Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

Rosemary C C. Bagot, Hannah M M. Cates, Immanuel Purushothaman, Zachary S S. Lorsch, Deena M M. Walker, Junshi Wang, Xiaojie Huang, Oliver M M. Schlüter, Ian Maze, Catherine J J. Peña, Elizabeth A A. Heller, Orna Issler, Minghui Wang, Won min Song, Jason  L Stein, Xiaochuan Liu, Marie A A. Doyle, Kimberly N N. Scobie, Hao Sheng S. Sun, Rachael L L. NeveDaniel Geschwind, Yan Dong, Li Shen, Bin Zhang, Eric J J. Nestler

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.

Original languageEnglish (US)
Pages (from-to)969-983
Number of pages15
JournalNeuron
Volume90
Issue number5
DOIs
StatePublished - Jun 1 2016

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Bagot, RC. C., Cates, HM. M., Purushothaman, I., Lorsch, ZS. S., Walker, DM. M., Wang, J., Huang, X., Schlüter, OM. M., Maze, I., Peña, CJ. J., Heller, EA. A., Issler, O., Wang, M., Song, W. M., Stein, J. L., Liu, X., Doyle, MA. A., Scobie, KN. N., Sun, HS. S., ... Nestler, EJ. J. (2016). Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility. Neuron, 90(5), 969-983. https://doi.org/10.1016/j.neuron.2016.04.015