Dissecting the Contributions of Neurogenesis-Defined Subpopulations of Hippocampal Neurons to Balancing Memory Stability and Malleability

The ability to update memories underpins adaptive behaviours, ensuring that our internal models of the world remain consistent with the dynamic environments we inhabit. Striking a balance between memory stability (the persistence and robustness of memories over time) and malleability (the capacity to update memories in response to new information) is thus essential to learn from experience and adapt to change. While the biological foundations of memory stability are increasingly understood, the mechanisms supporting memory malleability – and how they balance with stability – remain largely unknown. What distinguishes a stable memory from a malleable one? What processes govern the updating of malleable memories, and what prevents updates in stable memories? How is the balance between stability and malleability regulated? To answer these questions, we will leverage our recent discovery that the propensity for stability or malleability of a memory shifts over time in association with activity dynamics in corresponding neurogenesis-defined hippocampal neuron subpopulations. Specifically, we showed that Early-Born Neuron (EBN) activity supports stable memory states and prevents memory updating, while Late-Born Neuron (LBN) activity is associated with malleable states and promotes memory updating. Based on these findings, we hypothesise that a key mechanism regulating the stability/malleability balance lies in the interplay between activity dynamics of hippocampal EBNs and LBNs, with mutual interactions between these subpopulations underpinning memory updating and its flexible use in response to shifting contingencies. Building on this hypothesis, our proposal will use cutting-edge genetic, cellular, network, and behavioural approaches in rodents to dissect mutual interactions between EBN and LBN activity dynamics, thus revealing fundamental mechanisms that regulate the stability/malleability balance, critical for survival and resilience in dynamic environments.