Exploring brain plasticity with single-cell precision

Our brains are made up of billions of neurons that constantly adapt to new information. Known as neuroplasticity, this flexibility helps us think clearly, remember things, and respond to the world around us. But as we age, this adaptability can decline, leading to memory problems and other cognitive issues, including conditions like Alzheimer’s disease.

Associate Professor Kristen O’Connell, an associate professor at The Jackson Laboratory (JAX) studies individual brain cells to assess this neuroplasticity and uncover the intricate mechanisms behind it. Her research has primarily used a cutting-edge technique called Patch-seq to understand the relationship neuronal gene expression and the mechanisms that allow neurons to integrate incoming information into a salient output signal that can be propagated to the next neuron in the circuit.

Although scientists have learned much about these processes by studying gene activity in individual cells, genes don’t always tell the full story, especially in aging brains. That’s because the amount of protein doesn’t always correlate with the expression level of the genes that encode them. This mismatch may be a key reason why brain function declines with age, O’Connell said.

In the past, studying proteins cell by cell was nearly impossible, which is why gene expression levels are so often used as a proxy for protein expression. But now, O’Connell, along with Brian Hoffmann, Director of the Protein Sciences Service, is accelerating this research using exciting new technology available at JAX: a state-of-the-art mass spectrometry system that allows scientists to analyze proteins present within individual cells. JAX is one of just a few research institutions equipped with this mass spectrometer – the Bruker timsTOF Ultra 2 - which provides data that could help with the development of new diagnostic tools and clinical therapies with unprecedented speed and precision.

These efforts are supported by a new $2.2 million award from the Simons Foundation, funding two projects: “How does sleep sustain lipid function across adult life” and “Protein and Lipid Homeostasis in the Aging Brain.” O’Connell and Hoffmann serve as co-principal investigators, collaborating with scientists at Stanford University, UCSF, and Columbia University.

The goal of these projects is to create a detailed picture of how proteins and lipids change in the brain over time, and how these changes affect memory and cognition. This could lead to new ways to protect brain health and prevent cognitive decline as we age.

“Having these new methods to examine biological domains that are crucial for brain function-and that we believe are key determinants of how the brain ages-is essential for advancing this research,” says O’Connell.

This kind of technical innovation, which overcomes previous time and sensitivity constraints, propels research into exciting new territories and that is what JAX Scientific Services is all about, says Hoffmann.

“We continually pursue new technologies,” he says. “We want to provide JAX investigators with tools that enable them to answer important biological questions that couldn’t be addressed just a few years ago.”

The Simons Foundation, which champions collaborative science through grant funding, education, and outreach, supports projects like O’Connell’s and Hoffmann’s through its “Plasticity and the Aging Brain Collaboration,” which first funded O’Connell’s work in 2022.

This new round of funding is a continuation, and evolution, of that initial support, says O’Connell, expanding their efforts in neuroplasticity to include the power of proteomics and lipidomics, Hoffmann’s specialty in the Mass Spectrometry and Protein Chemistry laboratory within the Protein Sciences core at JAX.

“The Simons Foundation makes this possible. This kind of work can be difficult to fund, but Simons has embraced these high-risk, high-reward projects, building on what we believe is possible. Without their support, this research would be challenging to pursue.”

Ideally, she says, this research will generate resources that scientists working on Simons Collaboration projects—and across the neuroscience field—can use to support their studies, answer crucial questions about the aging brain, and eventually develop therapies to prevent diseases like Alzheimer’s.

“It’s exciting to think about what our two teams can accomplish together,” says Hoffmann. “I feel that we’re pushing the field in a way that no one has before.”