Summary: Scientists have identified a never-before-seen layered organization within one of the brain’s most important memory centers. The CA1 region of the hippocampus was found to contain four distinct bands of neuron types, each defined by unique genetic signatures that change subtly across the structure.
This hidden architecture explains why different parts of CA1 support different behaviors, such as memory, navigation, and emotions. The discovery also offers a new framework for understanding why specific neurons are more vulnerable in diseases such as Alzheimer’s disease and epilepsy.
Key facts:
Four distinct neuronal layers: The CA1 region contains four continuous sheets of specialized neuron types rather than a gradual cellular mixture. Single-cell genetic mapping: Researchers visualized more than 330,000 RNA molecules in more than 58,000 neurons to build the atlas. Disease relevance: The layered structure may explain the selective loss of neurons in Alzheimer’s, epilepsy, and other brain disorders.
Source: USC
Researchers at the Mark and Mary Stevens Institute for Computing and Neuroimaging (Stevens INI) at the Keck School of Medicine of USC have identified a previously unknown pattern of organization in one of the most important areas of the brain for learning and memory.
The study, published in Nature Communications, reveals that the CA1 region of a mouse hippocampus, a structure vital for memory formation, spatial navigation and emotions, has four distinct layers of specialized cell types.
This discovery changes our understanding of how information is processed in the brain and could explain why certain cells are more vulnerable in diseases such as Alzheimer’s and epilepsy.
“Researchers have long suspected that different parts of the CA1 region of the hippocampus handle different aspects of learning and memory, but it was unclear how the underlying cells were arranged,” said Michael S. Bienkowski, PhD, senior author of the study and assistant professor of physiology and neuroscience and biomedical engineering.
“Our study shows that CA1 neurons are organized into four thin, continuous bands, each representing a different type of neuron defined by a unique molecular signature. These layers are not fixed in place; instead, they subtly shift and change thickness throughout the hippocampus.
“This changing pattern means that each part of CA1 contains its own mix of neuron types, which helps explain why different regions support different behaviors. This may also clarify why certain CA1 neurons are more vulnerable in conditions such as Alzheimer’s disease and epilepsy: if a disease targets the cell type of one layer, the effects will vary depending on where in CA1 that layer is most prominent.”
Using a powerful RNA labeling method called RNAscope with high-resolution microscopy imaging, the team captured clear snapshots of single-molecule gene expression to identify CA1 cell types within mouse brain tissue. Inside 58,065 CA1 pyramidal cells, they visualized more than 330,000 RNA molecules: the genetic messages that show when and where genes are activated.
By tracking these activity patterns, the researchers created a detailed map showing the boundaries between different types of nerve cells in the CA1 region of the hippocampus.
The results showed that the CA1 region consists of four continuous layers of nerve cells, each marked by a different set of active genes. In 3D, these layers form sheets that vary slightly in thickness and structure across the hippocampus. This clear, layered pattern helps make sense of previous studies that viewed the region as a more gradual mix or mosaic of cell types.
“When we visualized patterns of genetic RNA at single-cell resolution, we could see clear stripes, like geological layers in a rock, each representing a different type of neuron,” said Maricarmen Pachicano, a doctoral researcher at Stevens INI’s Center for Integrative Connectomics and co-senior author of the paper.
“It’s like lifting a veil over the brain’s internal architecture. These hidden layers may explain differences in how hippocampal circuits support learning and memory.”
The hippocampus is among the first regions affected in Alzheimer’s disease and is also implicated in epilepsy, depression and other neurological conditions. By revealing the layered structure of CA1, the study provides a roadmap to investigate which specific types of neurons are most vulnerable in these disorders.
“Discoveries like this exemplify how modern imaging and data science can transform our view of brain anatomy,” said Arthur W. Toga, PhD, director of the Stevens INI and the Ghada Irani Chair in Neuroscience at the Keck School of Medicine of USC.
“This work builds on Stevens INI’s long tradition of mapping the brain at all scales, from molecules to entire networks, and will inform both basic neuroscience and translational studies targeting memory and cognition.”
The new CA1 cell type atlas, created from data from the Hippocampal Gene Expression Atlas (HGEA), is freely available to the global research community. The data set includes interactive 3D visualizations accessible through the Schol-AR augmented reality application, created on the Stevens INI, which allows scientists to explore the layers of the hippocampus in unprecedented detail.
Because this layered pattern in mice resembles what has been observed in primate and human brains (including how the CA1 region changes thickness), the researchers believe it may be a common feature in many mammalian brains.
While additional studies are needed to confirm this organization in humans, the finding provides a promising foundation for future comparative and translational research into how hippocampal architecture supports memory and cognition.
“Understanding how these layers connect to behavior is the next frontier,” Bienkowski said. “We now have a framework to study how specific neural layers contribute to functions as different as memory, navigation and emotions, and how their disruption can lead to disease.”
About the study
In addition to Bienkowski and Pachicano, the study’s other authors include Shrey Mehta, Angela Hurtado, Tyler Ard, Jim Stanis and Bayla Breningstall.
Funding: This work was supported by the National Institutes of Health/National Institute on Aging (K01AG066847, R36AG087310-01, supplement P30-AG066530-03S1), the National Science Foundation (grant 2121164), and funding from the USC Center for Neural Longevity. The research data reported in this publication was supported by the Office of the Director of the National Institutes of Health under award number S10OD032285.
Key questions answered:
A: Scientists discovered that the CA1 region is organized into four distinct layers of specialized neuron types rather than being a gradual mixture of cells.
A: CA1 plays a central role in learning, memory formation, spatial navigation, and emotional processing.
A: Different layers may be selectively vulnerable in disorders such as Alzheimer’s disease and epilepsy, which helps explain why damage varies by region.
Editorial notes:
This article was edited by a Neuroscience News editor. Magazine article reviewed in its entirety. Additional context added by our staff.
About this neuroscience research news
Author: Laura LeBlanc
Source: USC
Contact: Laura LeBlanc – USC
Image: Image is credited to Neuroscience News.
Original research: Open access.
“Laminar organization of pyramidal neuron cell types defines distinct subregions of the hippocampal CA1” by Michael S. Bienkowski et al. Nature Communications
Abstract
Laminar organization of pyramidal neuron cell types defines distinct subregions of the hippocampal CA1
Investigating the cell type organization of hippocampal CA1 is essential to understanding its role in memory and cognition and its susceptibility to neurological disorders such as Alzheimer’s disease and epilepsy.
Multiple studies have identified different organizing principles for gene expression and how it reflects cell types within the CA1 pyramidal layer, including gradients or mosaics.
Here, we identified sublaminar gene expression patterns within the mouse CA1 pyramidal layer that extend along the entire hippocampal axis.
Our findings reveal that CA1 subregions (CA1d, CA1i, CA1v, CA1vv) contain differentially distributed layers of constituent cell types and can be identified by regional gene expression signatures.
This work offers new insight into the organization of CA1 cell types that can be used to further explore hippocampal cell types across species.
