Cutting-edge methodologies for tagging and tracing active neuronal coding in the brain

Decoding the neural substrates that underlie learning and behavior is a fundamental goal in neuroscience. Identifying “key players” at the molecular, cellular, and circuit levels has become possible with recent advancements in molecular technologies offering high spatiotemporal resolution. Immediate-early genes are effective markers of neural activity and plasticity, allowing for the identification of active cells involved in memory-based behavior. A calcium-dependent labeling system coupled with light or biochemical proximity labeling allows characterization of active cell ensembles and circuitry across broader brain regions within short time windows, particularly during transient behaviors. The integration of these systems expands the ability to address diverse research questions across behavioral paradigms. This review examines current molecular systems for activity-dependent labeling, highlighting their applications in identifying specific cell ensembles and circuits relevant to various scientific questions and further discuss their significance, along with future directions for the development of innovative methodologies.