Place cells are neurons in the brain’s memory center, the hippocampus, that help the brain keep track of the body’s location in space. Arrays of these cells form a cognitive map, firing off electrical signals when the body is in a particular location in its environment. These cells walk a delicate functional tightrope. They have to remain stable so that the brain remembers when the body has re-entered a familiar location, and they have to be ready to adapt as the environment around the body changes. How these cells achieve this balance has, until now, remained a mystery to neuroscientists.
Now, in a new study published in Science, researchers led by Jayeeta Basu, a neuroscientist at New York University, showed how place cells in the hippocampus use a combination of signals from another brain region called the entorhinal cortex to maintain stability of existing information while incorporating new learning.1 The findings answer key questions about how human memory works and may lead to a better understanding of memory and learning disorders.
“Our study, by focusing on the stability of hippocampal representations, fills in a substantial gap in the understanding of how long-range inputs control neuronal circuits essential for memory recall,” said Basu in a press release.
Building a Picture of Recall in the Brain
To study how place cells are made and maintained, the team looked at the CA3 region of the hippocampus, which is home to a rich population of place cell neurons. These cells receive a range of electrical signals from the lateral entorhinal cortex (LEC).
The LEC is a waystation between the neocortex and the hippocampus. The neocortex blasts the LEC with sensory information about the world around us. The LEC organizes this and sends the hippocampus an ordered output it can understand. The information is relayed through long neuronal connections, called projections.
In mice, researchers looked at two types of projections from the LEC to the hippocampus. Glutamatergic projections usually carry signals that excite and stimulate the neurons they connect to. Gamma-aminobutyric acid (GABA)ergic projections normally dial activity down.
To examine these projections, the team used a pair of techniques in their study: patch-clamp electrophysiology to measure current in the cells and optogenetics to isolate activity in the two different types of neuronal projections. The team found that the glutamatergic and GABAergic projections worked in tandem, like a DJ deftly balancing competing song tempos, to fine-tune the rate of neuronal activity in the CA3.
The researchers found that glutamatergic projections excited some place cells but also activated other neurons that broadcast stop signals to prevent overactivation. GABAergic projections turned down the activity of these stop signals. The two contrasting inputs, working together, helped the CA3 place cells achieve a stable firing pattern that firmed up existing cognitive maps while learning new information.
Brain Signaling is Key for Learning, But Not Recall
To see how these projections affected the mice’s memories, the researchers had the mice run on special textured treadmills with specific reward zones. When the researchers shut off either the glutamatergic or GABAergic projections, the mice found it harder to locate the reward zones.
If the projections were shut down after the mice had previously learned where the zones were, they had no problem locating them again. This, said the authors, shows that LEC-CA3 connections are key for encoding memories, but not for recalling them.
In sum, the findings explain how the brain learns about our environment at the cellular level. The researchers said they hope their work on how these in-brain maps form could have applications in treating conditions where memory and learning are disrupted. Previous work from Basu’s team showed that disruption to connections between the LEC and another region of the hippocampus, called CA1, caused learning problems and mismatched fear responses to neutral conditions that resemble post-traumatic stress disorder in humans.2
“A better understanding of circuits supporting place maps may guide the future design of more precise treatments for conditions that affect memory,” said Basu.
- Robert, V et al. Cortical glutamatergic and GABAergic inputs support learning-driven hippocampal stability. Science. 2025.
- Basu, J et al. Gating of hippocampal activity, plasticity and memory by entorhinal cortex long-range inhibition. Science. 2016;351(6269):aaa5694.
