessels and glial fibrillary acidic protein (GFAP)-positive astrocytes in vehicle (VEH) and resveratrol (RESV) treated groups.
(A1–C2) compare the distribution of RECA-1+ microvessels in the dentate gyrus (DG, A1, A2), the CA1 subfield (B1, B2) and the CA3 subfield (C1, C2) of the hippocampus between VEH treated (A1, B1, C1) and RESV treated (A2, B2, C2) animals. Bar charts in D1–D4 compare area fraction of RECA-1+ structures in different regions of the hippocampus between the two groups (n = 6/group). Note that, RESV treatment increased the area fraction of RECA-1+ structures in the CA1 subfield and the entire hippocampus (D2, D4; p < 0.05–0.01, two-tailed, unpaired Student's t-test). (E1–G2) compare the distribution and morphology of GFAP+ astroctyes in the DG (E1, E2), the CA1 subfield (F1, F2) and the CA3 subfield (G1, G2) of the hippocampus between VEH treated (E1, F1, G1) and RESV treated (E2, F2, G2) animals. Bar charts (H1–H4) compare area fraction of GFAP+ structures in different regions of the hippocampus between the two groups (n = 6/group). Note that, RESV treatment considerably decreased the area fraction of GFAP+ structures in all subfields of the hippocampus as well as for the entire hippocampus (H1–H4, p < 0.001). Scale bar, (A1–C2 and E1–G2), 25 μm. *, p < 0.05, **; p < 0.01; ***; p < 0.001.
Figure 8
Figure 8. Distribution of OX-42 (CD11b)-positive microglia in the hippocampus of vehicle (VEH) and resveratrol (RESV) treated groups.
(A1–C2) compare the distribution and morphology of OX-42+ microglia in the dentate gyrus (DG, A1, A2), the CA1 subfield (B1, B2) and the CA3 subfield (C1, C2) of the hippocampus between VEH treated (A1, B1, C1) and RESV treated (A2, B2, C2) animals. E1 and E2 show representative examples of microglial morphology traced with Neurolucida from VEH treated (E1) and RESV treated (E2) rats. Most microglia in VEH-treated aged rats exhibited enlarged soma, shorter processess and reduced ramification of processes (arrows in A1, B1, C1, and the cartoon in E1), implying a tendency towards conversion into amoeboid or activated microglia. In contrast, most microglia in RESV treated rats maintained longer processes with extensive ramifications (arrowheads in A2, B2, C2, and the cartoon in E2) suggestive of resting microglia. Bar charts in (D1–D4) compare area fraction of OX-42+ structural elements in different regions of the hippocampus between the two groups (n = 7/group). RESV treatment increased the area fraction of OX-42+ structures in the CA1 subfield and the entire hippocampus (D2, D4; p < 0.05, two-tailed, unpaired Student's t-test). Bar charts in (F1–F4) compare the number of segments (F1), the total process length (F2), the number of intersections (F3) and the number of process endings (F4) in microglia traced from VEH and RESV treated aged animals (n = 42 microglia/group). Note that RESV treated animals displayed greater numbers of segments (F1, p < 0.01), increased process length (F2, p < 0.05), increased numbers of intersections at 0–10 μm and 20–30 μm distances from the soma (F3, p < 0.05), and greater numbers of process endings (F4, p < 0.05). Scale bar, (A1–C2 and E1–G2), 25 μm; (E1–E2), 10 μm. *, p < 0.05, **; p < 0.01.
Figure 9
Figure 9
Distribution of ED-1 (CD68)-positive activated microglia in the dentate hilus (DH) and granule cell layer (GCL) of vehicle (VEH, A1) and resveratrol (RESV, A2) treated groups. (B1 and B2) are magnified views of dentate hilar regions from A1 and B2. The bar chart in C compares numbers of ED-1+ activated microglia between VEH and RESV treated rats (n = 6/group). Values represent means and standard errors. Note that, the RESV treated group exhibited decreased numbers of ED-1+ activated microglia than the VEH treated group (p < 0.05, two-tailed, unpaired Student's t-test). Scale bar, (A1–A2), 100 μm; (E1–E2), 50 μm. *, p < 0.05.

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