Stress in early life alters brain cell structure and behavior in mice

Canadian researchers show that stress modifies the morphology of brain cells in mice, directly influencing the rodents' level of physical activity.

Astrocytes in the lateral hypothalamus region of the brain, an area involved in the regulation of sleep and wakefulness, play a key role in neuron activity in mice and affect their behavior, Canadian researchers have found.

Led by Ciaran Murphy-Royal of Université de Montréal's affiliated hospital research centre, the CRCHUM, the scientists detail their finding in a study published in Nature Communications.

In so broadening medical science's understanding of cerebral mechanisms, the discovery could someday help in the treatment and prevention of depression in humans, the researchers say.

According to the scientific literature, early-life stress leads to a five-fold increase in the risk of developing a mental-health disorder as an adult, notably causing treatment-resistant disorders.

Less active, day or night

As brain cells, astrocytes are sensitive to variations in the blood concentration of metabolites and, in response to changes in the blood, astrocytes can modulate the extent of their interaction with neurons, their neighboring cells.

In mice, those changes are particularly responsive to the level of corticosterone, the stress hormone in the rodents' blood.

In adult mice who experienced early-life stress, we saw abnormally high levels of corticosterone. The impact of stress on behavior also differed according to sex."

Ciaran Murphy-Royal, professor in UdeM's Faculty of Medicine

Notably, he said, "females were less active at night, while males were hyperactive during the day."

In people with depression who have experienced a similar type of stress, this sex differences have also been observed.

Lack of maternal care

Lewis R. Depaauw-Holt, the study's first author and a PhD student on Murphy-Royal's team, was able to recreate early-life stress conditions in young rodents by separating them from their mothers.

Over 10 days, for four hours a day, he kept the young mice apart from their mothers. This lack of maternal care occurred during a critical period of brain development for the rodents, the equivalent of ages three to seven in human children.

"The differences in activity levels between female and male mice were also seen within a group of neurons that produces neuropeptides called orexins," said Murphy-Royal.

"Located in the lateral hypothalamus, these orexin neurons contribute to regulating sleep-wake cycles," he said. "In males, these neurons showed hyperactivity, while in females we saw hypoactivity."

In mice that experienced early-life stress, astrocytes were smaller and had fewer branches, especially in females. These branches are essential for transmitting information to neighbouring neurons and interacting with nearby cells.

"In our field of expertise, we believe that the changes in astrocyte morphology are a marker of dysfunction," said Murphy-Royal. "In humans, we see these variations in diseases like Parkinson's or Alzheimer's."

A single pathway?

What if these changes in behavior, neuron activity and morphology in both sexes were tied to a single stress-signalling pathway?

To test their hypothesis, the CRCHUM research team deleted glucocorticoid receptors in astrocytes to which corticosterone, the stress hormone, would normally bind.

"Without these receptors, neuronal activity and mouse behaviors returned to baseline similar to that of mice who did not experience early-life stress," said Murphy-Royal.

"And, even if their astrocytes didn't return to their normal size, they did regain their complexity, visible in the number of branches they use to interact with neighbouring cells."

Contrary to what scientists believed until now, astrocytes are disturbed by stress before neurons are, the study reveals.

In humans, the challenge of countering the effects of early-life stress will surely be more complex than in rodents, Murphy-Royal cautioned, but one thing is for sure: astrocytes could turn out to be an excellent therapeutic target for preventing depression.