Immune cells in the human brain may be important for regulating organ development within the uterus, as they cause a dramatic increase in critical types of neurons, new research suggests.
Estimates suggest that these important cells, known as inhibitory interneurons, account for approximately 25% to 50% of neurons in the adult cortex, wrinkled tissues that cover the brain’s surface. In fact, the human cortex carries more than twice as much interneurons as the mouse cortex.
These interneurons relay signals between other brain cells and help to continue suppressing that signal with chemical messengers called GABA. As the main “inhibitory” messenger of the brain, GABA helps defeat brain activity by being less likely to fire neurons, thus balancing the “excitatory” signals that amplify brain activity. Various disorders are linked to interneuron problems, such as epilepsy, autism, and schizophrenia.
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Now, in a study published in Nature on August 6, researchers have revealed the power to drive interneurons to multiply in the developing human brain.
“That’s why traditional animal models can’t be used,” Diankun Yu, an assistant pediatrics researcher at the University of California, San Francisco (UCSF), told Live Science. To clarify this mechanism that can only be deployed in the human brain, researchers have developed organoids. This is a miniature 3D structure grown from stem cells, mimicking the full-size structure found in the human body.
Prior to organoid studies, laboratory animals studies suggested that there were fewer cortical interneurons in the offspring compared to those who had not experienced maternal immune system activation during pregnancy and those who had not experienced immunity agitation. This type of activation can occur in response to, for example, viral or bacterial infections. The study authors investigated this in previous studies in lab mice. This study identified the key player behind the link, Microglia, a resident immune cell in the brain.
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Over the past five years, scientists have begun to recognize how the immune and nervous systems develop in parallel.
“Microglia really tweak and regulate nervous development,” she said of the findings of a new study. “It really adds a new dimension to how microglia functions.”
The team developed organoids based on previous research from other research groups. This resembles the key structure of the fetal brain where many cortical interneurons arise. The structure was temporary, appearing around the eighth week of human pregnancy and disappeared about eight months after birth, Piao said. Researchers have found a way to incorporate microglia into the model, but this has not been done before, she added.
The team found that organoid microglia are an important source of insulin-like growth factor 1 (IGF1) in developing minibrains, and that this substance helps to promote the dramatic increase in interneurons seen in early development.
When the team tested what happens when they turn IGF1 signaling off in a variety of ways, they found that it blocks rapid increase in interneurons. However, “When we deleted this gene in a mouse model of microglia, we did not see any changes,” Piao said. This suggests that this series of events kicked off by microglia IGF1 may be human-specific.
“These findings demonstrate the evolutionary adaptation of microglial function to support an increased demand for interneurons in the human cortex,” the researchers wrote in their report. In short, this finding suggests characteristics of human evolution that may help explain our unique cognitive abilities.
That said, organoids are not accurate replicas of the human brain, so there are limitations to what 3D models can convey. “So far, this model is excellent enough, especially in the proliferation stage, the very early stage,” Yu said. However, he noted that these organoids are not the same at the later stages of brain development. It also doesn’t capture circuit-level activity in the brain, Piano said, showing only activity within smaller, isolated structures.
Future research could help to further uncover this previously unknown role of immune cells in the brain, she said.
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