Five-year NIH grant supports collaborative research into rejuvenating the aging brain

Scientists at UC Santa Cruz, UC Berkeley, and Stanford are working together to discover and treat the causes behind age-associated cognitive decline

Yi Zuo
Neuroscientist Yi Zuo is studying how the brain changes with age. (Photo by Carolyn Lagattuta)

UC Santa Cruz is leading a novel study of the aging brain in collaboration with researchers at UC Berkeley and Stanford University. Funded by a roughly $2.5 million grant from the National Institutes of Health, the five-year project will enable scientists to track changes in aging brains over an extended period of time.

As we grow old, inflammation in our brains can become excessive. In low amounts, this inflammation acts as a helpful immune response, but too much can impair cognitive function and lead to declines in processes like memory.

Researchers at UCSC, UC Berkeley and Stanford are working together to find and neutralize the factors that cause these declines, using mice as models. They’re looking specifically at changes to blood composition and how immune cells in the brain and central nervous system called microglia alter cognition with age.

Lead investigator Yi Zuo, a professor of molecular, cell and developmental biology at UCSC, said she never expected to study aging as part of her neuroscience work. “But maybe because I'm getting older, my parents are getting older…, I have more and more people whose real lives are affected by aging,” she said.

Zuo’s lab specializes in the study of synapses—gaps between nerve cells that electrical or chemical signals jump across. The synaptic connections allow us to think, move, and feel. Altering them changes the brain’s abilities.

The scientists hypothesize that as we age, chronic inflammation leads to microglia destroying important synapses. To combat this process, they designed a treatment consisting of the hormone oxytocin and an inhibitor for an inflammatory pathway. The team will watch how the cocktail affects the brain over time as well as look for differences in the way the blood of old and young mice impacts inflammation.

In addition to studying changes in synapses and inflammation, Zuo will also measure behavioral shifts in the mice, testing processes like memory. The length of the grant will allow the team to examine these physical and behavioral results over multiple years.

“We typically are looking at what happens to experimental animals or human subjects very quickly after the intervention,” said Irina Conboy, a professor of bioengineering at UC Berkeley. “But we don't know what happens long term.”

Some parameters cannot be expected to change immediately, she explained. She used networks of neurons in the brain as an example.

“Even if you are improving something quickly, it takes some time for the brain rewiring to catch up and result in a better cognitive response,” she said.

Conboy’s lab brings to the group a specialization in aging and blood-based rejuvenation research. She and Zuo will be joined by Philippe Mourrain, a professor of psychiatry and behavioral sciences at Stanford University. Neuroscientists often examine individual or small groups of synapses. Mourrain’s lab designs ways to study the big picture of neural processing.

“Your brain has 200 billion neurons in the neocortex,” he said. “That would be like 300 trillion synaptic connections. Some would say it's like the equivalent of 2,000 Milky Ways, where you need to understand every single star as its own microprocessor but also in connections with all the others as part of a network.”

For this project, the group will use an imaging technique called array tomography to observe huge numbers of individual synapses. His lab will “investigate this constellation of connections,” and identify how it changes with treatment.

As Mourrain’s group studies the larger picture, Zuo’s lab will focus on individual synapses and microglial cells. They will track real-time changes in single animals over hours, days, months, and eventually, years.

“It is very difficult to piece together the information by a snapshot,” said Zuo. “This will give us a continual dynamic view.”

The scientists expect their treatments to result in a long-term decrease in inflammation and an increase in cognitive function. In previous studies, Zuo and Conboy have seen success with this treatment in the short-term, and this project will help them determine exactly how it works over a longer period of time.

The team also plans to identify specific factors that change in the blood with age and cause chronic inflammation. Once they tease apart the specific mechanism, they hope to design another treatment.

“If we identify what the young blood can bring into the brain, then we don't need the young blood itself,” said Zuo. “Maybe something can be purified to synthesize that and bring it into the brain.”

The collaboration of the three labs will include meetings and workshops for sharing techniques.

“I’m greatly excited about the collaborative work—that it really cross-pollinates innovative technologies of the three laboratories,” said Conboy. “They synergize. Each professor alone would not be able to accomplish that work.”

Mourrain agrees. “I really, really enjoy this collaboration,” he said. “I feel very good about it, because the intervention has already been proven to work. And all the tools that we are using, whether in Yi's lab, Irina’s, or in mine, we've validated them over the past 10 years. So we can just move forward now.”