The present work seeks to advance quantitative understanding of semicircular canal biophysics and biomechanics and is organized around three specific aims: 1) Examine sulfated glycosaminoglycans (GAGs) in vivo by tracking the time-course of expression in the cupula and extracellular space around stereocilia following mechanical and aminoglycoside insults. Inner ear GAGs are known to play essential roles in development, mechanics, regeneration, repair, and protection. Our experimental approach using new xyloside conjugates is revealing entirely new information about this important process. 2) Map the spatial distribution of hair bundle displacements across the sensory epithelium in response to physiological stimuli in vivo. The diverse temporal response properties of afferent neurons correlate with projections in the crista ampullaris, but we do not yet know how or if responses depend upon spatial maps of hair bundle displacements. We will measure micromechanical displacement fields while recording afferent responses innervating the same region of the crista. 3) Detail mechano-electrical transduction (MET) current adaptation and its relationship to active amplification by semicircular canal hair cells. Our recent results suggest that the most sensitive semicircular canal afferent neurons rely on hair cell amplification to increase sensitivity to low strength stimuli. We will investigate the role of MET adaptation and electrical mechanisms in this important process by tracking bundle displacements and recording from hair cells in vivo. Results are expected to have long-term impact by enhancing understanding of semicircular canal micromechanics, cupulogenesis and self-repair, amplification by hair cells, and efferent control of motion sensation by the brain.

Public Health Relevance

Disorders of the vestibular system are debilitating and common, afflicting approximately 30% of the population over the age of 65 (Schappert, 1994). The present application is directly relevant to the biomechanical and biophysical substrates underlying sensitivity of semicircular canals under both physiological and pathological conditions. Unique in vivo experimental techniques will be applied to examine cupulogenesis/self-repair, glycosaminoglycan expression following damage, micromechanics, hair cell amplification, and efferent control.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC006685-09
Application #
8439856
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2004-05-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
9
Fiscal Year
2013
Total Cost
$495,195
Indirect Cost
$113,986
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Rabbitt, Richard D; Brichta, Alan M; Tabatabaee, Hessam et al. (2016) Heat pulse excitability of vestibular hair cells and afferent neurons. J Neurophysiol 116:825-43
Holman, Holly A; Tran, Vy M; Kalita, Mausam et al. (2016) BODIPY-Conjugated Xyloside Primes Fluorescent Glycosaminoglycans in the Inner Ear of Opsanus tau. J Assoc Res Otolaryngol 17:525-540
Highstein, Stephen M; Mann, Mary Anne; Holstein, Gay R et al. (2015) The quantal component of synaptic transmission from sensory hair cells to the vestibular calyx. J Neurophysiol 113:3827-35
Zhu, Hong; Tang, Xuehui; Wei, Wei et al. (2014) Input-output functions of vestibular afferent responses to air-conducted clicks in rats. J Assoc Res Otolaryngol 15:73-86
Tran, Vy M; Kuberan, Balagurunathan (2014) Synthesis of fluorophore-tagged xylosides that prime glycosaminoglycan chains. Bioconjug Chem 25:262-8
Lumbreras, Vicente; Bas, Esperanza; Gupta, Chhavi et al. (2014) Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling. J Neurophysiol 112:1246-55
Highstein, Stephen M; Holstein, Gay R; Mann, Mary Anne et al. (2014) Evidence that protons act as neurotransmitters at vestibular hair cell-calyx afferent synapses. Proc Natl Acad Sci U S A 111:5421-6
Rabbitt, Richard D; Brownell, William E (2011) Efferent modulation of hair cell function. Curr Opin Otolaryngol Head Neck Surg 19:376-81
Dittami, Gregory M; Rajguru, Suhrud M; Lasher, Richard A et al. (2011) Intracellular calcium transients evoked by pulsed infrared radiation in neonatal cardiomyocytes. J Physiol 589:1295-306
Dharia, Sameera; Rabbitt, Richard D (2011) Monitoring voltage-dependent charge displacement of Shaker B-IR K+ ion channels using radio frequency interrogation. PLoS One 6:e17363

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