New detailed brain growth atlas in mice offers insights into brain development

HERSHEY, Pa. — Brain growth and maturation doesn’t progress in a linear, step-wise fashion. Instead, it’s a dynamic, choreographed sequence that shifts in response to genetics and external stimuli like sight and sound. This is the first high-resolution growth chart to explain changes of key brain cell types in the developing mouse brain, led by a team at Penn State College of Medicine and the Allen Institute for Brain Science.

Using advanced imaging techniques, the researchers constructed a series of 3D atlases that are like time-lapsed maps of the brain during its first two weeks after birth, offering an unparalleled look at a critical period of brain development. It’s a powerful tool to understand healthy brain development and neurodevelopmental disorders, the researchers explained.

The study, published today (Oct. 29) in Nature Communications, also detailed how regions of the brain change in volume and explained the shift in density of key cell types within them.

“The resolution of existing brain growth charts is poor, like a blurry photo. We’ve created a brain growth chart at the resolution of individual cells. It’s like a high-definition photo where the details appear sharp and in-focus,” said Yongsoo Kim, professor of neuroscience and experimental therapeutics at Penn State College of Medicine and senior author on the paper.

The mouse brain is a mammalian model for the human brain, with similar brain chemistry and neural circuitry conserved between the two. This early postnatal phase in mice is roughly equivalent to the crucial development period between late pregnancy and early childhood in humans, the researchers explained. Not only does the brain rapidly mature during this window, it’s also when the brain begins to respond and adapt to external stimuli like sight and sound, shaping where the brain expands in volume and how the brain is wired.

“This is also when many neurodevelopmental disorders, like autism spectrum disorder, begin to unfold. These disorders can arise from both genetic and environmental risk factors but if a problem appears during the early postnatal phase, it can spread as brain development continues,” Kim said. “Areas with the most rapid expansion are likely to be the most vulnerable.”

The researchers captured images of the whole mouse brain at every other day from postnatal day four to two weeks to create the high-resolution 3D growth chart. They used serial two photon tomography, an advanced imaging technique that scans the whole brain with microscopic details. This technique allows for researchers to visualize individual cells in their precise location in the brain.

Growth isn’t uniform across the whole brain, according to the researchers. They found that the cerebellum increased in volume the most during the early postnatal period. This is the part of the brain at the back of the head that fine-tunes movement, coordinates balance and is involved in some cognitive functions.

The researchers also studied two specific cell types that play a key role in shaping the circuits that transmit and process information in the brain. They traced how the density of these cell types changed across different regions of the brain to better understand the brain’s normal development trajectory.

GABAergic neurons are inhibitory nerve cells that act like brakes in the brain and play a key role in communication in the brain. Kim explained that neurodevelopmental disorders are often associated with broken brake systems, which is why the team wanted to see how GABA cell types populate in the brain.

They observed that the density of GABAergic neurons decreased significantly in the cortex — the outermost region of the brain — stabilizing around postnatal day 12. In contrast, the density of these neurons increased markedly in the striatum, a structure in the deep brain involved in movement and reward. The findings suggest that the development and population of these cells is dynamic and continues after birth.

The second cell type they examined is microglia, the brain’s immune cells. Kim described these cells as similar to gardeners. Their main role during development is to prune cells and unnecessary connections, shaping and fine-tuning the brain’s wiring.

Microglia showed a striking shift, too. Up until postnatal day eight, these cells are heavily populated in the brain’s white matter, tissue that’s made up of large networks of nerve fibers that facilitate communication between different parts of the brain. Around postnatal day 10, the population of microglia in the white matter decreases dramatically and begins to expand in the brain’s grey matter, which is composed primarily of nerve cells.

Microglia also appear to more densely populate areas that process sensory information around the time when mice’s eyes and ears begin to open. While Kim said they don’t yet know the significance of this shift, it suggests that microglia may engage in brain maturation in response to external stimuli experienced after birth, like sight and sound.

The team also created a publicly available, interactive version of the atlases and growth charts to facilitate data sharing and collaboration.

“The real significance of this paper is that we provide a spatial framework so other people can begin to do more high-level integrative analysis, which combines molecular, cellular and spatial data to provide a more complete picture of brain and development,” Kim said.

This work is part of the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative, or The BRAIN Initiative, whose goal is to provide a comprehensive understanding of the brain. Partners work collaboratively and bring together their findings into a more unified picture of the hundreds of different brain cell types.

Other Penn State College of Medicine authors on the paper include Fae Kronman and Deniz Parmaksiz, joint degree students in the MD/PhD Medical Scientist Training Program;  Hyun-Jae Pi, data scientist; and Daniel Vanselow, research project manager.

During the time of the research, first author Josephine Liwang earned a doctoral degree in neuroscience at Penn State College of Medicine. Co-authors Steffy Manjila, Yuan-Ting Wu and Donghui Shin were also affiliated with Penn State College of Medicine at the time of the study.

Yoav Ben-Simon, Michael Taormina, Sharon W. Way, Hongkui Zeng, Bosiljka Tasic and Lydia Ng from the Allen Institute for Brain Science also contributed to the paper.

Funding from the National Institutes of Health supported this work.

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