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

TitleEpigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice.
Publication TypeJournal Article
Year of Publication2018
AuteursWang, J, Hodes, GE, Zhang, H, Zhang, S, Zhao, W, Golden, SA, Bi, W, Menard, C, Kana, V, Leboeuf, M, Xie, M, Bregman, D, Pfau, ML, Flanigan, ME, Esteban-Fernández, A, Yemul, S, Sharma, A, Ho, L, Dixon, R, Merad, M, Han, M-H, Russo, SJ, Pasinetti, GM
JournalNat Commun
Volume9
Issue1
Pagination477
Date Published2018 02 02
ISSN2041-1723
KeywordsAnimals, Anthocyanins, Caffeic Acids, CpG Islands, Depression, Drug Evaluation, Preclinical, Epigenesis, Genetic, Glucosides, Inflammation, Interleukin-6, Leukocyte Common Antigens, Male, Mice, Inbred C57BL, Neuronal Plasticity, Neuropeptides, Polyphenols, rac1 GTP-Binding Protein, Social Behavior, Stress, Psychological
Abstract

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.

DOI10.1038/s41467-017-02794-5
Alternate JournalNat Commun
PubMed ID29396460
PubMed Central IDPMC5797143
Grant ListR01 MH104559 / MH / NIMH NIH HHS / United States
R21 MH112081 / MH / NIMH NIH HHS / United States
IK6 BX003785 / BX / BLRD VA / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
R01 MH090264 / MH / NIMH NIH HHS / United States
P50 AT008661 / AT / NCCIH NIH HHS / United States