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Science. 2017 Jun 16;356(6343):1185-1188. doi: 10.1126/science.aan4491.

Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.

Author information

1
Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. eric.nestler@mssm.edu.

Abstract

Early life stress increases risk for depression. Here we establish a "two-hit" stress model in mice wherein stress at a specific postnatal period increases susceptibility to adult social defeat stress and causes long-lasting transcriptional alterations that prime the ventral tegmental area (VTA)-a brain reward region-to be in a depression-like state. We identify a role for the developmental transcription factor orthodenticle homeobox 2 (Otx2) as an upstream mediator of these enduring effects. Transient juvenile-but not adult-knockdown of Otx2 in VTA mimics early life stress by increasing stress susceptibility, whereas its overexpression reverses the effects of early life stress. This work establishes a mechanism by which early life stress encodes lifelong susceptibility to stress via long-lasting transcriptional programming in VTA mediated by Otx2.

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PMID:
28619944
PMCID:
PMC5539403
DOI:
10.1126/science.aan4491
[Indexed for MEDLINE]
Free PMC Article

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