BDNF increases with behavioral enrichment and an antioxidant diet in the aged dog

Abstract

The aged canine (dog) is an excellent model for investigating the neurobiological changes that underlie cognitive impairment and neurodegeneration in humans, as canines and humans undergo similar pathological and behavioral changes with aging. Recent evidence indicates that a combination of environmental enrichment and antioxidant-fortified diet can be used to reduce the rate of age-dependent neuropathology and cognitive decline in aged dogs, although the mechanisms underlying these changes have not been established. We examined the hypothesis that an increase in levels of brain-derived neurotrophic factor (BDNF) is one of the factors underlying improvements in learning and memory. Old, cognitively impaired animals that did not receive any treatment showed a significant decrease in BDNF mRNA in the temporal cortex when compared with the young group. Animals receiving either an antioxidant diet or environmental enrichment displayed intermediate levels of BDNF mRNA. However, dogs receiving both an antioxidant diet and environmental enrichment showed increased levels of BDNF mRNA when compared with untreated aged dogs, approaching levels measured in young animals. BDNF receptor TrkB mRNA levels did not differ between groups. BDNF mRNA levels were positively correlated with improved cognitive performance and inversely correlated with cortical Aβ((1-42)) and Aβ((1-40)) levels. These findings suggest that environmental enrichment and antioxidant diet interact to maintain brain levels of BDNF, which may lead to improved cognitive performance. This is the first demonstration in a higher animal that nonpharmacological changes in lifestyle in advanced age can upregulate BDNF to levels approaching those in the young brain.

Figure 1. A. BDNF mRNA levels in the five canine groups

BDNF mRNA copy numbers per 50 ng total RNA. CC: control environment/ control diet; EC: behavioral enrichment/control diet; CA: control environment/ antioxidant diet; EA: behavioral enrichment/antioxidant diet; Y: young canines; * = p<0.05 (one-way ANOVA and post hoc one sided Dunnett’s test). n=5–6 per group. B. Full-length TrkB mRNA levels do not differ between the five canine groups. TrkB mRNA copy numbers per 50 ng total RNA. CC: control environment/ control diet; EC: behavioral enrichment/control diet; CA: control environment/antioxidant diet; EA: behavioral enrichment/ antioxidant diet; Y: young canines; p=0.83 (one-way ANOVA). n=5–6 per group.

Figure 2. BDNF mRNA levels are inversely correlated with Aβ

A. BDNF mRNA copy number is lower in animals with higher levels of Aβ_1–40. B. BDNF mRNA copy number is lowest in animals with higher Aβ_1–42. Note that the x axes use log transformed raw Aβ values. Correlations are Pearson correlations. Symbols represent (▲)-Y, (●)-CC, (■)-EC, (X)-CA, (▼)-EA.

Figure 3. A. Spatial memory scores using a 3-choice delayed non-match to sample task

Dogs provided with the combination treatment showed a significant reduction in spatial memory error scores (Dunnett’s test comparison of EA to CC group). CC: control environment/ control diet; EC: behavioral enrichment/control diet; CA: control environment/antioxidant diet; EA: behavioral enrichment/ antioxidant diet. n=5–6 per group. B. Trend towards an association between BDNF mRNA levels and spatial error scores. Animals that performed more poorly and learned the task with more errors generally showed lower BDNF mRNA copy numbers. Symbols represent (▲)-Y, (●)-CC, (■)-EC, (X)-CA, (▼)-EA (Pearson correlation, r = −0.38, p = 0.09).