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

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Science  16 Jun 2017:
Vol. 356, Issue 6343, pp. 1185-1188
DOI: 10.1126/science.aan4491

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Early life stress in depression susceptibility

The linkage between stress early in life and behavioral depression in adulthood is complex. Peña et al. were able to define a time period in early development when mice are especially susceptible to stress. Mice subjected to stress during this time period were less resilient to stress in adulthood. Genes regulated by the transcription factor orthodenticle homeobox 2 (OTX2) primed the response toward depression in adulthood. Although early stress could establish the groundwork for later depression, that priming could be undone by intervention at the right moment.

Science, this issue p. 1185


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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