When a person has a new experience, their brain faces a subtle but critical decision: should this experience be categorized with other stored memories, or should it be filed away as its own new memory? Getting it right allows the brain to help people navigate the world. But getting it wrong can cause false associations to form, which is a feature of several psychiatric conditions such as bipolar disorder and schizophrenia.
In a study published in the journal Nature Neuroscience, UCLA Health researchers have now identified the specific brain circuit that may be responsible for making that call.
Researchers at the UCLA Integrative Center for Learning and Memory found that a region of the brain's prefrontal cortex, which is associated with decision-making and long-term memory, plays an active role in controlling how memories are organized in the brain's hippocampus, which is the primary memory storage center. Using mice, they were able to trace the specific pathway through which this memory integration happens.
"We've known for a long time that the prefrontal cortex and hippocampus work together in memory, but how the prefrontal cortex actually controls which memories get linked has been a mystery," said the study's first author André de Sousa, a postdoctoral researcher at UCLA Health. "This study identifies a specific circuit that can bidirectionally regulate that process."
Two key factors determine whether the brain will link two memories together: how similar the experiences are and how far apart in time that they occur. Experiences that happened close together in time, such as within a few hours, tended to be merged in the hippocampus automatically. When experiences were separated by several days, a more deliberate process appeared to take over.
Using mice, the research team found that a brain region called the ventromedial prefrontal cortex, or vmPFC, becomes significantly more active when an animal encounters a new environment several days after a previous one, especially when the two environments are clearly different. That surge in activity, the researchers found, is the brain's way of keeping those memories apart.
The researchers found the vmPFC acts like a quality control checkpoint. After several days, the prefrontal cortex has had enough time to consolidate an earlier memory. When a new experience comes along, it will compare the new experience to that earlier memory. If they are meaningfully different, the vmPFC signals the hippocampus to use a fresh set of neurons to record the new experience, which keeps the memories distinct. When the two experiences are similar, the vmPFC disengages, allowing the hippocampus to encode both memories in many of the same neurons and link them together. If the vmPFC is prevented from doing its job, the hippocampus loses this discriminatory ability and begins to incorrectly merge unrelated memories.
To demonstrate this, the UCLA researchers exposed mice to two distinct environments one week apart. When the mice visited the second environment, the researchers switched off the vmPFC in the mice and the mice behaved as if the two environments were the same. When the mice were given a mild foot shock in the second environment, they showed fear responses when placed in the first environment again despite nothing alarming having happened there.
However, when researchers silenced the vmPFC when mice were exposed to two different environments just five hours apart, nothing changed. The memories were linked regardless. De Sousa said this suggests the vmPFC's role is specifically about managing memory organization across longer time spans, after it has had adequate time to consolidate what came before.
The study also traced the precise pathway the vmPFC uses to exert its influence using a combination of advanced techniques including miniature microscopes mounted on the heads of mice to watch individual neurons fire in real time and switching specific neurons on or off using drugs or light.
They found the signal traveled from the vmPFC to a relay region called the medial entorhinal cortex, which in turn communicates with the hippocampus. When this vmPFC-to-entorhinal pathway is blocked, memories that should stay separate get incorrectly merged. When it was artificially activated, memories that would normally be linked were pushed apart even when the experiences occurred close together in time.
At the end of this pathway, a specific type of inhibitory neuron in the hippocampus called a neurogliaform cell appears to act as the final gatekeeper, regulating which neurons get recruited to store a new memory and which do not.
"What's striking is that this circuit can work in both directions," said de Sousa. "We can make memories merge that shouldn't, or keep separate memories that would otherwise be linked, just by manipulating this one pathway. That tells us this is a fundamental control mechanism."
De Sousa said the findings provide a potential framework for understanding what goes wrong in conditions where memory organization is disrupted. Disorders including schizophrenia, bipolar disorder and certain anxiety disorders are associated with the formation of inappropriate associations and with impaired communication between the prefrontal cortex and hippocampus.
The findings may also have relevance to aging. Memory organization difficulties are a well-documented feature of cognitive decline, and prefrontal-hippocampal communication is known to deteriorate with age.
Further studies are needed to continue investigating how the prefrontal cortex works with the hippocampus to guide appropriate behavior.
"The prefrontal cortex supports several important cognitive functions, including working memory, long-term memory storage, and decision making. We are interested in understanding how it combines these processes with prior knowledge to influence hippocampal activity during memory formation and retrieval," de Sousa said. "This work could help reveal how the brain integrates different cognitive functions to support adaptive behavior, and how these interactions may become disrupted in aging or disease."
