Browsing by Author "Pfau, Madeline L."

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    Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice
    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.; Estebam-Fernández, Adelaida; Yemul, Shrishailam; Sharma, Ali; Ho, Lap; Dixon, Richard A.; Merad, Miriam; Han, Ming-Hu; Russo, Scott J.; Pasinetti, Giulio M. (Nature, 2018)
    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 highthroughput 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 stresssusceptible 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.
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    Estrogen receptor α drives pro-resilient transcription in mouse models of depression
    Lorsch, Zachary S.; Loh, Yong-Hwee Eddie; Purushothaman, Immanuel; Walker, Deena M.; Parise, Eric M.; Salery, Marine; Cahill, Michael E.; Hodes, Georgia E.; Pfau, Madeline L.; Kronman, Hope; Hamilton, Peter J.; Issler, Orna; Labonte, Benoit; Symonds, Ann E.; Zucker, Matthew; Zhang, Tie Yuan; Meaney, Michael J.; Russo, Scott J.; Shen, Li; Bagot, Rosemary C.; Nestler, Eric J. (Nature Publishing Group, 2018-03-16)
    Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.