How do you find a brain cell nobody knew existed?

Researchers investigating the source of spatial signals in the hippocampus studied the entorhinal cortex and discovered neurons with multiple firing fields arranged in a regular hexagonal pattern, which they named grid cells. This unexpected finding, confirmed through experiments in larger environments, revealed a new type of spatially tuned neuron crucial for understanding navigation and memory.

The discovery of grid cells stemmed from a fundamental question about the origin of place cells, which were first identified by O’Keefe in 1971. Place cells are neurons in the hippocampus that activate when an animal is in a specific location, but the source of their spatial signal was unknown. This curiosity motivated researchers to investigate the brain region that provides input to the hippocampus, known as the entorhinal cortex, which at the time was largely unexplored.

The entorhinal cortex was a challenging area to study due to its inaccessibility and the lack of prior research. Guided by anatomical knowledge, the researchers strategically placed electrodes in this region to record neural activity. Their initial expectation was to find some form of spatially responsive cells, but they did not anticipate discovering any cells with periodic firing patterns.

Experiments were conducted in rats, and the recordings revealed cells with multiple firing fields rather than a single one, which was typical of place cells. These multiple firing fields appeared in a highly regular pattern, which was initially puzzling. Early tests were done in relatively small environments, making it difficult to fully appreciate the periodic nature of the firing fields.

To better understand the phenomenon, the researchers expanded the experimental environment to a much larger space—a two-meter-wide circular arena. In this larger setting, the firing fields of these cells aligned in a strikingly regular hexagonal lattice pattern. This clear geometric arrangement confirmed the existence of a new type of spatially tuned neuron, which they named grid cells.

Despite the compelling evidence, the researchers initially doubted their findings, suspecting the regular pattern might be an artifact. However, further experimentation and analysis validated the discovery. This breakthrough provided crucial insights into how the brain encodes spatial information and opened new avenues for understanding navigation and memory.