Understanding Circuits

Project Summary We propose to build a next generation crowdsourcing platform (code named “FlyWire”) for mapping the fly connectome using transmission electron microscopy images that were acquired at Janelia Research Campus. FlyWire will depart from EyeWire, a previous crowdsourcing platform, in two major ways: (1) Much higher throughput will be attained by leveraging the latest in deep learning. (2) FlyWirers will consist mainly of fly neuroscientists, while EyeWirers were primarily nonscientists.

Project Summary Trans‐synaptic bidirectional tracing tools for imaging and omics analysis A central question in systems neuroscience is how hormones, such as estrogen, regulate animal behavior at the level of synapses and circuits. The Shah lab has recently identified hormone-responsive neuronal populations in the hypothalamus and amygdala that mediate distinct behaviors between the sexes.

ABSTRACT To interpret the detailed ultrastructural information of the connectomes in Drosophila and other species, it will be necessary to know the physiological functions of synapses between specific cell types. One key step will be the identification of the neurotransmitter receptors that reside at each site and the connectivity of post-synaptic receptors to specific presynaptic partners. This proposal will combine three cutting-edge technologies to establish methods for tagging neurotransmitter receptors and mapping their subcellular location and synaptic partners.

! PROJECT SUMMARY Deciphering the brain’s wiring diagram is widely thought to be necessary towards understanding how brain circuits process information. However, this goal is extremely challenging because currently available methods to study brain connectivity suffer from important limitations.

Project Summary The goal of this proposal is to develop a widely adoptable, high-throughput, functional connectomics platform to semi-automatically reconstruct and analyze the synaptic connectivity of functionally characterized neuronal microcircuits. We will develop this pipeline in the context of understanding neural microcircuits that control walking, using the Drosophila ventral nerve cord (VNC) as a model system.

Project Summary/Abstract We have recently published a 3D electron microscopy volume of the whole fruit fly brain. However mapping of synaptic `wiring diagrams' or connectomes of neuronal circuits from this volume is currently completely manual and therefore slow. Our long-term goal is to increase understanding of how circuits process and transform information, both by accelerating connectomics mapping, and increasing the power and accessibility of analysis tools.

PROJECT SUMMARY Mapping the synaptic connectivity of brain circuits is essential for obtaining a mechanistic understanding of the neural basis of behavior, learning, and cognition. While anatomical approaches can reveal the physical architecture of neural circuits, only a functional approach can reveal the strength and dynamics of each synapse in a network. These parameters are crucial for building any type of quantitative and explanatory model for how neural circuits compute, encode, and store information.

PROJECT SUMMARY Synaptic dysfunction is a common feature of neuropsychiatric disease. For example, a hallmark of age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s is synaptic fibrilization and aggregation of key proteins that participate in synapse and cell loss. Maladaptive plastic changes in synapse structure and function underlie key aspects of behavioral and mood disorders ranging from addiction to depression, as well as neurodevelopmental diseases like schizophrenia and autism.

Project Summary/Abstract Connectomics is a new field, created with the goal of densely or completely mapping the connections in the brain. Because this goal is at present only achievable for small organisms, connectomics has taken on two forms in the study of larger brains. Macroscale connectomics is used to describe the connections between brain areas, which in experimental animals is achieved with tracers, while humans it is typically pursued at a very coarse scale with diffusion imaging, a form of MRI.

Project Summary/Abstract A fundamental goal in neuroscience is to understand how information is processed in neuronal circuits. Ultimately, we would like to understand the relationship between circuit structure and network function. However, the immense complexity of most brain networks has been a significant barrier to progress. Neurons are a primary computational component of networks in the brain, yet we do not have a comprehensive list of their types for even the simplest mammalian neuronal circuit.