Abstract

A major factor in human and animal presbyacusis is the degeneration of the cochlear lateral wall tissues and stria vascularis. These tissues supply energy to the organ of Corti in the form of the endocochlear potential (EP). In young animals, this 90 mV potential has been shown to be of fundamental importance in the operation of the cochlear amplifier and subsequent determination of auditory thresholds. Gerbils aged in quiet show an age-related decline of EP, the basis of metabolic presbyacusis. Over the last grant cycle we have developed a model of the aged ear in young gerbils using the chronic application of furosemide to the cochlea to block the generation of the EP. Here we further explore the effects of acute and chronic EP manipulation on cochlear transduction and the encoding of sound in auditory-nerve fibers. Moreover, we explore cell replication as a possible mechanism fundamental to the EP decline with age. There are three specific aims.
Specific Aim 1 examines the effects of EP modulation by direct current injection into the scala media of normal, EP-impaired, and aged cochleas.
This aim will test the hypothesis that EP is the primary factor controlling neural thresholds and otoacoustic emissions. Moreover, it tests whether direct current injection can serve to ameliorate metabolic presbyacusis.
Specific Aim 2 focuses on how populations of auditory-nerve fibers respond to EP decline, with specific regard to the thresholds of low- and high-spontaneous rate (SR) fibers.
This aim tests the hypothesis that the thresholds of low-SR fibers located in the cochlear base are more sensitive to EP decline than corresponding high-SR fibers. It will also examine the characteristics of these fibers with acoustic stimuli in EP-impaired cochleas.
Specific Aim 3 investigates the role of lateral wall fibrocytes in the production and maintenance of the EP. The hypothesis is that fibrocyte proliferation is essential for EP homeostasis, and a reduced rate of replication is the basis for the decline in EP observed in aged animals. These experiments will involve the infusion of mitotic inhibitors and gap junction uncouplers into the cochlea. Taken together, the three aims explore the major causes and effects of metabolic presbyacusis and have direct application to future interventions to help restore age-related hearing loss. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014748-07
Application #
6733538
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Finkelstein, Judith A
Project Start
1997-09-01
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
7
Fiscal Year
2004
Total Cost
$255,500
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

Lang, Hainan; Jyothi, Vinu; Smythe, Nancy M et al. (2010) Chronic reduction of endocochlear potential reduces auditory nerve activity: further confirmation of an animal model of metabolic presbyacusis. J Assoc Res Otolaryngol 11:419-34
Lang, Hainan; Schulte, Bradley A; Goddard, John C et al. (2008) Transplantation of mouse embryonic stem cells into the cochlea of an auditory-neuropathy animal model: effects of timing after injury. J Assoc Res Otolaryngol 9:225-40
Lang, Hainan; Schulte, Bradley A; Zhou, Daohong et al. (2006) Nuclear factor kappaB deficiency is associated with auditory nerve degeneration and increased noise-induced hearing loss. J Neurosci 26:3541-50
Moody, Marcus W; Lang, Hainan; Spiess, Adam C et al. (2006) Topical application of mitomycin C to the middle ear is ototoxic in the gerbil. Otol Neurotol 27:1186-92
Lang, H; Schulte, B A; Schmiedt, R A (2005) Ouabain induces apoptotic cell death in type I spiral ganglion neurons, but not type II neurons. J Assoc Res Otolaryngol 6:63-74
Mills, David M; Schmiedt, Richard A (2004) Metabolic presbycusis: differential changes in auditory brainstem and otoacoustic emission responses with chronic furosemide application in the gerbil. J Assoc Res Otolaryngol 5:1-10
Wang, Yong; Meng, Aimin; Lang, Hainan et al. (2004) Activation of nuclear factor kappaB In vivo selectively protects the murine small intestine against ionizing radiation-induced damage. Cancer Res 64:6240-6
Lang, H; Schulte, B A; Schmiedt, R A (2003) Effects of chronic furosemide treatment and age on cell division in the adult gerbil inner ear. J Assoc Res Otolaryngol 4:164-75
Schmiedt, Richard A; Lang, Hainan; Okamura, Hiro-oki et al. (2002) Effects of furosemide applied chronically to the round window: a model of metabolic presbyacusis. J Neurosci 22:9643-50
Spector, A A; Ameen, M; Schmiedt, R A (2002) Modeling 3-D deformation of outer hair cells and their production of the active force in the cochlea. Biomech Model Mechanobiol 1:123-35

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