Researchers at The University of Texas at Dallas' Center for Vital Longevity (CVL) and Columbia University's Zuckerman Mind Brain Behavior Institute have identified shared patterns of brain network organization and age-related change between mice and humans.
The finding that brain system segregation, a measure of how strongly brain regions cluster into functionally specialized networks, decreases with age in mice provides a new framework for probing the mechanisms of cognitive aging and informing strategies to improve brain health in aging humans.
Dr. Gagan Wig , associate professor of psychology in the School of Behavioral and Brain Sciences , is corresponding author of an article published online March 23 in Proceedings of the National Academy of Sciences that demonstrates that mice share key features of human brain network aging, establishing a platform for cross-species investigation.
In humans, large-scale functional brain networks support coordinated brain function while remaining distinct in their roles. Over time, however, this distinctiveness declines, and the networks become less differentiated.
"The process of network dedifferentiation is linked to declining memory function in older adults and is prognostic of Alzheimer's disease dementia," Wig said. "We also know that environmental exposures — including chronic stress, diet and exercise — modulate dementia risk, and we have begun to see their impacts on human brain network changes. Experiments with humans are limited in their ability to isolate the specific factors and mechanisms driving brain changes across the lifespan — it's difficult to control for all potential sources of individual differences that may lead to accelerated aging."
Cross-species models of brain network decline offer a powerful platform to study its underlying drivers and isolate the most significant factors shaping these changes, Wig said.
"With the animal model we can now test what might make us more vulnerable or more resilient to aging and examine how disease processes and potential treatments, including those relevant to Alzheimer's disease, affect brain networks in ways that can be directly compared to observations in humans," he said.
Ezra Winter-Nelson, a cognition and neuroscience doctoral student and lead author of the study, said that while mice have often been useful models to understand molecular and cellular changes in the brain, the new findings show that they also can be used to examine how complex brain networks change with age.
"The mouse model serves as a bridge not only between humans and animals, but also across spatial scales," Winter-Nelson said. "What's more, you can document an entire mouse lifespan in two to three years, which allows us to get valuable longitudinal data, and ask questions about environments, genetic influences, diet and stress."
In the study, researchers performed resting-state functional MRIs at various points in the lives of awake mice ages 3 to 20 months. The study was distinctive because the imaging scans were performed on awake mice as opposed to imaging the animals under anesthesia, Wig said. Just as in humans, brain activity in mice differs under anesthesia compared to awake rest.
"Over the past 15 years, we've worked to establish the mouse as a model that we can compare directly to humans," Kahn said. "We know now that system segregation exists in mice, and it decreases with age as in humans, though in humans it decreases faster."
The discovery that when accounting for lifespan, functional brain network organization declines more rapidly in humans than in mice was a surprise and highlight of the work, Wig said.
"Our findings indicate that mice exhibit more modular network organization compared to humans in young adulthood, and that, when scaled to their lifespan, humans show more rapid age-related decline in this organization," he said. "These differences are important to consider in understanding the limitations of animal models and in identifying what makes human aging unique."
Winter-Nelson said the researchers took care not to base analyses on potential human-animal similarities that may not exist.
"Some brain systems in humans underlie things like language, planning or complex cognitive processes that we don't intend to imply are present in mice," he said. "Instead, we focus on quantifying the network as a whole. We're confident in the similarities we have identified in terms of overall organization of brain networks."
Other UT Dallas-affiliated authors include CVL research scientist Micaela Chan MS'12, PhD'16, postdoctoral researcher Ziwei Zhang PhD'24 and Liang Han PhD'22.
In addition to Columbia University, other contributors are from the Technion-Israel Institute of Technology and the Allen Institute for Brain Science.
The work was supported by a grant ( R24AG065172 ) from the National Institutes of Health's Animal Models for the Social Dimensions of Health and Aging Research Network , the National Institute on Aging ( R01AG063930 , R01AG092219 ), the James S. McDonnell Foundation, and The Carol and Gene Ludwig Center for Research on Neurodegeneration at Columbia.The finding that mice, like humans, exhibit declining brain network organization as they age lays the foundation for cross-species comparative analysis to identify the causes and consequences of brain network decline, according to study co-senior author Dr. Itamar Kahn, a principal investigator at Columbia's Zuckerman Institute and an associate professor of neuroscience at Columbia University.
