Mechanism of adult brain changes caused by early life stress.

Peña et al., working with mice, demonstrate a mechanisms by which early life stress encodes lifelong susceptibility to stress by changing a reward region of adult brains that increases susceptibility to adult social defeat stress and depression-like behaviors. While early stress could establish the groundwork for later depression, this priming could be undone by intervention at the right moment. Their work suggests the relevance of follow up studies in humans compromised by early life stress to see whether similar genetic regulatory changes have occurred. Their 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.