Navigational Frames of Reference as Critical Regulators of Hippocampal Interneuron Coding Properties

Efficient spatial navigation relies on the hippocampus integrating local (proximal) and global (distal) cues, collectively called frames of reference, to guide behavior and support memory. Although these cues control the anchoring of principal cell fields, how these frames tune interneuron functions remains unknown. Traditionally, interneurons such as O-LM and VIP cells have been viewed primarily as speed encoders, although some also encode spatial information or respond to discrete stimuli. Using calcium imaging in freely behaving mice performing a new spatial learning task that differentiates between reference frames, we demonstrate that O-LM cells displayed a striking bimodal activity pattern, altering both their speed and spatial encoding properties. In contrast, VIP interneurons were largely unaffected by changes in the frame of reference, instead correlating with familiarization. Notably, linear decoding using speed scores revealed that only O-LM interneurons provide an accurate readout of the dominant reference frame, enabling prediction of the animal’s navigation strategy. These findings highlight that hippocampal interneurons can flexibly adapt their functions depending on cognitive factors such as the reference frames used to guide behavior.