The general problem that I will address is how neurons integrate their inputs and compute their outputs. Central to integration and computation is the morphology of neurons, and in particular that of their highly branched dendritic arbors, which receive synaptic input from other neurons or sensory input from the outside world. The connections between axonal and dendritic processes define the nervous system's structure, which is viewed as a prerequisite for understanding neural function; connectomics, the global study of neuronal connectivity, has emerged as a major goal of neuroscience. In this Pioneer proposal, I want to take an orthogonal approach to neuronal morphology. My hypothesis is that the cell biology of the neuron-the transport and turnover of materials-places very strong constraints on both building and maintaining dendrites. Furthermore, I propose that these constraints are so strong that they actually compromise the functioning of neurons: I hypothesize, for example, that the changes in diameters of dendritic processes across branch junctions are dictated by transport constraints and that they actually degrade signal propagation. If this is true, then morphology is a compromise between cell biology and neuronal function, and determining the nature of the tradeoff is likely to provide key insight into connectivity. The morphological rules that I will uncover will provide powerful a prioris for determining connectivit maps, and may help to solve a major problem in connectomics: how well does the connectivity map need to be in order to understand the function? To test this hypothesis, one needs a system in which morphology can be measured precisely (and in the most general sense, which includes protein localization), where it can be manipulated in a controlled way, and where morphology can be correlated with function. The Class IV dendritic arborization mechanoreceptor of Drosophila larvae meets these requirements, and will be the initial focus of study. The experimental goals are: (i) to use light and electron microscopy to discover the full set of branching rules?that is, how diameters, angles, branch lengths, and protein & organelle distributions change over branch points. And: (ii) to use calcium and voltage recordings, together with behavior, to characterize the function of the neuron. The measurements will be done in wild-type flies and in mutants, in which the morphology has been modified using precise genetic manipulations. The theoretical goal is to determine the extent to which the observed anatomical and functional characteristics optimize transport and developmental constraints on the one hand, and signal processing constraints on the other hand. The theory will be done in close coordination with experiments performed in the same laboratory. The nature of the tradeoff between these conflicting costs and benefits will provide tremendous insight into neuronal architecture. This research, via the combination of precise experimental measurement and theoretical modeling, will add inestimably to our understanding of the relationship between form and function in the nervous system. We hope that principles will be found that apply broadly across nervous systems and that the principles will have practical value in the determination of the structure of neural networks.

Public Health Relevance

The relationship between the morphology of neurons and the way that they process information is poorly understood. We will investigate the following questions: how do cell-biological limitations constrain neuronal morphology and how does this impact neuronal function? The transformative nature of this approach is that the principles uncovered here are likely to have a large impact on our understanding of neuronal connectivity and architecture.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZRG1)
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Ferrante, Michele
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Yale University
Schools of Medicine
New Haven
United States
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