Formation of neural circuits follows a stereotypical program across neural systems of axon extension, exuberant innervation and pruning of inputs that fail a selection process. Increasing evidence reveals this process to be an integrated effort by neurons and glia to build an orderly arrangement of cells and synaptic contacts. We have shown that formation of synaptic contact between the calyx of Held, perhaps the largest nerve terminal in the CNS, and its postsynaptic partner passes through a competitive phase during rapid growth over only a few days. The competitive phase has a sharp onset at postnatal day 2 in mice and rapid resolution of competition within 3 days for most MNTB cells, so the CH:MNTB system offers experimental advantages over other model systems. We will exploit novel technology, serial blockface scanning electron microscopy, across developmental age to provide a time-series view of all structural changes within this system that reveals all constituen cells at nanoscale resolution. Preliminary data suggest novel modes of physical interaction between growing calyces and glia in the developing brain and observed synaptic input onto glial cells at early neonatal ages. This unique data set, coupled to our novel whole-head slice preparation and genetic and viral vector tools developed during the last grant period, anchors investigations of the onset of neural activity from embryonic ages, roles for neural activity in calyx growth and competition, and potential synaptic communication among neurons and glia during neural circuit maturation. In sum, we will provide the first holistic view of neural circuit development that incorporates all cell types and describes circuit formation from the time of initial contact at embryonic ages to mature topography by hearing onset during the second postnatal week.

Public Health Relevance

The goal of this project is to reveal new principles and mechanisms for assembly of brain circuits that capture integrated neuronal and glial programs for early brain development. Increasingly, brain disorders such as autism, other forms of cognitive impairment and epilepsy are associated with developmental defects in brain structure and neuronal and glial function. Factors that mediate synaptogenesis and shaping of neural circuits also have tremendous potential as therapies for pathologies in adulthood, which include neurodegenerative disorders or brain injury.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Study Section
Auditory System Study Section (AUD)
Program Officer
Platt, Christopher
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West Virginia University
Schools of Medicine
United States
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Brandebura, Ashley N; Morehead, Michael; Heller, Daniel T et al. (2018) Glial Cell Expansion Coincides with Neural Circuit Formation in the Developing Auditory Brainstem. Dev Neurobiol 78:1097-1116
Holcomb, Paul Steven (2018) Adding new dimension to neuroscience. J Neurosci Res 96:1123-1124
Kolson, Douglas R; Wan, Jun; Wu, Jonathan et al. (2016) Temporal patterns of gene expression during calyx of held development. Dev Neurobiol 76:166-89
Holcomb, Paul S; Morehead, Michael; Doretto, Gianfranco et al. (2016) Rapid and Semi-automated Extraction of Neuronal Cell Bodies and Nuclei from Electron Microscopy Image Stacks. Methods Mol Biol 1427:277-90
Perkins, Guy A; Jackson, Dakota R; Spirou, George A (2015) Resolving presynaptic structure by electron tomography. Synapse 69:268-82
Holcomb, Paul S; Deerinck, Thomas J; Ellisman, Mark H et al. (2013) Construction of a polarized neuron. J Physiol 591:3145-50
Holcomb, Paul S; Hoffpauir, Brian K; Hoyson, Mitchell C et al. (2013) Synaptic inputs compete during rapid formation of the calyx of Held: a new model system for neural development. J Neurosci 33:12954-69
Marrs, Glen S; Morgan, Warren J; Howell, David M et al. (2013) Embryonic origins of the mouse superior olivary complex. Dev Neurobiol 73:384-398
Marrs, Glen S; Spirou, George A (2012) Embryonic assembly of auditory circuits: spiral ganglion and brainstem. J Physiol 590:2391-408
Perkins, Guy A; Tjong, Jonathan; Brown, Joshua M et al. (2010) The micro-architecture of mitochondria at active zones: electron tomography reveals novel anchoring scaffolds and cristae structured for high-rate metabolism. J Neurosci 30:1015-26

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