Scientists have spent decades studying the brain’s cells, connections, genes and proteins. Another essential element of brain biology has received much less attention: lipids. These fatty molecules make up the membranes surrounding neurons, help insulate the myelin that protects nerve fibers, and play an important role in communication between brain cells.
Although lipids are essential for brain function, scientists have struggled to determine where different types of lipids are located. Conventional imaging techniques cannot easily distinguish individual lipid molecules, leaving a major gap in our understanding of the chemical organization of the brain.
“So scientists only have a fuzzy picture of how lipids differ in one part of the brain to another,” explains Giovanni D’Angelo, professor at the Kristian Gerhard Jebsen Foundation Chair in Nutrition and Metabolism at EPFL. “This discrepancy is important because changes in brain lipids are increasingly linked to pathologies ranging from depression to Alzheimer’s disease.”
EPFL researchers have now taken a major step towards filling this gap. A team led by D’Angelo, Luca Fusar Bassini and Gioele La Manno created a detailed map showing how lipids are distributed in the mouse brain.
Their Lipid Brain Atlas reveals that these molecules are arranged in highly organized patterns. Some correspond to familiar anatomical structures, while others expose chemical limitations that previous approaches had overlooked. The patterns are so distinctive that researchers could identify the origin of a brain tissue sample simply by examining its lipid composition.
The results were published in Nature.
Scientists identify 539 distinct chemical areas in the brain
To construct the atlas, the researchers used mass spectrometry imaging, a technique that allows them to identify lipid molecules in thin sections of brain tissue. A laser scans each slice one spot at a time, producing detailed information about what lipids are present and where they are located.
The team looked at 172 different lipids in 109 brain slices taken from 11 mice. This generated around 7 million measurements, which the scientists combined into a comprehensive 3D reconstruction using machine learning tools developed specifically for the project.
The resulting atlas revealed 539 chemically distinct territories, which the researchers named “lipizones.” Each has a characteristic combination of lipids, creating a recognizable chemical signature.
Many of these regions correspond to established brain structures and cell types. Others reveal unexpected relationships between groups of nerve cell bodies and distant regions connected by their fibers. Such connections are often difficult to detect using maps based on gene activity.
“In fact, lipids work like zip codes, giving distant but related parts of the brain the same chemical address,” D’Angelo explains.
Hidden chemical patterns challenge previous brain maps
The new atlas also revealed surprising differences within parts of the brain that scientists previously thought were relatively uniform.
A striking example is white matter, the tissue containing nerve fibers that connect different regions of the brain. Rather than having a largely consistent chemical composition, the white matter contains many distinct lipid areas.
“This shows that the chemistry of the cells that make myelin is much more varied than their genes alone suggest,” explains Luca Fusar Bassini.
The researchers also detected previously unknown chemical boundaries in the choroid plexus, the structure responsible for producing cerebrospinal fluid, as well as in the tissues lining the internal cavities of the brain.
Together, these results show that lipid mapping can reveal important features of brain organization that are not apparent from anatomy or genetic information alone.
Pregnancy triggers widespread changes in brain lipids
Beyond identifying the brain’s chemical structure, the atlas offered new insights into how that structure changes during pregnancy.
When the researchers examined pregnant mice, they found significant changes in lipid composition in many regions of the brain. Overall, these changes were more pronounced than the typical lipid differences seen between male and female mice.
The cortex, which makes up the outer layer of the brain, showed particularly significant changes. Meanwhile, levels of galactosyl ceramide, an important component of myelin, rose sharply throughout much of the brain’s white matter.
These findings suggest that pregnancy involves significant changes in the brain’s chemical composition, potentially helping its neural connections adapt to the body’s changing demands.
“Together, these changes suggest that the brain is readjusting its own wiring to meet the demands of pregnancy,” says Gioele La Manno. “The Atlas reveals that the brain is constantly adjusting its lipids to meet the body’s changing needs.”
A new tool to understand brain aging and diseases
THE Lipid Brain Atlas is available free onlineenabling scientists around the world to explore this previously difficult-to-study aspect of brain biology.
By combining lipid information with existing genetic and cellular maps, researchers can better understand how the brain is organized and how its chemistry changes over time.
The atlas also establishes a detailed benchmark for healthy mouse brain tissue. Scientists can use it to study how disruptions in lipid distribution might contribute to brain development, aging and disorders such as Alzheimer’s disease and depression.
Although the specific map of the mouse brain cannot be directly applied to humans, the approach used to create it could help researchers discover comparable patterns in the human brain.
“What is transferred to humans is not the map, it is the method, and the fact that we now know that a healthy brain has a very organized lipid map,” explains Luca Fusar Bassini.
Gn Health
