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The ability to faithfully store and retrieve memories is an important adaptive quality that allows humans to reflect on, engage with, and respond to an ever-changing environment. Research in the Rajasethupathy lab focuses on observing and manipulating large-scale neural dynamics in real-time in behaving animals, to understand memory processing in the mammalian brain during health and disease.

Neuroscience seeks to understand how computations in the brain give rise to meaningful behavior, and in many ways, memory lies at the heart of this endeavor. Research in the Rajasethupathy lab is focused on understanding neural-circuit mechanisms of memory storage and retrieval in guiding adaptive behavior. The lab explores fundamental questions regarding the distributed nature of memory representations as they form, stabilize, and reorganize over time, an approach that requires the simultaneous monitoring of neural dynamics spanning multiple brain regions over multiple timescales.

More specifically, the Rajasethupathy lab uses fast volumetric cellular resolution imaging approaches for observing neural dynamics, as animals engage with complex virtual environments, to dissect dynamic and distributed population codes of memory representations. These experiments are then coupled with real-time optogenetic manipulation of neural dynamics to appropriately bias the animal’s neural activity and resulting behavior. The eventual goal is to understand not only how memories are allocated and maintained in neural circuits, but ultimately to understand how they are appropriately (or inappropriately) retrieved to guide adaptive (or maladaptive) behavior.

Another goal of the Rajasethupathy lab is to complement neural-circuit approaches with genomic and transcriptomic approaches, to untangle the scale and complexity of the molecular genetic features that drive circuit properties underlying memory-guided behaviors. The Rajasethupathy lab works to develop and apply methodologies that provide molecular annotation to activity-defined cell populations, with the hopes of identifying molecular logic that enables specialized circuit architectures and circuit computations, which in turn support memory allocation, maintenance, and retrieval. Over the long term, they hope to fill a long-standing need in neuroscience of bridging the gap between genes and circuits in order to better understand cognitive behaviors.

While pioneering studies of memory have illuminated the molecular and physiological mechanisms that occur in individual synapses, the next frontier in memory research will require, among other approaches, a more circuit-level and genome-scale understanding of memory processes in the brain, tackling questions such as: How is information encoded and integrated across multiple brain regions during learning and recall? How do top-down memory circuits form and engage with bottom-up circuits to faithfully retrieve memory representations? What are the gene-regulatory mechanisms that enable allocation and maintenance of neurons within these memory ensembles? And how are these circuit-level and genome-wide properties of memory ensembles disrupted during disorders of memory? By leveraging transformative technologies at the convergence of systems genetics and systems neuroscience, the Rajasethupathy lab hopes to address these questions to further our understanding of memory processes in health and disease.

Rajasethupathy is a faculty member in the David Rockefeller Graduate Program, and the Tri-Institutional M.D.-Ph.D. Program.