Angsty adolescents often mature into sullen adults, but a new study suggests that well-timed interventions could mitigate some negative effects of a stressful childhood—at least in mice.
In a new study published in Science, researchers prevented the long-term effects of childhood trauma in mice by increasing the expression of six key genes, all controlled by a protein called OTX2. The findings are the first to implicate OTX2 in long-term susceptibility to stress, and the first to identify a window during which therapy for traumatized mice is most likely to succeed. “Well-timed interventions may be effective for ameliorating the effects of early life stress,” coauthor Catherine Pena of Mount Sinai School of Medicine in New York, told Fatherly. “Even very short-acting treatment in the young mice ameliorated the effects of early life stress.”
We know that early childhood trauma can shape an adult’s life. From a neuroscientific perspective, this is probably because stress messes with the brain’s reward circuitry across species. Pena and colleagues knew from prior studies that one particular region of the brain—the ventral tegmental area, or VTA—controls long-term mood and depression, and wondered whether early trauma could alter how genes are expressed in that region.
So they bred angsty teenage mice, exposing “early postnatal” and “late postnatal” rodents to stressful events. “Age matching between humans and mice isn’t exact,” Pena says. “But you could roughly say that the early postnatal mouse period maps from the third trimester to the infant stage of human development. The late postnatal window is open for preschool through early elementary school-aged children, and closed by the time they get to college.”
Both baby mice and teenage mice that were exposed to stress initially had trouble gaining weight, but otherwise developed normally. Until they grew up and met other mice. When normal adult mice confront their fellow rodents to wrestle over territory or mates, they occasionally lose. That’s stressful (scientists call it “defeat stress”) but well-adjusted mice lick their wounds and bounce back. Indeed, the mice that were traumatized as toddlers did just that—their early childhood trauma appeared to have no effect on how they responded to stress as adults. When they suffered social defeat, they got right back on the horse (or whatever mice ride).
Not so with the mice exposed to stress as children or teenagers. When those mice suffered social defeat, they began to display the telltale signs of murine depression. They avoided other mice, stood still during lab-administered swim tests rather than flailing in the water like normal mice, and drowned their sorrows by choosing sugar water over regular water.
This suggests that, for mice anyway, there’s a window for early trauma. Up until a certain age (early postnatal—or infancy) you can stress out mice without ruining their lives. But from about preschool onward, traumatic experiences predispose mice led to depression even as adults. Pena and colleagues confirmed this by examining gene expression within the depressed mice. They found that childhood and teenage stress “prime” the VTA brain region for depression by decreasing OTX2, a protein that keeps six genes that likely influence depression in check.
Interestingly, when Pena and her team artificially boosted OTX2 in mice, the stressed rodents were no longer more susceptible to depression. This suggests high levels of OTX2 could mitigate the long-term effects of early childhood trauma. Unfortunately, “there are not currently drugs designed to directly boost OTX2,” Pena says. “In fact, studies…suggest that too much OTX2 is bad for the brain.” Nonetheless, Pena says drugmakers could ultimately use these findings to design drugs that combat depression. “Understanding the cellular actions of OTX2 will give us clues as to how early life stress reprograms this brain region,” she says. “We may be able to develop treatments to target those processes more broadly.”
Pena adds that very few human studies have examined windows of stress vulnerability during childhood. At what ages are human children most susceptible to the kinds of stressors that can impact their lives as adult? Are there windows for optimal intervention and treatment? Since this study only examined mice, we cannot draw any conclusions from it about human depression.
But future studies may pivot from mice to humans, and answer that very question. “Intervention at the right time might mean that lifelong drug treatments are unnecessary,” Pena says. “In contrast to most antidepressant treatments, which are taken for years.”