Peña Catherine J, Kronman Hope G, Walker Deena M, Cates Hannah M, Bagot Rosemary C, Purushothaman Immanuel, Issler Orna, Loh Yong-Hwee Eddie, Leong Tin, Kiraly Drew D, Goodman Emma, Neve Rachael L, Shen Li, Nestler Eric J
Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Science. 2017 Jun 16;356(6343):1185-1188. doi: 10.1126/science.aan4491.
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 () as an upstream mediator of these enduring effects. Transient juvenile-but not adult-knockdown of 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 .
早年生活应激会增加患抑郁症的风险。在此，我们在小鼠中建立了一种“两次打击”应激模型，其中特定出生后时期的应激会增加成年后社会挫败应激的易感性，并导致持久的转录改变，使腹侧被盖区（VTA）——一个脑奖赏区域——处于类似抑郁的状态。我们确定发育转录因子正齿同源盒2（Otx2）作为这些持久效应的上游调节因子发挥作用。在VTA中短暂敲低幼年而非成年小鼠的Otx2，通过增加应激易感性来模拟早年生活应激，而其过表达则可逆转早年生活应激的影响。这项工作建立了一种机制，通过该机制，早年生活应激通过由Otx2介导的VTA中持久的转录编程来编码对压力的终身易感性。
