Researchers at the University of Chicago have uncovered new rules governing how synapses in the brain change during memory formation, challenging traditional views of synaptic plasticity. The study, published in Nature Neuroscience, suggests that the brain’s memory processes are far more dynamic than previously thought, with neuronal activity continually evolving even after an experience becomes familiar.
Synaptic plasticity—the strengthening or weakening of connections between neurons—has long been thought to follow the rule that “neurons that fire together, wire together.” This principle, known as Hebbian Spike Timing-Dependent Plasticity (STDP), suggests that the more two neurons fire simultaneously, the stronger their connection becomes. However, the new research shows that another mechanism, called Behavioral Timescale Synaptic Plasticity (BTSP), plays a more significant role in shaping how memories are encoded in the hippocampus, a brain region critical for memory.
Dynamic Changes in Place Cells
The study focused on “place cells,” neurons in the hippocampus that activate when an animal is in a specific location, creating a cognitive map of its environment. These cells were first discovered in the 1970s, earning the researchers the 2014 Nobel Prize in Medicine. However, the new research reveals that place cell activity is not static, even in familiar environments. Instead, the patterns of activity continue to change over time, suggesting that synaptic plasticity is constantly reshaping how memories are stored.
“When you enter a room, it’s new at first, but it quickly becomes familiar. You might expect that the neuronal activity representing that room would stabilize, but it doesn’t—it keeps changing,” said Mark Sheffield, PhD, Associate Professor of Neurobiology at the University of Chicago and senior author of the study.
To understand these changes, Antoine Madar, PhD, a postdoctoral researcher in Sheffield’s lab, analyzed place cell activity in mice as they navigated familiar and unfamiliar environments. Surprisingly, the activity patterns were slightly different each time the mice returned to the same location. Madar then developed a computational model to test different plasticity rules and found that BTSP, rather than the traditional STDP rule, best explained the observed changes in place cell activity.
A New Rule for Synaptic Plasticity
BTSP is a relatively recent discovery, and the study provides new insights into how it works. Unlike STDP, which only explains gradual changes in synaptic strength, BTSP can account for both subtle and dramatic shifts in place cell activity. The researchers found that BTSP is triggered by large, infrequent jumps in calcium levels within neurons, which occur more often during learning and memory formation.
“Our study shows that BTSP is more impactful than STDP in shaping hippocampal activity during familiarization,” Madar said. “This helps explain the diversity of place cell dynamics we observed.”
Encoding the Entire Experience
While the study highlights the dynamic nature of hippocampal activity, the purpose of these shifting representations remains unclear. One possibility is that they help the brain distinguish between similar memories that occur in the same place but at different times. This process could be crucial for avoiding memory confusion, a symptom seen in many neurological and cognitive disorders.
“Every time you return to a room, it’s a different day, a different time, and perhaps a different experience,” Sheffield said. “The brain somehow tracks these subtle changes, encoding not just the environment but the entire experience—like having coffee one time and lunch another. These dynamics in-memory representations might be encoding those slight differences.”
The findings open new avenues for understanding how the brain forms and stores memories, with potential implications for treating memory-related disorders. Future research will explore how these dynamic processes contribute to learning and memory in more complex scenarios.
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