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

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.

Sex differences: Transcriptional signatures of stress exposure in male and female brains

“…With the development of modified chronic social defeat paradigms applicable to females, it will be interesting to see if behaviorally resilient individuals can be identified among females and investigate their transcriptional profile as has already been done for males . Other stress paradigms applied in other life phases (perinatality, adolescence) that in the past have shown to generate resilient and susceptible phenotypes such as early life stress will also be a powerful way to further address the matter of sex difference in stress resilience . Identifying differences in stress resilience and when they emerge is a key point to dissect the origin of sex differences in stress response and susceptibility to psychopathologies, since, for many of these disorders, differences start to emerge after puberty (for a review see).…”

“…80,91 Other stress paradigms applied in other life phases (perinatality, adolescence) that in the past have shown to generate resilient and susceptible phenotypes such as early life stress will also be a powerful way to further address the matter of sex difference in stress resilience. [153][154][155] Identifying differences in stress resilience and when they emerge is a key point to dissect the origin of sex differences in stress response and susceptibility to psychopathologies, since, for many of these disorders, differences start to emerge after puberty (for a review see 156 ). Moreover, future studies should also try to address how transcriptional changes in response to acute stress contribute to behavioral susceptibility to chronic stress.…”

Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus

“…Putative regulators in cis with the DEGs included three striking candidates: OTX2, NR2F6, and MTF1. OTX2 was recently shown to regulate depression-related consequences of early life stress in male mice (females were untested) through actions in dopaminergic neurons (Peña et al, 2017). MTF1 is notable for its role in binding and responding to heavy metals, perturbations of which have been implicated in ASDs (Arora et al, 2017; Hagmeyer et al, 2015); furthermore, this transcription factor was itself enriched in the LC of males, providing hints of a potential regulator of some of our observed sex differences.…”

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

“…[2][3][4][5] However, it is also understood that proximal factors, such as stressful life events, contribute to the onset of mental illnesses into adulthood. 6 Although these trajectories appear to be distinct, recent evidence suggests that transient, stress-induced perturbations in transcriptional programs during sensitive periods may influence susceptibility to later life stressors 7 or prolong the sensitive period altogether. 8 It is likely that both early and later life stress may exert lasting negative influences on transcription, cell functioning and behavior, through common epigenetic mechanisms.…”