Women are roughly twice as likely as men to develop depression, anxiety and other stress-related problems, including difficulty with attention, and new research sheds light on the biological reasons why.
Studying mice whose mothers had inadequate supplies to make nests -- a model for early-life stress in humans -- the researchers found that only female mice developed problems with attention, in part because they had fewer "tuning" neurons in the part of the brain that makes sense of rules and regulating emotions.
The findings were published in Cell Reports.
To conduct the study, the 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. Pups therefore received less consistent and more hypervigilant care from their stressed mothers compared to control pups that were never moved from standard cages. After seven days, the mice returned to cages with everything they needed.
The team found that when the mouse pups reared by stressed mothers reached adulthood at two months old, the female mice found it difficult to adapt their behavior to changing circumstances. The 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, and relies upon a specific form of cognitive flexibility and attention -- similar to how children learn different rules for behavior at home versus school, the author added.
The female mice that experienced stress in early life took far longer to learn this 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. 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, 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.
The 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," the author said. "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."
Attention disorders in early-life stressed mice!
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