Interactive actions of Bdnf methylation and cell metabolism for building neural resilience under the influence of diet
Introduction
An increasing body of evidence suggests that a large number of neuropsychiatric disorders are the result of complex interactions between genetic factors and the environment (Dauncey, 2012) and that epigenetic mechanisms may mediate these effects (Choi and Friso, 2010). Diet is one of the most crucial factors for species survival and adaptation, and here we examine the possibility that foods influence the brain by building an “epigenetic memory” that could be instrumental in resistance to neurological challenges. The strong dependence of the brain on energy implies that metabolic stimuli such as dietary factors have the intrinsic ability to influence brain plasticity (Agrawal et al., 2014) and epigenetic variability.
BDNF malfunction has been implicated in the pathology of neurological and psychiatric disorders (Greenberg et al., 2009, Zuccato and Cattaneo, 2009). Bdnf transcription and function are under regulation of DNA methylation (Martinowich et al., 2003), and abnormal epigenetic regulation of the Bdnf gene is emerging an underlying mechanism for various neurological disorders (Boulle et al., 2012). DNA methylation is the one of most stable forms of epigenetic variability involved in the control of transcription and function of selected genes (Godfrey et al., 2007, Moore et al., 2013) can repress Bdnf gene expression via transcriptional repressor methyl-CpG-binding protein (MeCP2) (Chen et al., 2003, Ma et al., 2009). Since BDNF can act on plasticity and metabolism it is termed a “metabotrophin” (Gomez-Pinilla, 2008, Gomez-Pinilla et al., 2008), and these inherent properties of BDNF may be crucial to translating the effects of foods on the brain. For example, one potential intermediary may be nicotinamide adenine dinucleotide (NAD +), a cofactor in oxidation/reduction (hydride transfer) reactions. The action of NAD on energy regulation is under the scope of the sirtuin family of proteins (Cantó and Auwerx, 2012). SIRT1 influences the activity of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), which is one of the most versatile metabolic transcriptional co-activators of genes involved in energy metabolism (Nemoto et al., 2005, Rodgers et al., 2008) and mitochondrial function (Finkel, 2006).
The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease, schizophrenia and depression (Young and Conquer, 2005). On the other hand, dietary intakes of saturated fats do the opposite (Sánchez-Villegas et al., 2011, Tyagi et al., 2013). The current studies were designed to determine whether exposure to omega-3 fatty acids during the whole period of brain formation promotes epigenetic variability and protection against metabolic perturbations. Results introduce the idea that metabolism and epigenetics are closely associated events that contribute to program an epigenetic memory through long-term brain plasticity. These results provide fundamental information for the design of therapeutic applications and public health policy.
Section snippets
Animals and experimental design
Female Sprague–Dawley rats (250–280 g) were obtained from Charles River Laboratories (Wilmington, MA, USA) on 3rd day of pregnancy and were kept under standard housing condition (22–24 °C) with 12-h light/dark cycle in two dietary groups. Pregnant female rats were fed either a low omega-3 fatty acid (Low-n-3) or a high omega-3 fatty acid diet (High-n-3) through gestation and lactation. The two custom diets used were based on the composition of the American Institute of Nutrition diet (AIN-93G)
Dietary interventions influences anxiety-like behavior
We assessed the influence of dietary manipulations on anxiety-like behavior by utilizing elevated plus maze test (EPM). Two-way ANOVA analysis revealed a significant effect of maternal diet (F1,28 = 39.38, p < 0.01) and transitioned diet (F1,28 = 11.47, p < 0.01) for percentage of time spent in open arms. We found that transition from low omega-3 to WD decreased percentage of time spent in open arms as an indication of elevated anxiety-like behavior (Low-n-3/WD Vs Low-n-3/No WD, p < 0.01). Animals that
Discussion
We report a potential mechanism by which early nutrition can influence long-term plasticity by acting on epigenetic regulation of the Bdnf gene. For example, this epigenetic memory could provide an underlying mechanism for the process by which the brain builds up cognitive reserve to resist periods of hardship. Early feeding with a diet rich in n-3 fatty acids protects against cognitive decay resulting from subsequent exposure to a WD. The WD increased Bdnf methylation specific to exon IV in
Conclusion
These studies show that early life exposure to omega-3 fatty acids can promote epigenetic variability, which confers resilience to metabolic perturbations incurred in later life. Further detailed studies are required to determine the action of particular periods of brain development on plasticity of the BDNF system during adulthood. The results also portray cell energy metabolism as an important factor by which the environment impacts the epigenome. In turn, results are consistent with a
Author contributions
Conceived and designed the experiments: ET FGP. Performed the experiments: ET YZ RA ZY. Analyzed the data: ET YZ. Contributed reagents/materials/analysis tools: ET FGP. Wrote the paper: ET FGP.
Acknowledgments
This work was supported by the National Institutes of Health Grant NS050465. We also acknowledge the kind support of the Letten Foundation and Professor Letten Saugstadt. There is no conflict of interest for any of the contributing authors.
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