CAREER: A multiple memory systems approach to understand interval timing

University Of Utah, Salt Lake City UT

Investigators

Abstract

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Many functions of the nervous system such as learning and memory, inferring cause and effect, and predicting future outcomes depend upon the brain’s ability to perceive and form memories of the duration of events. Despite progress in establishing the neural basis of timing on the scale of milliseconds and circadian timing over hours, many fundamental questions remain about time encoding on the intermediate scale of interval timing (i.e. second to tens of minutes). To investigate how interval time is represented in the brain we will develop a novel behavioral paradigm that will be used in concert with imaging methods we have developed to monitor and manipulate thousands of brain cells in medial entorhinal cortex. This work will provide a basis for understanding how the brain performs complex functions that depend upon encoding of time on the scale of seconds to minutes. The research also has the potential to guide our understanding of disease and provide targeted therapies for several prevalent neurodegenerative diseases and psychiatric disorders. Furthermore, this grant will support broader impacts through a science-communication workshop that is designed to support senior-level neuroscience graduate students, with a strong emphasis on supporting students from under-represented backgrounds. This proposal will address fundamental questions regarding the neural circuit mechanisms underlying interval timing. Prior work suggests that medial entorhinal cortex (MEC) could play a selective role only during the initial learning phase of interval timing behavior. However, an intriguing hypothesis is that MEC might be necessary for interval timing before and/or after learning, depending on whether the particular timing behavior is amendable to striatal-based procedural learning, rather than playing selective role only during the initial learning phase of interval timing behavior. In this view, timing behavior that require temporal information to be flexibly represented or rapidly learned might continuously require MEC. On the other hand, simple timing behaviors with task parameters that remain constant might only require MEC during initial learning and could be solved later on through brain circuits that serve procedural learning, such as the dorsal striatum. This proposal will apply a novel interval timing paradigm to test the hypothesis that MEC is necessary for interval timing before and/or after learning, depending on the constraints imposed by the particular timing behavior to be learned. In order to test this hypothesis we will leverage several methodological approaches that we have recently developed for large-scale cellular resolution functional imaging in MEC in behaving mice. By combining these methods with a series of causal neural manipulations we will determine which brain circuits are differentially involved in interval timing behavior across tasks that require rapid, flexible timing versus static, repetitive timing. Further, we will determine the neural dynamics in MEC that underlie learning of rapid, flexible timing behavior. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.