An Integrated Circuit Model for Temporal Coding in Lateral and Medial Entorhinal Cortex

/Abstract Interval timing, the ability to estimate event durations on the scale of seconds to minutes, is crucial for adaptive behaviors. Prior work investigating the neural basis of interval timing has focused on brain circuits in the basal ganglia and frontal and parietal cortices. However, recent research, including our own, indicates that the entorhinal cortex (EC) also plays a key role in the learning of timing behavior. In our recent work, we have discovered "time cells" in the medial entorhinal cortex (MEC) that fire at fixed intervals, forming sequences crucial for timing behavior. In contrast, lateral entorhinal cortex (LEC) neurons exhibit ramping activity over seconds to minutes as animals forage and/or perform spatial navigation tasks. This suggests distinct neural dynamics in the LEC and MEC for encoding elapsed time, hinting at different roles in timing behavior. A major limitation of this interpretation is that all LEC recordings to date have been from animals not engaged in active timing tasks, making it impossible to determine whether these neural correlates of ramping activity are actually involved in timing behavior or are simply a result of other task demands. To determine the functional roles of LEC and MEC in timing behavior, it is necessary to use tasks with explicit timing demands. Using a novel behavioral paradigm in which mice are trained to report non-matching stimuli durations, combined with neural recording and manipulation techniques, this proposal tests a model in which LEC and MEC function together to encode elapsed time and drive interval timing behavior. Specifically, we hypothesize that LEC encodes event boundaries through brief phasic activity, which then helps align sequential dynamics in MEC to these salient moments. In Aim 1, we will determine if LEC activity is necessary to align MEC time cell sequences and whether LEC activity is essential for learning timing behavior. In Aim 2, we will examine neural dynamics simultaneously in LEC and MEC during timing behavior to see if they function independently or in an integrated manner. Since interval timing is a fundamental component of nearly all major brain functions, understanding the cellular and circuit mechanisms of interval timing will provide a basis for understanding how the brain performs complex functions that depend on encoding time on the scale of seconds to minutes. This work also has the potential to guide the development of therapies targeting specific neural mechanisms in a wide range of diseases and psychiatric disorders that display altered temporal processing, including Alzheimer’s Disease, Parkinson’s Disease, and Schizophrenia. Project Number: 1R21MH140161-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: JAMES HEYS | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $423,500 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 ICN-N (92)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288262