Polarity, both in arrangement of cellular processes and intracellular proteins and organelles, is essential to the proper functioning of a wide array o tissues in the human body. This is particularly true in the central nervous system, where polarity dictates cell fate during division, controls cell migration and nuclear movement, and determines the location of axons and dendrites. However, the role of polarity in competition between developing inputs on a single neuron has yet to be examined. Defining the polarity mechanisms that may dictate competition is of significant clinical relevance, as disorders such as autism and schizophrenia are believed to arise from under- or over-pruning of terminals during this phase of development. Additionally, defects in polarity have been shown to be associated with deafness and may potentially play a role in age-related decline in retinal function. Recently, the calyx of Held (CoH) connection to the medial nucleus of the trapezoid body (MNTB) has emerged as a model system for competition;it possesses easily identifiable inputs throughout development, a well-defined single terminal as an endpoint for competition, and a rapid and early developmental timeframe of 48-72 hours from P3 to P6. My preliminary data demonstrates that MNTB cells also exhibit intrasomatic polarity, with an eccentrically located nucleus, extensive nuclear foldin where it faces the cytoplasm, and competing terminals that grow preferentially over the cell surface away from the eccentric nucleus. These qualities make the MNTB:CoH connection ideal for studying the role of polarity in competition. I hypothesize that MNTB neurons express intrasomatic polarity transiently during CoH competition and that intrasomatic polarity extends to the somatic surface to determine the positioning of competing inputs and selection of a single, winning input. To show this, I will utilize the novel technologies of serial block-face scanning electron microscopy (SBEM), automated segmentation of neuronal structures, and three-dimensional reconstruction of neurons and their internal structures. A conditional transgenic mouse line will be used to selectively disrupt nuclear eccentricity within MNTB neurons for comparison with normally developed animals. By combining these approaches, this research will establish the contribution of intrasomatic polarity to terminal placement and competition, which may be applicable to many areas of the developing nervous system. Additionally, these findings may also reveal new avenues of research for diagnosis, treatment and prevention of disorders such as autism and schizophrenia.

Public Health Relevance

Disorders such as autism and schizophrenia may arise from miswiring of the brain early in development. In order to determine how such problems may arise, the factors which dictate normal connectivity in the brain must first be understood. One such factor - the structural arrangement, or polarity, of the interior of the neuron - may provide novel avenue of approach to understanding what goes wrong in these disorders.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDC1)
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Sklare, Dan
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West Virginia University
Schools of Medicine
United States
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Holcomb, Paul Steven (2018) Adding new dimension to neuroscience. J Neurosci Res 96:1123-1124
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