Microglia in the embryonic brain sense maternal stress and influence brain development
Neuroimmune cells in mice are sensitive to the effects of stress during pregnancy, producing disruptions in brain development with long-lasting effects.
Recent research by Dr. Jessica Rosin, a new investigator with UBC’s Faculty of Dentistry found that male offspring of stressed mothers had a reduced number of oxytocin neurons in the hypothalamus and showed social impairments that persisted into adulthood. Her insights, published in Developmental Cell were acknowledged May 9, 2022 with a 2021 Brain Star Award.
“This paper starts to provide key linkages into how the maternal environment influences the developing brain and also underscores differences in its responses between males and females,” Rosin told Laura Herperger, a writer for Alberta Children’s Hospital Research Institute, where Rosin conducted the study along with senior author Dr. Deborah Kurrasch. In humans, neurodevelopmental disorders such as autism and attention deficit/hyperactivity disorders (ADHD) are more common in boys. This mouse model study, which utilized single-cell RNA sequencing, may help explain the sex-based differences in prevalence.
The hypothalamus, a powerful brain region that is responsive to external stressors, is essential for maintaining homeostasis in the body. Processes such as sleep, hunger, body temperature, thirst, circadian rhythm, and reproduction are controlled by this region of the brain. Equally important, though less appreciated, the hypothalamus also influences social behaviours. Microglia are immune cells within the brain that play an important role in responding to injury and foreign insults. They can also sense external influences, including stress, which can cause them to interact with neighbouring cells to control the local environment. This regulatory interplay between hypothalamic neurons and microglia as they both integrate stressors is an area of growing interest in neuroscience.
In the study, Rosin and colleagues sought to determine if microglia in the embryonic hypothalamus were stress responsive and, if so, whether their activation in the fetal brain disrupts nearby neural stem cell (NSC) programs. The researchers identified four subsets of microglia in the developing brain, including a subpopulation adjacent to NSCs that proved responsive to cold stress in pregnant mice.
Rosin found that exposing the pregnant mice to intermittent cold temperatures released a flood of inflammatory signals, particularly in males. The cold exposure also decreased paraventricular nucleus (PVN) oxytocin neurons – but only in male embryos. This effect was reversed by depleting microglia from the embryonic brain, which demonstrated a key role for these neuroimmune cells in mediating maternal stress cues. Adult mice exposed to stress before birth displayed altered social behaviours, which was also dependent on microglia, again, only in males.
“Jessica’s paper is especially exciting because it demonstrates for the first time a direct mechanism by which fetal microglia influence neurodevelopment in a sex specific manner in response to the maternal environment,” says Dr. Kurrasch, Rosin’s post-doctoral supervisor. “I am thrilled Jessica has now launched her own lab at UBC, and I am eager to watch her successes as she continues this project and expands into other novel avenues of research as an independent PI.”
Next Steps
Dr. Jessica Rosin continues this work as a new investigator at UBC. “In regards to next steps,” she says, “our goal is to understand WHY males and females respond to maternal stress differently during gestation. We have found some interesting differences between males and females in our pathway analyses that may allow us to intervene during and/or after the stress to mitigate some of the disruptions.”
“As maternal stress exposure may also cause epigenetic changes in the offspring,” she adds, “we are also interested in transgenerational studies using our maternal stress mouse model, and plan to do this type of work by collaborating with Dr. Annie Vogel Ciernia in the Djavad Mowafaghian Centre for Brain Health.”
Read the paper
Jessica M. Rosin, Sarthak Sinha, Jeff Biernaskie and Deborah M. Kurrasch. (2021). A subpopulation of embryonic microglia respond to maternal stress and influence nearby neural progenitors. Developmental Cell 56(9): 1326-1345.
https://www.cell.com/developmental-cell/fulltext/S1534-5807(21)00244-6