Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice

• Published in: Nature communications Vol. 9; no. 1; pp. 477 - 14
• Main Authors: Wang, Jun, Hodes, Georgia E., Zhang, Hongxing, Zhang, Song, Zhao, Wei, Golden, Sam A., Bi, Weina, Menard, Caroline, Kana, Veronika, Leboeuf, Marylene, Xie, Marc, Bregman, Dana, Pfau, Madeline L., Flanigan, Meghan E., Esteban-Fernández, Adelaida, Yemul, Shrishailam, Sharma, Ali, Ho, Lap, Dixon, Richard, Merad, Miriam, Han, Ming-Hu, Russo, Scott J., Pasinetti, Giulio M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.02.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 49; 49/90; 631/378/1831; 631/378/2584/1695; 631/378/371; 64; 64/60; Abnormalities; Acetylation; Animals; Anthocyanins - administration & dosage; Anthocyanins - pharmacology; Antidepressants; Brain; Caffeic Acids - administration & dosage; Caffeic Acids - pharmacology; Cells (biology); Chromatin; CpG islands; CpG Islands - drug effects; Deoxyribonucleic acid; Depression - drug therapy; DNA; DNA methylation; Drug Evaluation, Preclinical - methods; Epigenesis, Genetic; Epigenetics; Gene sequencing; Glucosides - administration & dosage; Glucosides - pharmacology; Hematopoietic stem cells; High-throughput screening; Humanities and Social Sciences; Immune system; Inflammation; Inflammation - genetics; Interleukin 6; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - genetics; Introns; Leukocyte Common Antigens - genetics; Male; Mental depression; Mice; Mice, Inbred C57BL; multidisciplinary; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Neuropeptides - genetics; Neuropeptides - metabolism; Nucleotide sequence; Plasticity; Polyphenols - pharmacology; Progenitor cells; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Regulatory sequences; Resilience; Science; Science (multidisciplinary); Social Behavior; Stress, Psychological - drug therapy; Stress, Psychological - genetics; Stresses; Synaptic plasticity; Transplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02794-5

Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3′- O -glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants. Polyphenols have partial antidepressant effect without known mechanism. Here, the authors identify two phytochemicals from bioactive dietary polyphenols, show their antidepressant effect in a rodent model of depression, and that this effect is mediated by epigenetic and anti-inflammatory mechanisms.