BME PhD Prospectus Presentation: Michael Wallace

Title: "Understanding the Cellular and Molecular Determinants of Neuromodulator-Linked Plasticity During Motor Learning"

Advisory Committee: Dr. Michael N. Economo, PhD – BME (co-advisor) Dr. Brian Cleary, PhD – CDS, BME, Biology (co-advisor) Dr. John T. Ngo, PhD – BME (chair) Dr. Marina Picciotto, PhD – Yale University Dr. Steve Ramirez, PhD – PBS

Abstract: Motor learning depends on neuromodulatory signaling in the motor cortex and striatum, yet the receptor- and cell-type–specific mechanisms that translate these signals into plasticity remain unclear. Distinct neuronal populations express unique combinations of neuromodulator G-protein–coupled receptors (GPCRs) and intracellular signaling components, so identical neuromodulatory inputs can trigger divergent plasticity programs. In this project, I will define how individual neuromodulator GPCRs—alone and in combination—regulate transcriptional programs of plasticity during motor learning at single-cell resolution, testing the hypothesis that receptor-knockout effects on plasticity programs are predictable from transcriptomic cell-type identity. I will use an AAV-based in vivo Perturb-seq strategy enabling parallel CRISPR knockouts of neuromodulator GPCRs with neuron-selective expression, sparse infection, and high-throughput single-cell transcriptomics. Applied during a Rotarod learning paradigm, this framework will reveal how loss of specific receptors reshapes immediate early gene activation and broader plasticity programs across cell types in motor cortex and striatum. A combinatorial extension using dual-sgRNA constructs will then test whether receptor-pair interactions are predicted by shared Gα coupling, similar single-knockout profiles, or documented heteromerization. The resulting receptor- and cell-type–resolved map will clarify how neuromodulatory inputs and intracellular signaling architecture shape learning.