For more than thirty years, we have addressed problems in the biophysics and neurobiology of the mammalian cochlea. A gamut of techniques, ranging from animal behavior to single cell recording, was used to deal with various topics. For example, the relationship between compound cochlear and neural potentials and their single-cell precursors was defined. In addition, the properties and nature of cochlear summating potentials, the nonlinear properties of the cochlea as reflected in electrical responses, the analysis of electrical network properties of the organ of Corti, as well as various aspects of neural coding at the single fiber level were studied. All of these investigations were designed to address our primary aim: to delineate the physiological properties and functional roles of the two types of sensory receptors of the mammalian ear, inner and outer hair cells. Initially, these inquiries were pursued by indirect means. With the use of ototoxic antibiotics, portions of the outer hair cell population were destroyed and the effects studied with behavioral and electrophysiological methods. Subsequently, a more direct approach was employed to record intracellularly from inner and outer hair cells in vivo. These recordings provide the bulk of information available on the function of outer hair cells in the peripheral auditory system.

In addition to continuing in vivo hair cell work, three other research areas were developed. Differences between inner and outer hair cells were studied during the developmental maturation of the mammalian ear. Here we correlated the structural and physiological development of the cochlea in newborn gerbils whose auditory function is non-existent one week after birth but becomes adult-like three weeks after birth. A second research area examined the function of single, isolated outer hair cells in vitro. These cells possess the ability to change their shape in response to electric and acoustic stimuli. This motile response is modulated by efferent stimulation or by cholinergic agents, which simulate efferent action. It is commonly assumed that shape changes are the basis of a feedback mechanism that is responsible for the exquisite sensitivity and frequency resolving ability of the mammalian inner ear. Hence, we developed new techniques for the study of outer hair cell motility with the ultimate aims of identifying the molecular motor that powers the motile response and of describing the effects of cell motility on the aggregate cochlear response. The third area of concentration has been the study of acoustically evoked motion patterns, as well as the electrical and mechanical properties of the cellular elements of the organ of Corti. Development of the isolated hemicochlea preparation enabled us to visualize these motion patterns at different cochlear locations. Hitherto, the detailed movements within the organ of Corti were only surmised.

Our most recent efforts center on the molecular biology of the motor protein that drives outer hair cell motility. We identified the gene prestin from gerbil and mouse outer hair cells. This gene is responsible for the novel motor protein, prestin. A major effort is now underway to study the properties of this molecular motor. This research includes an extensive investigation of the functional effects of selected mutations in the protein's amino acid sequence. We are also investigating in vivo physiology in a prestin knockout mouse model and in several transgenic mice in which prestin function is altered.

Prestin molecule