The study reveals that infections during pregnancy combined with stress in adulthood can increase the risk of disorders such as schizophrenia and autism. This happens due to changes in cells of the brain's immune system, affecting neurons and causing cognitive and behavioral problems. However, by restoring these cells, scientists were able to reverse some of the damage, paving the way for new treatments.
Mental disorders profoundly affect people's thinking, emotions and behavior. Studies show that the accumulation of stress, whether due to infections or adverse social situations, can increase the risk of developing diseases such as schizophrenia.
One of the mechanisms that may be behind this problem involves microglia, which are cells of the brain's immune system. These cells play an essential role in defending the body and maintaining brain health, but when they undergo changes, they can be linked to mental and neurodegenerative disorders.
Although changes in these cells have already been identified in the brains of people with psychiatric illnesses and in animals used for study, there are still many questions about how these changes affect brain function and behavior..
In animal studies, researchers have observed that offspring of mothers exposed to infections during pregnancy exhibit severe difficulties in social behavior.
This is similar to problems seen in people with neurodevelopmental disorders, such as autism, especially when exposed to infections and other stressors during critical periods of development. Another experiment, which simulates a mood disorder in animals, involves subjecting mice to repeated social defeats, which leads to behaviors similar to depression.
Although these two models are widely used to study psychiatric disorders, there is evidence that a single factor is not enough to cause these diseases.
Research suggests that the combination of stressors, such as infections during pregnancy and trauma in childhood or adolescence, significantly increases the risk of developing schizophrenia. Interestingly, the effects of this interaction appear to be stronger in boys than in girls, suggesting that the impact of stress may vary by sex.
Microglia play a key role in these changes. These cells act to protect the brain and help eliminate toxins and damaged cells. Recent studies have shown that microglia can exhibit different behaviors depending on the region of the brain, the stage of development, and the sex of the individual.
Sex differences, for example, are important for the formation of neural circuits in the developing brain. In mice and humans with schizophrenia, there is evidence that microglia become less branched and denser in response to stress.
In addition, infections during pregnancy can permanently alter the way these cells respond to future challenges, which may be linked to an increased risk of psychiatric disorders. Despite these advances, much research has neglected the study of microglia in the cerebellum, a region of the brain that has been increasingly associated with mental disorders.
The cerebellum, traditionally seen as responsible for coordinating movement, is also involved in cognitive and emotional functions. Recent studies indicate that changes in the cerebellum may be associated with disorders such as schizophrenia and autism.
During development, microglia in the cerebellum help eliminate dead cells and excess neural connections, a process that may differ between boys and girls. However, little is known about how stress affects microglia in this region and how this may influence the development of psychiatric disorders.
Purkinje neurons reach their tree-like dendrites into the molecular layer of the developing cerebellum of a mouse.
To investigate this issue, scientists at Kyoto University in Japan developed an experimental model called 2HIT, in which mice are exposed to two combined risk factors: maternal infection during gestation and social stress in adulthood.
The results showed that this combination of stressors increases the activation of microglia in the cerebellum, affecting both males and females. In addition, they observed an increase in the death of Purkinje neurons, which are essential for cerebellar function.
Changes in the shape of immune cells in the brain after exposure to intense stress. The images show changes in microglia, the brain’s immune cells, in different groups of animals. (a) 3D images of microglial cells in the cerebellum of three groups: animals without stress (Control), exposed to intense stress (2HIT), and those that received a treatment to replace the altered microglia (2HIT+rMG). The images highlight these cells in two areas of the cerebellum: the cerebellar cortex (CbCrx) and the cerebellar nuclei (CbN). (b) Comparison of the shape of microglia in different regions of the brain: cerebellum (CbCrx, CbN), hippocampus (HPC), and ventral tegmental area (VTA). Microglia from different groups of animals are shown, including those resilient or susceptible to social stress (RSDS), animals that experienced prenatal infection (MIA), and those treated to restore microglia (rMG).
Advanced imaging techniques revealed that microglia from mice exposed to stress underwent a transformation, becoming more like microglia associated with inflammation. This process involved specific proteins, such as IL-6 and TGFβ, which are involved in the brain’s immune response.
The mice in the 2HIT group also showed changes in Purkinje cell activity and brain connectivity, which were associated with cognitive deficits and behavioral changes.
However, when the researchers replaced the altered microglia with healthy cells, the brain and behavioral abnormalities were significantly reduced.
This suggests that the combined impact of stress on cerebellar microglia may be a key factor in the development of psychiatric disorders and that modulating these cells could be a potential strategy for future treatments.
When certain cells in the brain, called Purkinje cells, deteriorate and the remaining neurons become less active, this can affect how a person perceives themselves and the world around them, causing cognitive and behavioral difficulties.
However, by targeting altered immune cells in the brain (microglia and macrophages), scientists were able to reduce this damage. This discovery opens up new possibilities for developing treatments for complex disorders related to stress and inflammation.
READ MORE:
Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition
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
Communications Biology. volume 8, Article number: 296 (2025)
Abstract:
The functional alteration of microglia arises in brains exposed to external stress during early development. Pathophysiological findings of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder suggest cerebellar functional deficits. However, the link between stress-induced microglia reactivity and cerebellar dysfunction is missing. Here, we investigate the developmental immune environment in translational mouse models that combine two risk factors: maternal infection and repeated social defeat stress (2HIT). We find the synergy of inflammatory stress insults, leading to microglial increase specifically in the cerebellum of both sexes. Microglial turnover correlates with the Purkinje neuron loss in 2HIT mice. Highly multiplexed imaging-mass-cytometry identifies a cell transition to TREM2(+) stress-associated microglia in the cerebellum. Single-cell-proteomic clustering reveals IL-6- and TGFβ-signaling association with microglial cell transitions. Reduced excitability of remaining Purkinje cells, cerebellum-involved brain-wide functional dysconnectivity, and behavioral abnormalities indicate cerebellar cognitive dysfunctions in 2HIT animals, which are ameliorated by both systemic and cerebellum-specific microglia replacement.
Comments