Michael Yassa, PhD
Professor, Chancellor’s Fellow
Department of Neurobiology and Behavior
University of California, Irvine
October 2, 2018
Dissecting Episodic Memory Computation
When was the last time you lost your keys? That one time you didn’t put them down in their usual spot, and they’ve vanished into thin air. Why does your memory do that to you? Using memory tasks and brain imaging, Dr. Yazza and his lab have identified differences in pattern separation in younger and older participants. (And what is a pattern? Leaving your keys in the same spatial location every day!) Older participants in their studies had a harder time discriminating between similar memories and showed differences in brain activity in pathways related to memory. They hope that their discoveries will aid in treatment for older adults displaying cognitive/memory impairments.
The brain is the ultimate learning machine. How does a three-pound mass of jelly store incredible amounts of information with relative ease and use this information to promote survival? The mechanisms of learning and memory and how they change with age and disease have been studied for hundreds of years and have captured the imagination of scientists and philosophers alike. With the advent of modern neuroscience tools, however, we now peer into the brain and understand the computations and processes that allow for this feat to occur. Work in my research group has been able to isolate and study memory computations and processes that are critical for episodic memory - memory for events and experiences. We use high-resolution functional brain imaging to probe the mechanisms used by the brain to distinguish among very similar memories, such as where you parked your car today vs. yesterday. This is a process known as pattern separation. Our studies have identified how this process occurs in the brain’s memory systems and developed cognitive tests to challenge the brain to perform this computation. Our work has also shown that information flowing into this memory system is divided into several parallel pathways. We have studied two of these pathways in detail and recognize now that one pathway (the lateral entorhinal and perirhinal pathway) carries information about individual items and objects in an experience, whereas another pathway (the medial entorhinal and parahippocampal pathway) carries information about spatial location. The hippocampus serves as a hub that combines those two inputs and creates a much more holistic representation of the experience.
Extending the knowledge gained from our techniques to understanding the aging brain, we quickly realized that a major facet of age-related memory loss is due to failures in pattern separation. We first tested young and older adults in mnemonic discrimination tasks that involve discriminating among very similar memories, observing a clear age-related deficit. We then used several highresolution imaging methods, including functional MRI (quantifying blood flow signals to active regions in the brain) structural MRI (quantifying volume and thickness of different regions) and diffusion MRI (quantifying connectivity along the white matter - the highways of communication in the brain). We showed that several alterations to the brain conspire to worsen memory as we get older. One of those alterations is a notable hyperactivity in the hippocampal region, which we demonstrated was a pathological condition. Our attempts to reverse this hyperactivity with a mild dose of antiepileptics was successful and we were able to enhance memory in patients with mild cognitive impairment - a possible early stage of Alzheimer’s disease. We additionally show that other interventions such as physical activity and caffeine intake can also enhance memory acutely. While we are still at the beginning stages of achieving a comprehensive understanding of memory systems and processes, much progress has been made. Will this work lead to better approaches to treating age-related cognitive decline, and, perhaps more importantly, will it lead to improved therapeutics for Alzheimer’s disease? We certainly hope so.