Overview and approach

Synapses are a fundamental unit of computation in the brain and vary widely in their structural and functional properties. Each synapse is a biochemically complex machine, comprised of hundreds of different proteins that vary in both identity and quantity across synapses. The functional significance for most of these differences in molecular composition are poorly understood.  Our goal is to understand how molecular diversity at synapses gives rise to useful variation in synaptic physiology, and how this may reflect the specialization of synapses to perform specific useful computations in their respective circuits.

We ask these questions in the context of odor-driven behaviors in the vinegar fly Drosophila melanogaster. We use the fly because we can make targeted, in vivo whole-cell recordings from individual identified neurons corresponding to specific processing channels. This, together with its compact size and sophisticated genetic toolkit, makes the fly olfactory system a powerful experimental system for relating synaptic physiology to circuit function. Our approach is to use carefully designed odor stimuli in combination with genetic strategies to constrain olfactory behavior to depend on the activity at a small number of identified synapses. We use molecular genetics to selectively manipulate these synapses, measure the functional outcomes using in vivo two-photon imaging and electrophysiological recordings, and make direct comparisons of synaptic function with neural coding and behavior. We are interested in two broad categories of questions:

Synaptic specialization

How do synapses that convey parallel streams of olfactory information vary in their functional properties, and what is the molecular basis for these differences? How does this relate to the transformations they perform, the stimuli that they prefer, and the behavioral responses they engage? We approach this question using a combination of single-cell transcriptional profiling, electrophysiology, optogenetics, and behavior. We are especially interested in comparing synapses in olfactory processing channels that differ dramatically along one or more axes, such as their kinetics of chemosensory transduction, the natural statistics of their ligands in the environment, or the ethological significance of their preferred stimuli. In complementary studies, we take a comparative approach to this question by comparing synapses in closely related Drosophila species. We ask how homologous olfactory channels (defined by conservation in anatomy and odorant receptor sequence) differ in the stimuli they process and the behaviors they  engage, and how this relates to variations in gene expression.

Synaptic basis of adaptive behaviors

We want to understand the molecular processes that regulate how synaptic properties are altered by context or experience to support adaptive behaviors. In particular, we focus on understanding how the molecular composition of the synapse is reorganized to mediate cell type-specific and synapse-specific forms of neural plasticity. We take advantage of the highly compartmentalized organization of olfactory circuits, and our ability to genetically isolate specific processing channels, to selectively activate identified subsets of synapses and link these to specific flexible behaviors. We apply a combination of transcriptional profiling, genetic manipulation, and electrophysiology at these synapses to probe the molecular mechanisms underlying synapse-specific plasticity.