title: Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.
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.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Bagot
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Cates
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Purushothaman
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Lorsch
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Deena M
authors.initials: DM
authors.lastname: Walker
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Junshi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Schlüter
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Maze
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Peña
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Heller
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Orna
authors.initials: O
authors.lastname: Issler
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Won-Min
authors.initials: WM
authors.lastname: Song
authors.affiliation: Department of Genetics and Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Doyle
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Scobie
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Hao Sheng
authors.initials: HS
authors.lastname: Sun
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Geschwind
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: li.shen@mssm.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: bin.zhang@mssm.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: eric.nestler@mssm.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003863:Depression / Q000235:genetics* / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006624:Hippocampus / Q000502:physiology; D051379:Mice; D009434:Neural Pathways / Q000378:metabolism*; D012919:Social Behavior; D059467:Transcriptome