How the brain decides which memories belong together could reshape schizophrenia research

 

Our memories of past events are typically not isolated, but they are linked to other related memories. This ability to establish connections between related memories is highly advantageous, as it helps us to recognize familiar patterns in new situations and make predictions that can inform our decisions.

Researchers at UCLA's Brain Research Institute recently carried out a study on mice aimed at better understanding how the brain decides what memories are connected and which ones are not. Their paper, published in Nature Neuroscience, pinpoints brain regions that could play a role in the organization of memories into coherent pools of knowledge.

"Our lab has long been interested in understanding how the brain connects related memories," André F. de Sousa, first author of the paper, told Medical Xpress. "In everyday life, new experiences are rarely processed in isolation. Instead, they are often shaped by what we have learned before. This ability allows us to link related events, build knowledge, and use past experiences to guide future behavior. However, this process needs to be carefully controlled."

While establishing connections between memories is very advantageous, in some cases it can be unhelpful or even detrimental. For instance, patients diagnosed with schizophrenia or some other psychiatric disorders can sometimes form false associations between experiences that are not actually related. Understanding how the brain establishes connections between memories could be highly valuable, as it could also shed light on how false or unhelpful connections are established.

Studying the mouse brain during behavioral tasks

The primary goal of the team's study was to identify brain circuits involved in the linking of memories. To do this, they carried out experiments involving adult mice that were completing a behavioral task.

"The mice explored two different environments," explained de Sousa. "If the two experiences happen close together in time, about 5 hours apart, the mice tend to link those memories. If the experiences happen much farther apart, about 7 days apart, the memories usually remain separate. However, if the two environments are very similar, the mice can still link them even after 7 days."

To understand what was happening in the mice's brain while they were linking memories together, the researchers used tiny microscopes developed at UCLA, called Miniscopes. Miniscopes allow researchers to monitor the activity of individual neurons while mice are exploring different environments.

"This allowed us to identify which neurons were active during the formation of each memory," said de Sousa. "We combined this approach with tools that allowed us to turn specific brain regions or pathways on and off, including optogenetics, chemogenetics, and viral approaches."

The data collected by de Sousa and his colleagues suggest that projections from the prefrontal cortex help to control what neurons in the hippocampus will be encoding a new experience. Interestingly, the selection of these neurons appeared to be influenced by the animals' earlier memories.

"These mechanisms determine whether two memories will become linked or remain separate, which directly affects the mice's behaviors," explained de Sousa. "Overall, our findings suggest that memory integration emerges from communication between multiple brain regions. We identified a pathway through which prior memories can influence how new experiences are encoded in the brain. This has been a major question in memory research for many years, but the specific circuit mechanisms involved were still not well understood."

Informing future research focusing on psychiatric disorders

The results of the team's experiments suggest that the linking of memories is mediated by the prefrontal cortex, which selects hippocampal neurons that will encode new experiences. This mechanism appears to ultimately determine what memories will become connected and which will be encoded as unrelated.

"In this way, the circuit acts as a control mechanism that helps organize memories without allowing different events to become inappropriately linked," explained de Sousa. "These findings may have important implications for understanding psychiatric disorders, such as schizophrenia, as well as age-associated cognitive decline, where memory organization and the ability to distinguish between related, but distinct experiences, are often disrupted."

In the future, the work by de Sousa and his colleagues could lead to the identification of circuits that contribute to the formation of unhelpful or unrelated memory connections in schizophrenia or other mental health disorders. As part of their next studies, the researchers plan to dive deeper into how the prefrontal cortex and hippocampus interact to organize memories and guide behavior.

"The prefrontal cortex is involved in several important cognitive functions, including working memory, long-term memory storage, and decision making," added de Sousa.

"We are interested in understanding how these functions interact to influence the way the hippocampus processes new experiences. More broadly, we want to understand how the prefrontal cortex uses prior knowledge and ongoing cognitive demands to influence hippocampal processing. This could help elucidate how the brain integrates different cognitive processes to guide memory formation, and how these interactions may become disrupted in aging or disease."