Early-life stress changes brain development in mice

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Stress early in the life of female mice leads to fewer “tuning” neurons in the part of the brain responsible for making sense of emotions and following rules, a new study shows.

Women are roughly twice as likely as men to develop depression, anxiety, and other stress-related problems, including difficulty with attention. The new study, which appears in Cell Reports, sheds light on the biological reasons why.

Researchers looked at mice whose mothers had inadequate supplies to make nests—a model for early-life stress in humans—and found that only female mice developed problems with attention, in part because they had fewer tuning neurons.

“The million-dollar questions are: What’s driving the development of depression and anxiety symptoms, and co-occurring attentional problems, and why is stress a predisposing factor?” says Kevin Bath, an assistant professor of cognitive, linguistic, and psychological sciences at Brown University.

“If we can understand the neurobiological mechanisms of how the brain is developing differently as a consequence of early-life stress, using our animal model, then we can better understand what types of things we need to do to get children back on the right course for healthy brain development,” Bath says.

Where’s mom?

To conduct the study, researchers moved four-day-old mice and their mothers from standard cages to ones where nest-building materials were inadequate. Food and water remained plentiful, but the mothers frequently departed their pups to search for anything that might work as nesting material.

The pups therefore received less consistent and more hypervigilant care from their stressed mothers compared to control pups that never left standard cages. After seven days, the mice returned to cages with everything they needed.

The researchers designed the condition to reflect common early-life stresses children face—growing up in a home with a single parent who works multiple jobs, for example. Previous work has shown that nearly 60 percent of individuals will experience at least one significant stress in childhood, says Bath.

“Females are taking a hit in terms of emotion and attentional processing, whereas the males are taking a hit in terms of spatial reasoning skills.”

When the mouse pups stressed mothers reared reached adulthood at two months old, the female mice found it difficult to adapt their behavior to changing circumstances. Researchers taught the mice to find a treat in a small container with a specific odor and texture. Once they learned to find a treat in containers that smelled one way, the researchers would change the setup and hide the food in containers with a different odor.

This is called rule-reversal learning, Bath says, and relies upon a specific form of cognitive flexibility and attention—similar to how children learn different rules for behavior at home versus school.

Slow learners

The female mice that experienced stress in early life took far longer to learn the new setup than the control females and made more mistakes along the way. The stressed males learned the new rules at the same rate as the control mice.

To understand the neurological factors for the learning impairment, the researchers looked in the orbitofrontal cortex—the part of the brain responsible for decision-making, specifically related to making sense of emotions and following rules—of the early-life stress and control mice.

“Early-life stress isn’t breaking the brain so much as pushing it on a different course of development.”

They found fewer parvalbumin interneurons, which help tune the activity of other neurons, in that area in the stressed female mice than the other mice. Other important decision-making areas of the brain had normal levels of tuning neurons.

Interestingly, Bath says, research from other labs has found decreased numbers of parvalbumin interneurons in the orbitofrontal cortex of clinically depressed patients.

The team confirmed the importance of those neurons for rule-reversal learning using optogenetics—a technique that allows scientists to control specific cells using light—to selectively turn off the parvalbumin interneurons in several brain regions, including the orbitofrontal cortex. Turning off the parvalbumin interneurons in the orbitofrontal cortex also hindered rule-reversal learning.

Sex differences

Researchers don’t yet know exactly what about the early-life stress model causes the difference in brain development. It could be the mothers’ parenting behaviors, or stress hormones in breast milk. The team is conducting more research on the mice using a drug that blocks a stress hormone to explore those questions.

Prior research from the same researchers on mice with early-life stress found that only female mice had depression-like symptoms, but male mice had problems with spatial reasoning and the part of the brain region responsible for fear-based learning matured much faster.

“It seems that the brains of both males and females are developing differently as a consequence of this altered parenting style,” Bath says. “Females are taking a hit in terms of emotion and attentional processing, whereas the males are taking a hit in terms of spatial reasoning skills.”

He added that his team will conduct more research to understand the reasons for the differences by sex. Possible explanations include differences in sensitivity of specific populations of neurons due to early hormonal changes or sex-specific genes, slightly different brain maturation timelines or different maternal care for male and female pups.

Stress relief

After Bath understands the mouse model, the goal is to learn what kind of interventions or medications can reverse or decrease the impact of early-life stress on neurobiological and behavioral outcomes. Ultimately, his hope is understanding how to help children get back on the right course of brain development after, or during, extremely stressful experiences.

“Can we provide some intervention in these children to basically decrease the levels of stress they are feeling or the amount of instability that they’re sensing, which could be the driving factor to shift the developmental program of the brain?” Bath says. “Early-life stress isn’t breaking the brain so much as pushing it on a different course of development.”

He believes that, for instance, growing up in a war zone causes the brain to develop such that a child has the best chance to detect danger and survive in that environment, but that these traits are harmful instead of beneficial when the child ends up in a classroom instead.

Additional authors are from Brown. The National Institutes of Health and the Robert J. and Nancy D. Carney Institute for Brain Science funded the research.

Source: Brown University