Current Research and Scholarly Interests
1. Assembly of the fly olfactory circuit
A central question in neural circuit assembly is how neurons connect specifically with their synaptic partners. We are using the fly olfactory circuit to investigate the general principles by which wiring specificity is established during development. The assembly of the fly olfactory circuit requires precise matching between axons from 50 olfactory receptor neuron types and dendrites from 50 projection neuron types. In the past 20 years, we have identified key cellular interactions and molecular mechanisms at specific steps of olfactory circuit assembly. More recently, we have also taken transcriptomic, proteomic, and live imaging approaches to complement genetic analyses of individual genes. We are currently integrating these approaches to deepen our understanding of the combinatorial cell-surface codes that instruct connection specificity.
2. Assembly of neural circuits in the mouse brain
We have studied a broad range of developmental processes in rodent brains using genetic tools we have developed. Some of these studies extend what we are learning in the fly, whereas others explore processes more prevalent in vertebrates. For example, cerebellar Purkinje cells have highly elaborate and planar dendritic trees, each of which receives presynaptic inputs from tens of thousands of granule cells. Our investigations of Purkinje cell dendrite morphogenesis have highlighted the importance of competitive interactions in dendritic growth and branching. Our studies of hippocampal network assembly have revealed that the same cell-surface proteins, teneurin-3 and latrophilin-2, can serve both as ligands and receptors to mediate attraction and repulsion, and these molecules are likely reused in the assembly of multiple nodes of the hippocampal networks. We are investigating the function of these molecules in the assembly of additional circuits as well as how they work both as ligands and receptors.
3. Organization and function of neural circuits
We have used genetic and viral strategies to decipher the organizational principles of the fly and mouse olfactory systems, as well as the input–output architecture of norepinephrine, dopamine, and serotonin systems at the scale of the entire mouse brain. We are now also combining single-cell transcriptomics with activity recording, manipulation, and TRAPing, as well as behavioral analyses, to interrogate the functional organization of a variety of neural circuits. Recent discoveries include the dissection of dorsal raphe serotonin neuron subsystems, reward representation in cerebellar granule cells and shared cortex-cerebellum dynamics, the unit of organization and evolution of the cerebellar nuclei, differential encoding of task variables by prefrontal cortical projection neuron classes, temporal evolution of prefrontal cortical neuron ensembles that promote remote memory retrieval, and neural basis of thirst drive for motivated behavior.
4. Tool development
We continue to develop tools to interrogate neural circuit assembly and organization with increasing precision. The MARCM (mosaic analysis with a repressible cell marker) method in flies and MADM (mosaic analysis with double markers) method in mice allow the visualization and genetic manipulation of isolated single neurons. The Q system further expanded binary expression tools in flies. We recently developed tools to map circuit organization in mammals. The TRIO (tracing the relationship between input and output) and cTRIO (cell-type-specific TRIO) methods allow rabies virus–based input tracing to neurons defined by projection, or by cell type and projection. The TRAP (targeted recombination in active population) method enables genetic access to neurons based on their activity, which in combination with tools for labeling, tracing, recording, and manipulating neurons, offers a powerful approach for understanding how neural circuits process information and generate behavior.