BMI Special Seminar // Lisa Traunmueller: Molecular and Cellular Control of Memory Circuits

Long-term memories are encoded by sparse neuronal ensembles whose coordinated activity during learning drives lasting circuit plasticity. While the mechanisms of ensemble formation have been intensely studied, the gene-regulatory and transcriptional mechanisms that give rise to cell-class-specific plasticity over time remain largely unexplored. Moreover, neuronal communication extends beyond classical synaptic transmission, yet the contribution of secreted signaling molecules, such as neuropeptides, to ensemble plasticity remains poorly understood. To begin to address these issues, we employed single-nucleus multiomic profiling across multiple time points following single-trial fear learning to identify long-lasting, cell-type-specific chromatin and transcriptional programs in hippocampal ensemble neurons, with the dentate gyrus emerging as a key locus of persistent ensemble plasticity. These molecular states coincide with enduring changes in excitability and synaptic organization and implicate sustained FOS/AP-1–dependent regulation as a mechanism for extending transient activity signals across memory consolidation. In a complementary study, we focused on a relatively understudied mode of neuronal communication—neuropeptide signaling—by examining the role of the neuropeptide precursor Secretogranin-2 (Scg2). We show that Scg2 is required for fear memory recall and the regulation of inhibitory connectivity, with excitatory neuron-derived SCG2 acting to shape parvalbumin interneuron gene expression and synaptic function. These effects are mediated, in part, through regulation of Erbb4, a critical determinant of synaptic connectivity between excitatory neurons and parvalbumin interneurons. Together, these studies highlight how ensemble dynamics are sculpted by cell-class-specific plasticity mechanisms that integrate synaptic and secreted forms of neuronal communication to support stable yet flexible memory representation