Molecular Cellular and Circuit Level Mechanisms of Working Memory Maintenance

Working memory allows past events to be transiently maintained in the brain so that it can be compared with ongoing experiences to drive behavior. This cognitive process has been shown to be severely impacted by the progression of many neuropsychiatric diseases and disorders. Thus, it is critical to understand the components of working memory to determine how normal mental function can be restored. Working memory must be selective to relevant stimuli and resistant to noise or irrelevant stimuli. It has been proposed that information is maintained through persistent activity at the single-cell or population level, either among local recurrently connected neurons or through long-range loops across multiple brain areas. Alternatively, it has been proposed that information could be maintained through activity-silent intracellular processes which are defined by specific genes and molecules. These theories are not necessarily mutually exclusive and may both be implemented in the nervous system. To achieve a comprehensive understanding of these mechanisms, it is necessary to investigate working memory across multiple biological scales spanning genes, cell types, local circuit dynamics, brain-wide communication, and behavior. Using a combination of multi-area two-photon calcium imaging, long-range anatomical tracing, cell-resolution optogenetic manipulation, and comprehensive spatial transcriptomic analysis, we will dissect working memory circuits as animals perform sensory-guided working memory tasks. In Aim 1, we will determine how specific stimuli are maintained in working memory by monitoring and perturbing local and long-range cortical activity to distinguish working memory maintenance from sensory-to-working-memory transformations. In Aim 2, we will determine the cellular and molecular mechanisms supporting local working memory by combining functional connectivity and gene expression measurements to distinguish their contributions to persistent activity and activity silent properties. Through this, we will determine the precise local and long-range dynamics that underlie working memory and the cellular and molecular properties that support these computations. Project Number: 1R21MH140102-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Jerry Chen | Institution: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS), BOSTON, MA | Award Amount: $449,625 | Activity Code: R21 | Study Section: Learning, Memory and Decision Neuroscience Study Section[LMDN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11303676