As research into the etiology (origin & cause) of mental illness continues and the rate of such illness continues to rise, studies like this one are linking various factors together to explain the growing epidemic. As with many health conditions, more than one trigger is needed to get the symptom train moving. Prior research had demonstrated that maternal immune activation is associated with offspring which demonstrated social behavior abnormalities. While this conclusion was based on animal studies where animals were given an infection during pregnancy, it coincides with observational studies in humans, where children whose mothers had infections during pregnancy have demonstrated higher rates of mental illness.
Other prior studies consistently demonstrate that inflammation in the brains triggered by such maternal infections seemed to play a role in these later mental illness symptoms. Digging further into the inflammation connection, studies demonstrated that immune cells living in the brain called microglia play a role in this inflammation. This study then looked specifically at these microglia in a part of the brain called the cerebellum.
The cerebellum portion of our brains sits in the rear of our brain at the base. It is long known to play the central role in coordination of movement and balance. Over the years, it has further been connected with other brain functions that require coordination of nerve messages between different brain regions. Many studies show that it exhibits dysfunction in a number of cognitive disorders and mental illnesses.
In this study, the researchers evaluated their ‘two-hit’ hypothesis. Knowing that more than one trigger was needed to trigger abnormalities, they looked at mice who were first exposed to intrauterine maternal immune activation (their moms were given an infection or inflammation during pregnancy) and then later post-natal were exposed to high stress. The cerebellar microglia were compared between these mice and those without those two triggers after the study along with a comparison of the mice’s behavioral patterns.
In the study, they found objective changes in the cerebellar microglia which correlated with behavioral pattern changes in the mice. The microglia were turning over fasting and had higher levels of two inflammatory cytokines, Interleukin 6 and Transforming Growth Factor Beta 1. Across the mice brains, there was also widespread “functional dysconnectivity” between brain regions. To further support their findings, they then gave microglial replacement therapy which reversed both the cerebellar microglia changes and the behavioral patterns.
In other words, the mice which experienced both maternal exposure to infection and early life stressors developed objective brain changes along with behavior changes which could be reversed by immune modulation in contrast to mice who did not have both triggers.
As we care for human patients, we have to be careful in extrapolating too much into clinical care, but this does support other research which tells us the following. Maternal inflammation levels during pregnancy contributes to children’s future mental health. Early life stressors affect a child’s risk of future mental illness. The combination of these factors amplifies these risks. Finally, these findings are supported with this understanding of a microglial mechanism through which these triggers contribute to the mental illnesses we see.
While we look out for more research, helping our current patients live healthier, more abundant lives in overcoming their mental illnesses begins with what we are already doing today. That includes caring for women’s health both before and during pregnancy so they minimize their child’s exposure to inflammatory triggers like toxins and infections. Once the baby is born, it means guiding parents on optimizing their children’s health through their brains growth and development. Beyond that, when we see children or young adults with mental illnesses, we search for such current inflammatory triggers that could be synergizing with past factors so that we can optimize their present health, regardless of what their mom’s pregnancy was like.
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Original Article:
Momoka Hikosaka, Md Sorwer Alam Parvez, Yuki Yamawaki, Souichi Oe, Yuan Liang, Yayoi Wada, Yukie Hirahara, Taro Koike, Hirohiko Imai, Naoya Oishi, Sina M. Schalbetter, Asuka Kumagai, Mari Yoshida, Takeshi Sakurai, Masaaki Kitada, Urs Meyer, Shuh Narumiya, Gen Ohtsuki. Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition. Communications Biology, 2025; 8 (1) DOI: 10.1038/s42003-025-07566-2
Thanks to Science Daily:
Kyoto University. “Don’t let this stress you out.” ScienceDaily. ScienceDaily, 3 March 2025. <www.sciencedaily.com/releases/2025/03/250303220106.htm>.
Sanctuary Functional Medicine, under the direction of Dr Eric Potter, IFMCP MD, provides functional medicine services to Nashville, Middle Tennessee and beyond. We frequently treat patients from Kentucky, Alabama, Mississippi, Georgia, Ohio, Indiana, and more... offering the hope of healthier more abundant lives to those with chronic illness.
