Operating Principles of Parallel Memory Systems

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.