Project Summary/Abstract: During learning, task-relevant neurons convert transient activity signals into stable modifications of their synaptic properties in order to alter their output and support memory formation, a process broadly called plasticity. The most enduring forms of plasticity require regulation of the genome. Inducible transcription factors (ITFs) are a subset of rapidly induced, activity-dependent genes that support plasticity by triggering downstream programs of gene expression that directly impact neuronal functions. Indeed, ITFs have been used as tools to track task- relevant neurons in vivo during behavior, and intensive efforts in the field have uncovered mechanisms that link diverse extracellular stimuli and depolarizing activity to ITF expression in neurons. Despite this long-standing interest in ITFs, a wide gap has emerged in the study of their neuronal functions: What features of neuronal activity do ITFs communicate to the nucleus? Can they regulate the genome in distinct ways in response to different forms of activity? Does ITF-mediated gene regulation support synaptic and behavioral adaptations tailored to the activity history of the cell? Answering these questions requires a shift of the status quo away from thinking of ITF expression as a generalized response to neuronal activity. This proposal presents the innovative hypothesis that the genome decodes learning rules to support synaptic plasticity through activity-reporting ITF expression pathways. This project establishes a discovery pipeline that will reveal genomic mechanisms underlying neural circuit plasticity by first profiling activity-dependent ITF expression mechanisms in the murine hippocampus, and then mapping and manipulating ITF target genes to determine their impact on local synapse functions. The results of this project have the potential to dramatically expand the repertoire of intracellular signaling and genomic mechanisms available to neurons and other excitable cell types to flexibly update their functions and phenotypes in response to extracellular stimuli.

Project Narrative: This New Innovator Award project proposal will explore how the genome transforms learning-related activity signals within brain circuits into changes of synaptic connections important for memory formation. This proposal puts forward an innovative hypothesis that a class of DNA-binding proteins that influence gene expression report the activity history of a neuron to its genome, enabling it to decode learning rules and support brain plasticity. The results of this project are expected to establish a new paradigm of gene regulation in learning and memory.