Understanding how information is processed in neuronal circuits is a central question in neuroscience and key to understanding how the brain works. A neuron's function is fundamentally dependent on how it is connected within its network. Therefore, understanding the relationship between network connectivity - circuit structure - and cellular function will help us to understand how neurons and networks transform information to bring about perception and behavior. Recent advances in large-scale electron microscopy have allowed us to begin detailed mapping of neural network anatomy. The olfactory circuit of Drosophila melanogaster is an excellent model system for this purpose because it contains a relatively small number of neurons in a small volume, existing tools allow genetically-targeted labeling, and our knowledge about functional properties of neurons in this system is rapidly expanding. We will exploit these key advantages to understand the rules underlying olfactory network organization. This proposal would generate for the first time, large-scale EM datasets in which long-range neuronal connectivity can be reconstructed and corresponded to identified cells whose in vivo physiology is known or can be examined in different animals. Specifically, we will examine the convergence and divergence of projection neuron connectivity to higher-order neurons in two target regions of the protocerebrum, the lateral horn and the mushroom body. We hypothesize that lateral horn neurons receive stereotyped and convergent connectivity from projection neurons of the same type. Interestingly, neurons in the lateral horn have recently been implicated in innate olfactory behaviors. In contrast, we hypothesize that mushroom body neurons, known to be crucial for olfactory learning, have more random and less stereotyped connectivity with projection neurons. These are fundamental questions about the structure and function of neuronal networks that are uniquely approachable in the olfactory system of the fly. Finally, by understanding the basic principles of neuronal network connectivity we will be poised to compare diseased and healthy brains to assess how circuit structure is affected in models of neurodegenerative disorders to rationally design treatment strategies.

Public Health Relevance

The goal of this proposal is to understand the organizational principles underlying network connectivity in the olfactory system. We will extract the network anatomy of the fly olfactory system using large-scale electron microscopy and relate stereotyped cellular function to the circuit's structure. Understanding the basic principles of neuronal connectivity and their relationship to function will help reveal how the brain is altered n neurodegenerative disorders that impact the sense of smell and point toward strategies remedy them.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Small Research Grants (R03)
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Communication Disorders Review Committee (CDRC)
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Sullivan, Susan L
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Harvard Medical School
Schools of Medicine
United States
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Tobin, William F; Wilson, Rachel I; Lee, Wei-Chung Allen (2017) Wiring variations that enable and constrain neural computation in a sensory microcircuit. Elife 6: