Where does fear live in the brain?

Researchers at Rice, Baylor College of Medicine show how rats remember fearful experiences

By Ana Rodriguez
Special to the Rice News

Researchers at Baylor College of Medicine and Rice University have revealed for the first time the patterns of electrical activity in rat brains associated with specific memories, in this case fearful experiences.

They discovered that before rats avoid a place they feared, their brains recalled memories of the physical location where the experience occurred.

Caleb Kemere. Photo by Jeff Fitlow

Caleb Kemere. Photo by Jeff Fitlow

The results appear in Nature Neuroscience, and the researchers hope that understanding how the brain remembers can one day shed light on what goes wrong when memory fails, as happens in Alzheimer’s disease.

“We recall memories all the time,” said senior author Daoyun Ji, an associate professor of molecular and cellular biology at Baylor. “For example, I can recall the route I take from home to work every morning, but what are the brain signals at this moment when I hold this memory in my mind?”

Studying the workings of the brain in people is difficult, so scientists have turned to the laboratory rat. They have learned that when the animal is in a particular place, neurons in the hippocampus, appropriately called place cells, generate pulses of activity.

“A number of place cells generate electrical activity called a ‘spiking pattern,'” Ji said. “When the rat is in a certain place, a group of neurons generates a specific pattern of spikes, and when it moves to a different place, a different group of neurons generates another pattern of spikes. The patterns are very distinct. We can predict where the animal is by looking at its pattern of brain activity.”

“This is the first time anyone has ever seen evidence of that memory retrieval process in the context of negative or fearful memories, despite several decades of work with the general experimental paradigm,” said Rice’s Caleb Kemere, an assistant professor of electrical and computer engineering and co-author of the paper. His lab designs systems to interact with and gather information from complex neural circuits in rodents.

“For the last 10 years, we have been able to observe individual patterns that we associate with memory retrieval, but only in the context of neutral or rewarded behaviors,” he said. “The innovation in these experiments is to deliver the startling experience in a maze rather than a little box.”

“Our laboratory rats cannot tell us what memory they are recalling at any particular time,” Ji said. “To overcome that, we designed an experiment that would allow us to know what was going on in the animal’s brain right before a certain event.”

To determine whether the spiking patterns are involved in memory, the experiment conducted by first author Chun-Ting Wu, a graduate researcher at the Ji lab, had a rat walk along a track, back and forth. After a period of rest, the rat walked the same track again, but when the animal approached the end of the track, it received a mild shock. After it rested again, the rat was placed back on the track. This time, however, when it approached the end of the track where it had received the mild shock, the rat stopped, turned around and avoided crossing the fearful path.

“Before a rat walked the tracks the first time, we inserted tiny probes into its hippocampus to record the electrical signals generated by groups of active neurons,” Ji said. “By recording these brain signals while the animal walked the track for the first time, we could examine the patterns that emerged in its brain. We could see what patterns were associated with each location on the track, including the location where the animal later got shocked.

“Because the rat turns around and avoids stepping on the end of the track after the shocks, we can reasonably assume that the animal is thinking about the place where it got shocked at the precise moment that it stops walking and turns away,” he said. “Our observations confirmed this idea.”

The researchers looked at brain activity in place neurons at this moment of avoidance. They found the spiking patterns corresponded to the location in which the rat had received the shock re-emerged, even though this time the animal was only stopping and thinking about the location.

“Interestingly, from the brain activity we can tell that the animal was ‘mentally traveling’ from its current location to the shock place,” Ji said. “These patterns corresponding to the shock place re-emerged right at the moment when a specific memory is remembered.”

One goal is to investigate whether the spiking pattern is required for the animals to behave the way they did.

“If we disrupt the pattern, will the animal still avoid stepping into the zone it had learned to avoid?” Ji said. “We are also interested in determining how the spiking patterns of place neurons in the hippocampus can be used by other parts of the brain, such as those involved in making decisions.”

Ji and his colleagues plan to explore the role that spiking patterns in the hippocampus might play in diseases, like Alzheimer’s, that involve memory loss.

“We want to determine whether this kind of mechanism is altered in animal models of Alzheimer’s disease,” Ji said. “Some evidence shows that it is not that the animals don’t have a memory, but that somehow they cannot recall it. Using our system to read spiking patterns in the brains of animal models of the disease, we hope to determine whether a specific spiking pattern exists during memory recall. If not, we will explore the possibility that damaged brain circuits are preventing the animal from recalling the memory and look at ways to allow the animal to recall the specific activity patterns, the memory, again.”

“If we alter that memory-retrieval process, would we change the animal’s perception of the world?” Kemere asked. “Can we use what we have learned about how memories are stored to manipulate the process of memory retrieval in the context of fearful memories? That would really give us, for the first time, a pathway towards the idea of selectively mitigating traumatic memories.”

Daniel Haggerty, a postdoctoral associate in the Ji lab, is a co-author.

The National Institutes of Health and the Simons Foundation supported the research.

Ana Rodriguez is a science writer and editor at Baylor College of Medicine.



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