Little is known about the role of micromechanical stress in regulating neuronal morphological and functional polarity. Diffuse axonal injury caused by mechanical impact displays characteristic axonal varicosities (swelling or beading), which are a prominent feature of traumatic brain injury (TBI). Abundant axonal varicosities are also a key sign for irreversible neurodegeneration in Alzheimer's and Parkinson's diseases, and multiple sclerosis. Under physiological conditions, a lower level of axonal varicosities can be observed in the brain. Although axonal varicosities profoundly affect action potential propagation and synaptic transmission, how they are specifically induced in axons by mechanical stress and regulated in health and disease remains a mystery. Our preliminary studies have led to several novel findings to shed light on this important question. We found that mechanical stress induces varicosity formation in unmyelinated axons, but not in dendrites or myelinated axons of central neurons. This process is unexpectedly rapid and reversible, where a transient receptor potential (TRP) channel acts as the major mechanosensitive (MS) ion channel. We further identified a novel binding protein of this channel, which regulates microtubule (MT) disassembly in response to Ca2+ influx. Moreover, we observed the rapid development of axonal varicosities in the brain of a mouse model of mild TBI. Based on our preliminary results, we propose an original hypothesis that micromechanical stress preferentially induces axonal varicosities in central neurons, and this process is regulated by axonal intrinsic and extrinsic mechanisms. To test this hypothesis, we will use a multidisciplinary approach including novel microbiomechanical assays, protein biochemistry, electrophysiological recording, state-of-the- art imaging, myelin coculture, knockout mice and a mild TBI mouse model. We will determine (Aim 1) whether targeting and activity of MS ion channels regulate polarized mechanosensation in central neurons, (Aim 2) how MT disassembly is induced by intra-axonal Ca2+ increase and in turn leads to varicosity formation, and (Aim 3) whether the pattern of axonal varicosity formation in the mild TBI mouse model is regulated by myelin, the MS channel and its binding protein. This project represents an underexplored research field with many open questions. This research is significant because it will provide novel mechanistic insights into a new form of central neuron polarity, polarized mechanosensation.

Public Health Relevance

This project is to study how micromechanical stress asymmetrically regulates the structure and function of nerve cells in the brain. The findings may contribute to the development of new strategies for diagnosis and treatment of mild traumatic brain and nerve injuries, as well as chronic disorders including glaucoma, Alzheimer's and Parkinson's diseases, and multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS093073-02
Application #
9288236
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Silberberg, Shai D
Project Start
2016-06-15
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$302,838
Indirect Cost
$93,734
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Nickel, Mara; Gu, Chen (2018) Regulation of Central Nervous System Myelination in Higher Brain Functions. Neural Plast 2018:6436453
Gu, Yuanzheng; Servello, Dustin; Han, Zhi et al. (2018) Balanced Activity between Kv3 and Nav Channels Determines Fast-Spiking in Mammalian Central Neurons. iScience 9:120-137
Servello, Dustin; Gu, Yuanzheng; Gu, Chen (2018) A Microbiomechanical System for Studying Varicosity Formation and Recovery in Central Neuron Axons. J Vis Exp :
Qi, Lin; Knapton, Erin K; Zhang, Xu et al. (2017) Pre-culture Sudan Black B treatment suppresses autofluorescence signals emittedĀ from polymer tissue scaffolds. Sci Rep 7:8361
Beceiro, S; Radin, J N; Chatuvedi, R et al. (2017) TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection. Mucosal Immunol 10:493-507
Jukkola, Peter; Gu, Yuanzheng; Lovett-Racke, Amy E et al. (2017) Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels. Front Mol Neurosci 10:344
Gu, Yuanzheng; Jukkola, Peter; Wang, Qian et al. (2017) Polarity of varicosity initiation in central neuron mechanosensation. J Cell Biol 216:2179-2199
Gu, Chen (2016) KIR4.1: K(+) Channel Illusion or Reality in the Autoimmune Pathogenesis of Multiple Sclerosis. Front Mol Neurosci 9:90