UC Irvine researchers discover the neurons responsible for “item memory”

Researchers from the University of California, Irvine, have discovered the neurons responsible for ‘item memory’, which will deepen our understanding of how the brain stores and retrieves the details of ‘what’ happened, and provide a new target for the treatment of Alzheimer’s disease.

Memories include three types of details: spatial, temporal and item, the ‘where, when and what’ of an event. Creating it is a complex process that involves storing information based on the meanings and outcomes of different experiences, and forms the basis of our ability to remember and narrate them.

The study, published online today in the journal Nature, is the first to reveal the role of specific cells in how the brain classifies and remembers new information, especially when linked to rewards or punishments.

Understanding this process is critical because it deepens our understanding of the fundamental way our brains function, especially in the areas of learning and memory. Our findings shed light on the complex neural circuits that allow us to learn from our experiences and store these memories in a structured way.”

Kei Igarashi, corresponding author, Chancellor’s Fellow and Associate Professor of Anatomy and Neurobiology

Researchers studied mouse brains, focusing on the deeper layers of the lateral entorhinal cortex, where they discovered specialized, item-outcome neurons that are essential for learning. Odors are crucial sensory cues for item memory in mice. Some neurons became active when exposed to the smell of banana associated with a sucrose water reward. Other neurons responded to the smell of pine, associated with a negative outcome of bitter water. In the LEC, a mental map was formed that was divided into these two categories.

Anatomically, neurons in the deep layer LEC are closely connected to neurons in another brain region, the medial prefrontal cortex. Team members noticed that neurons in the mPFC developed a similar mental map during the learning process.

They also found that when the activity of LEC neurons was inhibited, those in the mPFC failed to properly distinguish between positive and negative items, leading to learning deficits. Conversely, when the mPFC neurons were inhibited, the LEC’s ability to keep item memories separate was completely disrupted, impairing learning and item memory recall. These data indicated that the LEC and mPFC are codependent and work together to encode item memory.

“This study is a significant advance in our understanding of how item memory is generated in the brain,” Igarashi said. “This knowledge now opens up new possibilities for researching memory disorders, such as Alzheimer’s disease. Our data suggest that item memory neurons in the LEC lose activity in Alzheimer’s disease. If we can find a way to reactivate these neurons, this could lead to targeted therapeutic interventions.”

The two main authors of this work were graduate students Heechul Jun of the Medical Scientist Training Program and Jason Y. Lee of the Interdepartmental Neuroscience Program. Other team members included research technicians Nicholas R. Bleza and Ayana Ichii, as well as postdoctoral researcher Jordan Donohue of the Kei Igarashi lab. Igarashi is a joint faculty member in the Department of Biomedical Engineering and a member of the Center for Neural Circuit Mapping, the Center for the Neurobiology of Learning and Memory, and the Institute for Memory Impairments and Neurological Disorders.

The study was supported by the National Institutes of Health under awards R01MH121736, R01AG063864, R01AG066806, R01AG086441, F31AG069500, and F31AG074650; Research grant BrightFocus Foundation A2019380S; and UC Irvine Medical Scientist Training Program grant T32GM008620.