Pinpointing the 'oops' moment in the brain

Mice running mazes sometimes go left when they should go right. Now MIT’s Picower Institute for Learning and Memory researchers have found a certain pattern of brain waves that pinpoints the precise moment when rodents choose the correct path in a maze — as well as when they noticed their errors. They also discovered that these brain waves are delayed when the animals changed their minds and corrected their paths.

In humans and animals, rhythmic electrical oscillations — produced by millions of neurons firing in sync — are thought to play a role in memory formation and retrieval. But for the first time, Picower Institute neuroscientists linked a specific synchronized oscillation pattern with its correlating behavior.

The work, described in the April 24 online version of Cell, may lead to new therapies for patients suffering from Alzheimer’s disease and other memory impairments. Moreover, the results indicate that the trained mice in the study recognized and reversed their “oops moments," raising tantalizing questions about the extent to which animals can analyze and control their own cognitive processes.

Synchronized waves

Brain waves oscillate in different frequencies depending on state of mind: alpha waves correspond with being awake but relaxed; delta waves accompany deep, dreamless sleep. When we are focused attentively on a task, faster theta and gamma rhythms dominate. “Theta rhythms are very strong in the rodent hippocampus and a part of the cortex that functions as a network hub for memory and navigation,” says co-author Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and director of the RIKEN-MIT Center for Neural Circuit Genetics. “These waves are believed to be vital to the induction of long-term potentiation, a cellular mechanism of learning and memory.”

With Tonegawa, Picower Institute research scientists Jun Yamamoto and Junghyup Suh and postdoc fellow Daigo Takeuchi found that two areas of the brain — both critical for learning and memory and among the first to deteriorate in Alzheimer’s patients — communicate in high-frequency gamma synchronization at the moment when a working memory is used to make a decision.

Two distinct gamma oscillations — at higher and lower frequencies­ — are synced to a specific phase of theta oscillation, and this coupling of theta and gamma activity is thought to be crucial for cementing long-term memories of specific experiences or events. While the mechanisms underlying high-gamma activity and its unique response properties in humans are largely unknown, the MIT researchers’ work indicates it also may be key in short-term memory.

The hippocampus, a seahorse-shaped brain structure, plays an important role in storing and retrieving memories. Electrical and chemical signals flow through its CA3 and CA1 regions in a looping pathway. There is another pathway where information directly comes from entorhinal cortex layer III (EC3) to CA1. “We think that gamma oscillations may be a physiological mechanism by which EC3 output can coordinate CA1 activity to support retrieval of hippocampus-dependent memories at critical moments,” Yamamoto says.

While previous studies point to brain oscillations as a timing mechanism that helps drive the serial processing of short-term memories, “this is the first time that a brief moment of high gamma frequency oscillation synchrony has been closely linked to the execution of correct working memory, which is known to rely on explicit awareness of memory content,” Tonegawa says. “We speculate that the high gamma synchrony contributes to this kind of mental awareness.”

“This finding helps us understand how we maintain and use working memory in our daily lives and may lead to a novel therapeutic way to alleviate the cognitive symptoms of Alzheimer's disease patients,” Yamamoto says.

An “oops” moment

Using cutting-edge techniques, the researchers studied the real-time brain activity of rodents running a T-shaped maze. At the precise moment that the animals opted for the correct path, “we were amazed to record a single burst of synchronized high-frequency gamma oscillations,” Yamamoto says.

The study became even more intriguing when the researchers analyzed data from instances the animals started down the wrong fork of the maze and then quickly turned around to correct their mistake. “In these so-called ‘oops’ trials, we observed that the same synchronized high-frequency gamma oscillations, in a delayed manner, shifted to just before the mice turned around to go in the right direction,” Yamamoto says. “This was surprising because it showed the exact moment when the animals became aware of their mistake and corrected it.”

“Our findings may provide evidence that animals employ a behavior-monitoring process called metacognition, a form of higher-order thinking that involves ‘knowing about knowing,’” he says.

This work was supported by the RIKEN Brain Science Institute, the Picower Institute Innovation Fund and the Human Frontier Science Program.