Operating Principles of Parallel Memory Systems

Year of award: 2022


  • Prof Scott Waddell

    University of Oxford, United Kingdom

Project summary

Memory and motivation provide life with direction and purpose. Our studies using Drosophila have discovered that heterogeneity of the dopaminergic system is a fundamental organising principle of mnemonic networks. Identifiable parallel combinations of dopaminergic neurons reinforce valence- and reward-specific memories, and control state-dependent expression. Opponency provides an update function when learned expectations are not met. A recent synapse-level connectome, or wiring diagram, reveals unprecedented additional complexity of memory networks that needs to be deciphered. We will use single-cell transcriptomics to discover the 'wireless' neuromodulatory network - the information that connectomes lack. With cell-type specific genetic interventions we will determine how internal motivational states engage the wireless network to orchestrate and select activity within wired subcircuits of the dopaminergic system - to instruct appropriate formation and expression of different kinds of memory. We will also establish how breakdown of control in the dopaminergic system produces inappropriate compulsive reward-seeking. These experiments and approaches will transform our understanding of the molecular, cellular and network-level operating principles that permit diversity in the dopaminergic system to coordinate parallel state-dependent memory networks. Dysfunction within a heterogeneous system is likely to underlie the diversity of roles implicated for dopamine in numerous neurological and psychiatric disorders in humans.