Unraveling how aging reshapes brain circuits and behavior

Two recent grants totaling more than $2 million to Harvard Medical School will support two related projects that are part of the Simons Collaboration on Plasticity and the Aging Brain (SCPAB), which aims to understand plasticity-related changes in the brain during aging. This basic research will provide a foundation for future translational efforts to determine how these changes may contribute to poorer memory and declines in other cognitive abilities. 

These awards are funded by Simons Foundation International and administered by the Simons Foundation.

Movement and cognition as a window on the lifespan

In this project, a team of researchers is examining how behavior and brain circuits change as mice age, especially in the context of learning and decision-making. Their earlier work showed that younger and older mice not only perform differently but also use different strategies when making decisions. The team also found that spontaneous behavior—the natural way animals move and act when they’re not performing a specific task—changes systematically over the lifespan, and that key brain areas involved in planning and decision-making continue to change even after adolescence.

To study these changes more precisely, the team has built a powerful set of tools. One is a “movement clock” that can estimate an animal’s age solely from its behavior, helping distinguish aging-related changes from individual differences. The team has also created a “decision-making barcode,” a compact way of describing an animal’s thinking strategy, and is using advanced machine-learning methods to automatically analyze complex patterns in behavior.

Next, the collaborators will integrate these tools and discoveries into a shared framework. By combining rich behavioral data, large-scale brain recordings, and advanced data analysis, they aim to build a deeper understanding of how aging alters behavior and the underlying brain circuits.

Brain-specific thyroid hormone dysfunction drives age-related cognitive changes

A subset of this team of researchers will use the shared framework to test a specific hypothesis about whether a drop in the thyroid hormone T3 within the brain helps drive age-related changes in brain circuits and behavior. Their evidence suggests that older animals enter a low‑T3 brain state in which genes that support connections between brain cells are turned down, leading to changes in local and long-distance wiring. The team plans to map this state in detail in young and old mice, identify key molecules that control T3 levels in the brain, and test whether restoring T3-dependent signaling in specific cell types can reverse age-related changes in brain activity and behavior. They will also compare these results with human brain data to assess the relevance of these mechanisms to human aging.

A major focus is on brain circuits that use dopamine, a chemical messenger crucial for motivation and exploration. “Reward seeking and processing, threat perception, and randomness of locomotor exploration all depend on dopaminergic signaling in specialized and separate striatal subregions,” says Bernardo L. Sabatini, SB ’91, MD ’99, PhD ’99, the Alice and Rodman W. Moorhead III Professor of Neurobiology at HMS. The team will use new high-precision tools to measure dopamine signals in animals as they move and perform tasks, and will study how T3 levels alter these signals across different brain regions.

Finally, the collaborators will examine how brain inflammation may push the system into a low‑T3 state and whether restoring T3 signaling can improve cognitive performance, even when inflammation is still present. 

Principal investigators: Anne Churchland, PhD, professor of neurobiology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA); Sandeep Robert “Bob” Datta, MD ’04, PhD ’04, professor of neurobiology at HMS; Mario Dipoppa, PhD, assistant professor of computational neuroscience at the David Geffen School of Medicine at UCLA; Daniel Hochbaum, PhD ’14, assistant professor of medicine at Beth Israel Deaconess Medical Center; and Bernardo L. Sabatini.