October 1, 2020
How do we remember our past experiences and recall processes we learned long ago? Brain functionality, specifically as it relates to memory storage and recall, is one of the human body's greatest mysteries. Research led by Mark Sheffield, Assistant Professor of Neurobiology at the University of Chicago, offers new information on how memories are created and accessed.
Sheffield's work focuses primarily on the hippocampus, the part of the brain responsible for memory formation and recall. It's also the area of the brain likely responsible for memory disorders such as Alzheimer's disease. By using two-photon microscopy, a fluorescence imaging technique, Sheffield can capture the activity of large groups of neurons deep within the brain, thereby witnessing memory function in process.
"This technique allows us to look at the activity of many neurons at the same time," Sheffield said. "We want to be able to capture a memory as it forms, to see that learning, and then be able to track that memory over time and during recall. We are also interested in which factors influence memories, such as rewarding or fearful experiences."
Sheffield tested this process on mice (which, like humans, rely on the hippocampus for memory function). To do this, the two-photon microscopy process was coupled with a process for observing the activity of neurons in the hippocampus. During the imaging of neurons, mice ran on a treadmill that moved them through an immersive virtual environment that they had been exposed to for an hour a day for the previous 10 days. To motivate mice to traverse this familiar environment many times, a reward was placed at one end of environment which, when obtained, would virtually teleport the mice back to the start point.
Then, unbeknownst to the mice, the reward was taken away. Initially, because the reward was expected to be there, the neurons in their hippocampus did not change their activity. However, after the mice learned not to expect a reward, which took a few traversals of the environment, it triggered a striking change in hippocampal activity.
"We found a huge difference in how the neurons responded," Sheffield said. "Which neurons were active in the environment became different, and they were less reliable and less stable when the reward was no longer expected. What is remarkable to me is that these neurons encode memories of external events, yet they are hugely influenced by our internal expectations."
To test whether reward expectations influenced memory recall, mice were placed back in the same environment on subsequent days and the same neurons were again imaged.
"What we found was that when rewards were expected, the same neurons tended to be reactivated in the environment the next day," Sheffield explained. "Yet, neurons were not reactivated across days when reward was not expected. This provides a biological explanation for why we remember rewarding experiences better than unrewarding ones. It also tells us how much our expectations influence our memories."
Sheffield is currently investigating how inserting a fearful element into the virtual experience affects memory. In this experiment, a novel environment is paired with a random, mild tail negative stimulus or shock. Imaging shows what happens during memory formation when the stimulus occurs, and also details how the neurons respond when the mice return to the same environment where they received the stimulus. As rodents tend to freeze when placed in a fearful environment, the mice's physical responses when reintroduced to the environment will also be an indicator of whether they recall the negative experience in the absence of the stimulus.
"Again, this fear memory recall is dependent on what the animal expects to happen in the environment," Sheffield said. "Mice remember being shocked there, so expect that to happen again, and so freeze. This is a great behavioral readout of memory recall which we take advantage of to try and understand what the neurons are doing during this process."
Another aspect of this experiment involves studying how memory recall is impacted over time when the fearful aspect of the environment is entirely removed.
"If you keep exposing an animal to a fearful environment but without the shock, that fearful response from the animal will eventually be eliminated," Sheffield explained. "We want to track the same neurons throughout fear memory extinction to see how a single memory changes with experience."
Sheffield hopes that the insights learned about memory formation, recall, and extinction will eventually aid in the development of treatments for memory disorders. Learn more about his work on the Sheffield Lab website and @Sheffield_Lab.