Ultra-Sensitive Monitoring System Provides New Insights into Entorhinal Cortex

UCLA researchers have for the first time measured the activity of a brain region known to be involved in learning, memory and Alzheimer's disease during sleep. They discovered that this region, called the entorhinal cortex, behaves as if it's remembering something, even during anesthesia–induced sleep — a finding that counters conventional theories about sleep-time memory consolidation.

The research team simultaneously measured the activity of single neurons from multiple parts of the brain that are involved in memory formation. The technique allowed them to determine which brain region was activating other areas and how that activation was spreading, said the study's senior author, Mayank R. Mehta, a professor of neurophysics in UCLA's departments of neurology, neurobiology, and physics and astronomy.

In particular, Mehta and his team looked at three connected brain regions in mice — the neocortex, or "new brain," the newest part of the cerebral cortex to evolve; the hippocampus, or "old brain"; and the entorhinal cortex, an intermediate brain that connects the new and the old brains.

While previous studies have suggested that the dialogue between the old and the new brain during sleep was critical for memory formation, researchers had not investigated the contribution of the entorhinal cortex to this conversation, which turned out to be a game-changer, Mehta said.

Mehta's team found that the entorhinal cortex showed what is called persistent activity, which is thought to mediate working memory during waking life — for example, when people pay close attention to remember things temporarily, such as recalling a phone number or following directions.

"The big surprise here is that this kind of persistent activity is happening during sleep, pretty much all the time," Mehta said. "These results are entirely novel and surprising. In fact, this working memory–like persistent activity occurred in the entorhinal cortex even under anesthesia."

The study appears Oct. 7 in the early online edition of the journal Nature Neuroscience.

The findings are important, Mehta said, because humans spend one-third of their lives sleeping, and a lack of sleep results in adverse effects on health, as well as learning and memory problems.

It had been shown previously that the neocortex and the hippocampus "talk" to each other during sleep, and it is believed that this conversation plays a critical role in memory consolidation, the establishing of memories. However, no one had been able to interpret the conversation.

"When you go to sleep, you can make the room dark and quiet, and although there is no sensory input, the brain is still very active," Mehta said. "We wanted to know why this was happening and what different parts of the brain were saying to each other."

Mehta and his team developed an extremely sensitive monitoring system that allowed them to follow the activities of neurons from each of the three targeted portions of the brain simultaneously, down to the activity of a single neuron. This allowed them to decipher the precise communications, even when the neurons were seemingly quiet. They then developed a sophisticated mathematical analysis to decipher the complex conversation.

During sleep, the neocortex goes into a slow wave pattern for about 90 percent of the time. And during this period, its activity slowly fluctuates between active and inactive states about once every second.

Mehta and his team focused on the entorhinal cortex, which has many parts. The outer part mirrored the neocortical activity. However, the inner part behaved differently. When the neocortex became inactive, the neurons in the inner entorhinal cortex persisted in the active state, as if they were remembering something the neocortex had recently "said," a phenomenon known as spontaneous persistent activity.

Further, they found that when the inner part of the entorhinal cortex became spontaneously persistent, it prompted the hippocampus neurons to become very active. On the other hand, when the neocortex was active, the hippocampus became quieter. This data provided a clear interpretation of the conversation.

"During sleep, the three parts of the brain are talking to each other in a very complex way," he said. "The entorhinal neurons showed persistent activity, behaving as if they were remembering something — even under anesthesia, when the mice could not feel or smell or hear anything. Remarkably, this persistent activity sometimes lasted for more than a minute, a huge time-scale in brain activity, which generally changes on a scale of one-thousandth of a second."

The findings challenge current theories of brain communication during sleep, in which the hippocampus is thought to talk to, or drive, the neocortex. Mehta's findings instead indicate that the entorhinal cortex is the third key actor in this complex dialogue and that the neocortex is driving the entorhinal cortex, which in turn behaves as if it is remembering something. That, in turn, drives the hippocampus, while other activity patterns shut it down.

"This is a whole new way of thinking about memory consolidation theory," Mehta said. "We found there is a new player involved in this process and it's having an enormous impact. And what that third player is doing is being driven by the neocortex, not the hippocampus. This suggests that whatever is happening during sleep is not happening the way we thought it was. There are more players involved, so the dialogue is far more complex, and the direction of the communication is the opposite of what was thought."

Mehta theorizes that this process occurs during sleep as a way to unclutter memories and delete information that was processed during the day but is irrelevant. This results in the important memories becoming more salient and readily accessible. Notably, Alzheimer's disease starts in the entorhinal cortex, and Alzheimer's patients suffer from impaired sleep, so Mehta's findings may have implications in that area.