Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice - PubMed (original) (raw)

Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice

Alexis M Stranahan et al. Hippocampus. 2009 Oct.

Erratum in

Abstract

Diabetes may adversely affect cognitive function, but the underlying mechanisms are unknown. To investigate whether manipulations that enhance neurotrophin levels will also restore neuronal structure and function in diabetes, we examined the effects of wheel running and dietary energy restriction on hippocampal neuron morphology and brain-derived neurotrophic factor (BDNF) levels in db/db mice, a model of insulin resistant diabetes. Running wheel activity, caloric restriction, or the combination of the two treatments increased levels of BDNF in the hippocampus of db/db mice. Enhancement of hippocampal BDNF was accompanied by increases in dendritic spine density on the secondary and tertiary dendrites of dentate granule neurons. These studies suggest that diabetes exerts detrimental effects on hippocampal structure, and that this state can be attenuated by increasing energy expenditure and decreasing energy intake.

Copyright 2008 Wiley-Liss, Inc.

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Figures

Figure 1

Figure 1. Effect of diabetes and caloric restriction on the amount and pattern of wheel running

(A) Wild type mice increased their average daily running distance over the first four weeks of the experiment, then gradually reduced their mean distances over the subsequent weeks. There was no significant effect of caloric restriction on running wheel activity. (B) Wild type mice run significantly more at night, and there was no effect of caloric restriction on this pattern. (C) db/db mutant mice run significantly less than wild type mice. In addition, caloric restriction enhanced the amount of daily wheel running in db/db mice. (D) There was no effect of the diurnal cycle on the mean distance in db/db mice fed ad libitum. With caloric restriction, we observed a trend for increased activity during the dark phase (p=0.11). Asterisk (*) reflects significance at p<0.05 following 2-way repeated measures ANOVA (A and C) or 2-way ANOVA (B and D).

Figure 2

Figure 2. Caloric restriction and running enhance exploratory behavior in db/db mice

For all graphs, time of testing is indicated by the rectangle at the top of the graph. Testing at the onset of the dark phase is indicated by a diagonally striped rectangle, while testing at the onset of the light phase is shown with a white rectangle. (A) In wild type mice, there were no significant effects of exercise or caloric restriction on open field activity. (B) db/db mice exhibit lower levels of open field activity than wild type mice. Caloric restriction enhances open field exploration in sedentary db/db mice during the dark phase, while running wheel activity promotes locomotion in db/db mice on the ad libitum diet during the light phase. (C), There was no significant effect of running or caloric restriction on the proportion of time spent in the center of the open field in wild type mice. (D), db/db mice spent less time in the center of the open field than wild type mice, but there was no significant effect of running or caloric restriction. For all graphs, asterisk (*) indicates significance at p<0.05 following 2× 2 × 2 repeated measures ANOVA.

Figure 3

Figure 3. Effects of energy deficit induced by caloric restriction alone or in combination with running wheel activity on serum glucose and 3-hydroxybutyrate concentrations

(A) Fasting glucose measurements were made every four weeks throughout the experiment. Wild type runners on caloric restriction exhibit reduced fasting glucose levels during the eighth week of the experiment. (B) db/db mice were hyperglycemic (relative to wild type animals), even at the earliest time point. However, caloric restriction attenuated fasting hyperglycemia in these animals. (C) Serum ketone body (3-hydroxybutyrate) concentrations were elevated by caloric restriction in both sedentary and running wild type mice. (D) Although serum 3-hydroxybutyrate levels were elevated in sedentary db/db mice fed ad libitum, the db/db mice retain the capacity for caloric restriction-induced enhancement of serum ketone concentrations. Asterisk (*) indicates significance at p<0.05 following 2-way repeated measures ANOVA (A and B) or 2-way ANOVA (C and D).

Figure 4

Figure 4. Effects of reduced energy intake and voluntary exercise on body weights and hormone concentrations in wild type and db/db mice

(A) db/db mice were heavier than wild type mice under ad libitum diet, sedentary conditions. Caloric restriction reduced body weights in both wild type and db/db mice. (B) Serum insulin levels were reduced by caloric restriction in wild type mice. While sedentary db/db mice were hyperinsulinemic relative to wild type mice, caloric restriction with or without running wheel activity lowered insulin levels. (C) Serum leptin was depressed by caloric restriction in wild type mice; however, there was no effect of voluntary exercise or dietary restriction on elevated serum leptin levels in db/db mice. (D) Serum corticosterone measurements were made in samples collected during the middle of the resting phase (between 10 AM and 12 PM; lights on at 6 AM). Combined running and caloric restriction elevated serum corticosterone concentrations in wild type mice. In db/db mice, wheel running lowered serum corticosterone levels in animals fed an ad libitum diet. Asterisk (*) indicates significance at p<0.05 relative to animals in the same genotype. Pound sign (#) indicates significant difference between wild type and db/db mice in the sedentary, ad libitum diet condition.

Figure 5

Figure 5. Effects of running and caloric restriction on dendritic spine density in the hippocampus of db/db and wild type mice

(A) In wild type mice, running, caloric restriction, or both treatments all enhanced dendritic spine density in the dentate gyrus. While sedentary db/db mice fed ad libitum had fewer dendritic spines, relative to wild type mice in the same condition, this deficit could be partially mitigated by running, caloric restriction, or the combination. Asterisk (*) indicates significance at p<0.05 relative to animals in the same genotype. Pound sign (#) indicates significant difference between wild type and db/db mice in the sedentary, ad libitum diet condition. (B), Dentate gyrus granule neuron visualized with Golgi impregnation. Scale bar = 20 μm. (C), Dendritic segments from each of the conditions. Scale bar = 5 μm. Abbreviations: CR = caloric restriction, AL = ad libitum, RUN = runner, SED = sedentary.

Figure 6

Figure 6. Stability of dendritic length and arborization in wild type and diabetic mice following running and caloric restriction

(A), Schematic diagram showing dendritic branch orders. (B), Dendritic lengths are not significantly altered by physical activity or caloric restriction in the dentate gyrus of wild type mice. (C) There was no significant effect of genotype, physical activity, or diet on dendritic lengths in any branch order in db/db mice. (D), Total dendritic lengths were stable following running and caloric restriction in wild type and db/db mice. (E), The number of bifurcations per neuron was also unchanged following diabetes, physical activity, or caloric restriction.

Figure 7

Figure 7. Hippocampal BDNF levels are altered by diabetes, running, and caloric restriction

Voluntary running and caloric restriction exert additive effects on hippocampal BDNF levels in wild type mice. db/db mice also respond to running and caloric restriction, but with smaller increases in hippocampal BDNF concentrations. Asterisk (*) indicates significance at p<0.05 relative to animals in the same genotype. Pound sign (#) indicates significant difference between wild type and db/db mice in the sedentary, ad libitum diet condition.

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