Otolaryngology - Research

Eight laboratories provide state of the art research and research training in Auditory and Vestibular Anatomy, Pharmacology, Physiology of Taste and Smell, Cancer Molecular Biology and Genetics. 
In alphabetical order these are headed by Carol Bauer, MD; Kathy Campbell, PhD; Don Caspary, PhD; Robert Helfert, PhD; Larry Hughes, PhD; and Leonard Rybak, MD, PhD.  Special emphasis is on understanding basic mechanisms and their application to clinical problems such as ototoxicity, aging, Alzheimer's Disease, tinnitus, and cancer.

Auditory Anatomy Lab.
Robert Helfert, Ph.D
Terri Sommer B.A.

The long-term goal of our research is to identify predisposing factors underlying the degenerative changes that occur in the brain with age, so that therapeutic regimens can be developed.

Studies from our laboratory suggest that nerve cells in a major auditory center in the brain undergo degenerative changes during aging that compromise their ability to process sound.  We compared, quantitatively, changes in the synaptic organization of the auditory midbrain (inferior colliculus) among three age groups of rats (Helfert et al., J Comp Neurol, in press).  The resulting data revealed a balanced loss of excitatory and inhibitory synapses in the aging auditory brainstem without a corresponding loss of neurons.  The reduction in synaptic density was, though, related to a similar decline in dendritic density.  Because the sources of ascending input to the auditory midbrain maintain remarkably stable neuronal populations during aging, we doubt that the loss of dendrites is caused by deafferentation (loss of synaptic input).  Rather, we suspect that the dendritic regression may be the result of a primary degenerative process. 

Indeed, we have identified in the auditory midbrain two potential mechanisms underlying the synaptic losses: 1) an age-related decline in the activity of antioxidant enzymes with a corresponding elevation in lipid peroxidation, and 2) a decrease in the levels of the protective heat-shock proteins Hsp72 and Hsp73.  Thus, the mechanisms underlying neural senescence in the auditory midbrain may include a rise in oxidative stress along with the inability of older nerve cells to adequately protect themselves from the resulting increase in levels of toxic, oxygen-containing metabolites.  This impairment is probably not of the magnitude that would trigger neuronal death, but would perhaps be enough to hinder, among other processes, the metabolic effort involved in the maintenance of dendritic trees.  Presently, we are assessing postsynaptic changes that occur at the surviving synapses in the auditory brainstem of aged animals.  We have found that, at some synapses, the receptors reorganize their subunit composition to an "immature" form that may actually be functionally more efficient than the adult forms (Krenning et al., Larygoscope 108:26-31; 1998).  Thus, some of the receptor changes that occur in the auditory brainstem of aged animals may indeed be compensatory to the loss of synapses and dendrites. 

Toxicology Lab.
Leonard Rybak, MD, PhD.
Craig Whitworth M.A.

• Investigate the effects of toxic compounds on auditory function, morphology and biochemistry.
• Investigate potential protective agents their and mechanisms against ototoxic compounds.
• Determine the interaction between development and ototoxicity.

Compounds Investigated

• Cisplatin
• Heavy Metals
• Loop Diuretics
• Aminoglycoside Antibiotics

Electrophysiological Measures

• Endocochlear Potential (EP)
• Whole Eighth Nerve Compound Action Potential (CAP)
• Auditory Brainstem Response (ABR)
• Intracellular Potentials of the Stria Vascularis (strial potentials)
  

Morphological Measures

• Light Microscopy (LM)
• Scanning Electron Microscopy (SEM)
• Transmission Electron Microscopy (TEM)
• Immunohistochemistry

Biochemical Measures

• Cochlear Adenosine Receptors
• Antioxidant Enzymes
• Glutathione
• Cochlear Glucose Metabolism
• High Pressure Liquid Chromatography
• Pharmacokinetics of Ototoxic Compounds
  

In collaboration with:

Vickram Ramkumar, Ph.D., Department of Pharmacology
Satu Somani, Ph.D., Department of Pharmacology
George Dunaway, Ph.D., Department of Pharmacology
Larry Hughes, Ph.D., Departments of Surgery and Psychiatry