Fifty years ago, when the Mount Sinai School of Medicine opened its doors, four Nobel Prize winners gathered for its dedication and made predictions about how science would transform our understanding of our bodies and our world. One of the most intriguing was that doctors would one day understand the physical basis of memory—the structures and processes that allow the brain to store and retrieve experiences.

They were right.

After decades of research, much of it at Mount Sinai, doctors now have a deep understanding about how memory works, down to the molecular and cellular levels.

“We now think of the brain, and its 100 billion neurons, or nerve cells, in terms of networks,” says Mark Baxter, a professor of neuroscience at what is now the Icahn School of Medicine at Mount Sinai. “Instead of memory as something formed just anywhere in the brain, we realized over the decades that defined networks of cortical and subcortical areas are connected to form retrievable memories.”

Brain activity works like a circuit, so building and retrieving memories depends on connections within a network. Stronger connections yield stronger memories.

Denise Cai, from the Icahn School of Medicine at Mount Sinai, was able to watch as memories were encoded and linked through time. Credit: Mount Sinai Health System

While that idea is not new, scientists’ ability to test it is fairly recent. “It’s only in the last several years that we’ve had the technology to be able to track neural ensembles, which coordinate across many memories, across long periods,” explains Denise Cai, an assistant professor of neuroscience at the Icahn School of Medicine. “One way of thinking about this concept is that memory isn’t a snapshot—it is dynamically updated and edited across time. Any given memory is formed in relation to past and future memories.”

Cai focuses her research on how memories are related and linked, by tracking how brain activity in mice encodes different environments. By using a tiny microscope, made with a camera sensor from a cell phone, mounted on each mouse’s head, Cai recorded how hundreds of cells at a time were firing to produce memories. Her study provided the first evidence that mice are able to relate episodic experiences across time.

The study exposed mice to three environments and recorded their brain activity. “We placed the mice in three different contexts that were completely new to them and completely different from each other, with different smells, for instance,” Cai says. “One week separated the first environment, context A, from context B, but only five hours separated B and C. On average, we recorded 600 cells firing in each context to learn and remember the new environment.”

In the past, neuroscientists thought that different groups of cells would represent each of the three contexts. But a more recent view is that events more closely related in time would actually share overlapping neurons. “What we found was that if the mice associated context C with an aversive experience, they would freeze upon returning to that environment,” says Cai. “But they would also freeze upon reentering context B, because retrieving the memory of B triggered the recall of context C, which was aversive. In contrast, when we placed them in context A, they didn’t freeze. Those memories weren’t linked in time.”

For Cai, one of the most promising potential applications for this research is the treatment of post-traumatic stress disorder (PTSD). “Our new data showed that when mice learn a context for the first time and find it traumatic, they transfer that fear to neutral memories learned days apart,” she says. “One of the phenotypes of PTSD is the re-experiencing of fear. If we can understand a similar process at the cellular level in mice, we are in a better position to start developing targeted treatments to help humans prevent the relapses of fear.”

Though the Nobel Prize winners of half a century ago had the insight to predict a deeper understanding of memory, they could not have foreseen our current depth of understanding.

“Not only do we understand what happens at a very microscopic level, we now know that the electrical activity of brain cells is part of building memory,” Baxter says. “In the years ahead, the goal is to use our ability to measure the activity of certain networks in the brain to diagnose memory disorders, like Alzheimer’s disease and dementia, long before they are symptomatic. We hope to be able to intervene when the process of memory loss is just beginning. Eventually, we may even be able to apply outside stimulation to targeted areas of the brain in order to treat brain disorders.”

To learn more about how scientists are translating research into life-changing treatments, visit the New Heights in Medicine.