BLOOMINGTON, Ind.—Led by Dr. Jonathon Crystal, neuroscientists at Indiana University (IU) have reported the first evidence that non-human animals can mentally replay past events from memory. In addition to understanding animals, the discovery, reported in the journal Current Biology, could help advance the development of new drugs to treat Alzheimer’s disease.
According to Crystal, a professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences and director of the IU Bloomington Program in Neuroscience, “The reason we’re interested in animal memory isn’t only to understand animals, but rather to develop new models of memory that match up with the types of memory impaired in human diseases such as Alzheimer’s disease.”
Until now, most preclinical studies about potential new Alzheimer’s drugs have focused on how these compounds affect spatial memory, one of the easiest types of memory to assess in animals. However, the loss of spatial memory does not cause the most debilitating effects of Alzheimer’s disease. While scientists knew that rats could remember multiple unique episodes, they did not know whether they could replay a string of events in order. The IU researchers needed to create a paradigm shift.
As the study’s first author, Danielle Panoz-Brown, explained, “If your grandmother is suffering from Alzheimer’s, one of the most heartbreaking aspects of the disease is that she can’t remember what you told her about what’s happening in your life the last time you saw her. We’re interested in episodic memory—and episodic memory replay—because it declines in Alzheimer’s disease, and in aging in general.”
Episodic memory, which is different from spatial memory, is the ability to recall specific events in the correct order. An example is losing something and not being able to recall when, which is why people with memory impairment misplace things. For people to remember where they lost his car keys, they would have to mentally retrace their steps from “episode” to “episode.” If they are unable to recall each episode or place the episodes in chronological order, they would be very confused and still without their keys.
According to the article, “Vivid episodic memories in people have been characterized as the replay of multiple unique events in sequential order. The hippocampus plays a critical role in episodic memories in both people and rodents. Although rats remember multiple unique episodes, it is currently unknown if animals ‘replay’ episodic memories. Therefore, we developed an animal model of episodic memory replay.”
To do that, Crystal’s lab spent nearly a year working with 13 rats, which they trained to memorize a list of up to 12 different odors. The rats were placed inside an “arena” with different odors and rewarded when they identified the second-to-last odor or fourth-to-last odor in the list.
The team changed the number of odors in the list before each test to confirm that the rats were identifying the odors based on their position in the list, not by scent alone, to prove that the animals were relying on their ability to recall the whole list in order. Arenas with different patterns were used to communicate to the rats which of the two options was sought.
After the rats were trained, they successfully completed their task about 87 percent of the time across all trials. The results are strong evidence the animals were using episodic memory replay.
Further experiments confirmed that the rats’ memories were long-lasting and resistant to “interference” from other memories, both characteristics of episodic memory. The researchers also ran tests that temporarily suppressed activity in the hippocampus—the site of episodic memory—to confirm that the rats were using this part of their brain to perform their tasks.
As Crystal said, “Here, we show that rats can remember a trial-unique stream of multiple episodes and the order in which these events occurred by engaging hippocampal-dependent episodic memory replay. We document that rats rely on episodic memory replay to remember the order of events rather than relying on non-episodic memories. Replay of episodic memories survives a long retention-interval challenge and interference from the memory of other events, which documents that replay is part of long-term episodic memory.”
The need to find reliable ways to test episodic memory replay in rats is urgent, because new genetic tools are enabling scientists to create rats with neurological conditions similar to Alzheimer’s disease, according to Crystal. Until recently, only mice were available with the genetic modifications needed to study the effect of new drugs on these symptoms.
“We’re really trying push the boundaries of animal models of memory to something that’s increasingly similar to how these memories work in people,” he said. “If we want to eliminate Alzheimer’s disease, we really need to make sure we’re trying to protect the right type of memory.”