CRCNS Research Proposal: Hippocampal microcircuit dynamics inferred from finely-timed spike trains

This project aims to understand how sleep and memory are intertwined in the brain by measuring the changes that occur in synaptic connections between neurons during sleep. Such changes are thought to be the fundamental processes underlying the solidification of memories in the intact brain. Incorporating long-duration recordings of neuronal activity at microsecond resolution, this research will leverage sophisticated recording and statistical tools to observe how synaptic connections evolve during sleep and memory tasks in order to uncover the exact mechanisms by which sleep plays a role in the consolidation of memories.

Such insights are expected to address many central open questions in contemporary neuroscience regarding memory and the function of sleep. They could also lead to new ways of addressing memory disorders and developing therapeutic interventions for neuropsychiatric conditions in which sleep and memory are impacted. This project will help train undergraduate and master’s students from underrepresented populations and develop a course in Biological and Artificial Neural Networks, helping prepare students for careers in biomedical and computational sciences.

The proposed study addresses a critical gap in our understanding of synaptic modifications during sleep and learning by leveraging advanced extracellular neurophysiological techniques and statistical tools. The statistical approach outlined for inferring microcircuit structure from spike trains is designed to be robust to nonstationary background dynamics, and is complemented by a detailed experimental strategy comprising key objectives.

Utilizing bilateral recordings in hippocampal regions CA3 and CA1, this research will track spike trains at microsecond resolution from large neuronal populations during spatial memory tasks and various sleep stages. Fine-timescale analyses of these spike trains will infer and compare excitatory and inhibitory connectivity during pre- and post-task sleep, testing the Hebbian hypothesis that synaptic connections between co-active neuron pairs are strengthened following awake learning.

Focusing on sleep following the task, these analyses will also identify dynamic changes in CA3/CA1 microcircuits over time, testing the hypothesis that connections engaged during learning are strengthened during sleep, while others undergo downregulation. The design identifies the effects of learning and sleep on microcircuit dynamics, and aims to capture the general principles of synaptic plasticity in a memory-critical brain region.

The research will interrogate long-standing theories regarding the role of learning and sleep in modulating hippocampal microcircuit connectivity, potentially leading to significant advances in our understanding of neural plasticity and memory consolidation.

This project is funded jointly by the Neural Systems Cluster of the Division of Integrative Organismal Systems in the Directorate for Biological Sciences and the Division of Information and Intelligent Systems in the Directorate for Computer and Information Science and Engineering.

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.