Early changes in Alzheimer’s disease appear in the lateral entorhinal cortex, specifically in its layer II neurons. These neurons are among the first sites of anatomical and cellular changes in the disease and may underlie the earliest memory impairments. However, the functional role of the lateral entorhinal cortex has for a long time been unclear. In contrast, its neighboring region – the medial entorhinal cortex – has been well studied and is known to contain different functional types of neurons that are involved in spatial navigation. Although the medial entorhinal cortex is also affected by pathological changes in early disease-stages, evidence suggests that this occurs after the lateral entorhinal involvement.

Recent findings from the Moser group at KISN have revealed that lateral entorhinal neurons encode episodic time – the order and timing of events in our experiences (Tsao et al., Nature, 2018; Kanter et al., Science, 2025). This discovery provides a critical link between lateral entorhinal function and memory processes, opening new possibilities for understanding how early cognitive decline in Alzheimer’s disease develops.

Building on the discovery of episodic time encoding in the lateral entorhinal cortex in rodents, we shall in work package 1 investigate mechanisms of time-correlated drift in neural activity, and whether this is caused by external sensory or behavioral stimuli, or by internal brain processes. We will also examine how major changes in context and experience (like moving to a new environment) cause drift segmentations and identify neural activity patterns that underly these jumps in the drift pattern. Finally, we will compare how animals estimate time during an experience (prospective) versus after it (retrospective). To do this, we are designing animal tests to measure retrospective time estimates and link them to lateral entorhinal activity patterns. These behavioral tests will mirror those planned for human studies in work package 3.