The human brain’s ability to navigate – both physical spaces and abstract concepts – relies on a complex interplay between the entorhinal cortex (EC) and the hippocampus (HPC). For decades, researchers have understood the hippocampus as a crucial component of the brain’s “cognitive map,” a mental representation of spatial relationships. Now, a growing body of evidence suggests that the EC doesn’t just *provide* data to this map, but actively structures it, potentially using a grid-like system to organize information in a surprisingly versatile way.
The discovery of place cells in the hippocampus in 1971 provided the initial foundation for the cognitive map theory. These cells fire when an animal (or human) is in a specific location. Later, in 2005, grid cells were identified in the entorhinal cortex. These cells exhibit a unique hexagonal firing pattern, creating a kind of internal coordinate system for space. This hexagonal pattern isn’t limited to physical navigation; recent research indicates grid cells also represent conceptual spaces, suggesting a fundamental organizing principle for knowledge beyond just where things *are*, but how they relate to each other.
But how does this grid-based system translate into the ability to plan routes, imagine future scenarios, or retrieve memories? Researchers have observed “vector navigation” – the ability to navigate directly to a goal even across previously unexplored terrain – suggesting an internal representation of space that goes beyond simply remembering locations. Studies in bats and rats have identified neurons in the hippocampus that encode both direction and distance to a goal, rapidly reorganizing when the goal changes. Similar activity has been observed in human brain scans when subjects are learning goal-directed navigation.
A recent study, published in in eLife, builds on this understanding. Researchers hypothesized that projections from EC grid cell populations provide a coherent framework within the hippocampus, embedding a threefold periodic structure across spatial directions to support the representation of potential pathways. The core idea is that the consistent, hexagonal firing patterns of grid cells could be leveraged to create vector-like representations of movement. A straight pathway aligned with a grid orientation would activate a specific sequence of grid cells, creating a clear signal. However, the inherent 180-degree rotational symmetry of the hexagonal grid presents a challenge: orientations separated by 180 degrees appear indistinguishable, potentially limiting the uniqueness of these representations.
To address this, the researchers propose that the brain utilizes a threefold periodicity, aligning with the three principal axes of the grid. This would effectively triple the number of distinguishable pathways. Supporting this hypothesis is evidence from anatomical studies showing the EC as a major input source to the hippocampus, and functional studies demonstrating that grid cells encode not only position but also direction and speed. Computational models further suggest that grid cells are fundamental to the formation of hippocampal place fields, integrating information from multiple grid modules.
The study employed functional magnetic resonance imaging (fMRI) to investigate this periodicity in the human brain. Participants were presented with a novel 3D object, dubbed a “Greeble,” and asked to mentally manipulate its features to match a target prototype. This process created a conceptual space where locations were defined by variations in the Greeble’s characteristics. By analyzing brain activity during this task, researchers observed a threefold periodicity in hippocampal activity, phase-locked with the sixfold periodicity already established in the entorhinal cortex. Importantly, this periodicity wasn’t just observed in brain activity; it also manifested in participants’ behavioral performance, suggesting a direct link between the neural representation and cognitive processing.
The researchers also utilized a computational model, the EC–HPC PhaseSync model, to simulate the projections from the EC to the HPC. This model successfully reproduced the observed threefold activity periodicity, further supporting the hypothesis that the EC’s grid cell activity drives the organization of spatial and conceptual information within the hippocampus. The findings suggest that the brain leverages the periodic structure of grid cell activity to create a robust and flexible cognitive map, enabling efficient navigation and decision-making in both physical and mental spaces.
This research offers important insights into how the brain represents and processes information. The replication of hexagonal symmetry in the entorhinal cortex, coupled with the discovery of a novel threefold symmetry in both behavior and hippocampal signals, provides compelling evidence for a periodic mechanism through which the entorhinal cortex structures hippocampal vector representations. While simultaneous recordings from both the EC and HPC remain technically challenging, the use of fMRI and computational modeling provides a powerful approach to unraveling the complexities of this crucial brain circuit.
