Mary Ann Cheatham
Over the years, we have addressed problems in the biophysics and neurobiology of the mammalian cochlea. A gamut of techniques, ranging from animal behavior, through single cell recording, to molecular biology, were used to deal with various topics. For example, the relationship between compound cochlear and neural potentials and their single-cell precursors was defined, as well as the properties and nature of cochlear summating potentials. All of these investigations were designed to address our primary aim: to delineate the molecular 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. The subsequent study of isolated outer hair cells in vitro demonstrated that these cells possess the ability to change their shape in response to electric and acoustic stimulation. In fact, it is now commonly assumed that shape changes are the basis of a feedback mechanism responsible for the exquisite sensitivity and frequency resolving ability of the mammalian inner ear. Hence, we used a molecular approach to identify the motor that powers the motile response. Following the discovery of the novel motor protein, prestin, an extensive investigation was undertaken to define the in vivo physiology of a prestin knockout mouse, as well as several transgenic mouse models in which prestin function is altered
These investigations now provide a foundation for further studies using the mouse in auditory research. Given that mice and humans carry several homologous genes for hereditary deafness, mice provide an important animal model for studying hearing loss of genetic origin, which affects at least 1 in 2000 births. Because of the several mutagenesis programs now established worldwide, the numbers of genes associated with the inner ear will increase rapidly, thereby providing a genetic approach to the study of cochlear physiology. Our current focus is on the processes underlying cochlear amplification and how they are influenced by the tectorial membrane that overlies the organ of Corti and into which to the tallest outer hair cell stereocilia insert. When the tectorial membrane is detached, the cochlea is insensitive and no longer functions as a frequency analyzer. Our recent studies of various tectorial membrane mutants indicates that this accessory structure is required to stabilize a high-gain system required for cochlear amplification.
Collaborators at the Feinberg School of Medicine
Jaime García-Añoveros, Jeffrey Savas, Kazuaki Homma, Jing Zheng
Cheatham, M. A. and P. Dallos, The dynamic range of inner hair cell and organ of Corti responses, J. Acoust. Soc. Amer. 107, 1508-1520 (2000).
Cheatham, M.A., K.H. Huynh, J. Gao, J. Zuo, P. Dallos, Cochlear function in Prestin knockout mice. J. Physiol. (London) 560.3: 821-830 (2004).
Cheatham, M.A. ,Zheng, J., Huynh, K.H. , Du, G.G., Gao, J., Zuo, J., Navarrete.E. and Dallos, P. Cochlear function in mice with only one copy of the Prestin gene. J. Physiol. (London) 569.1: 229-241 (2005).
Zheng, J., G.G. Du, C.T. Anderson, J.P. Keller, R. Edge, A. Orem, P. Dallos and M.A. Cheatham, Analysis of the oligomeric structure of the motor protein prestin. J. Biol. Chem. 281: 19916-19924 (2006).
Cheatham MA, Huynh K, Zheng J, Du GG, Edge R, Anderson CT, Ryan AF, Zuo J, Dallos P, Evaluation of a prestin mouse model derived from the 129S1 strain, Audiol. and Neurotol. 12: 379-390 (2007).
Gao J, Wang X, Wu X, Aguinaga S, Huynh K, Matsuda K, Jia S, Patel M, Zheng J, Cheatham MA*, He DZZ*, Dallos P* and Zuo J*, Hyperpolarizing shifts of outer hair cell nonlinear capacitance and electromotility in prestin knockin mice do not change sensitivity or tuning, *Equal contributions. Proc. Natl. Acad. Sci. USA 104: 12542-12547 (2007).
Dallos P, Wu X, Cheatham MA, Gao J, Zheng J, Anderson CT, Jia S, Cheng WHY, He DZZ, Zuo J, Prestin-based outer hair cell motility is necessary for mammalian cochlear amplification. Neuron 58: 333-339 (2008).
Cheatham, M.A., Low-Zeddies, S., Naik, K., Edge, R., Zheng, J., Anderson, C.T. and Dallos, P. (2009). A chimera analysis of prestin knock-out mice. J. Neurosci., 29, 12000-12008.
Cheatham, M.A., Naik, K. and Dallos, P. (2011). Using the cochlear microphonic as a tool to evaluate cochlear function in mouse models of hearing. JARO 12, 113-125.
Cheatham, M.A., Goodyear R., Homma, K., Legan, K.P., Korchagina, J., Naskar S., Siegel, J.H., Dallos, P., Zheng, J., and Richardson, G.P. (2014). Loss of tectorial membrane protein, Ceacam16, enhances spontaneous, stimulus frequency and transiently-evoked otoacoustic emissions. J. Neurosci., 34, 10361-10378.
Keller JP, Homma K, Duan C, Zheng J, Cheatham MA, Dallos P. (2014). Generalizable calmodulin-mediated regulation of slc26 proteins as exemplified in slc26a5. J. Neurosci. 34, 1325-1332. PMCID: PMC3898292.
Cheatham, M.A., Edge, R.M., Homma, K., Leserman, E.L., Dallos, P. and Zheng J. (2015). Prestin-dependence of outer hair cell survival and partial rescue of outer hair cell loss in prestinV499G/Y501H knockin mice. PLoS One 10(12): e0145428.
Cheatham, M.A., Ahmad, A., Zhou, Y., Goodyear R.J., Dallos, P. and Richardson G.P. (2016). Increased spontaneous otoacoustic emissions in mice with a detached tectorial membrane. JARO 17, 81-88.
Xu, Y., Cheatham, M.A. and Siegel, J.H. (2017). Identifying the origin of effects of contralateral noise on transient evoked otoacoustic emissions in unanesthetized mice. JARO 18, 543-553.
Cheatham MA, Zhou Y, Goodyear RJ, Dallos P, Richardson GP (2018) Spontaneous otoacoustic emissions in TectaY1870C/+ mice reflect changes in cochlear amplification and how it is controlled by the tectorial membrane. eNeuro 5, 0314-0318.
Takahashi S, Yamashita T, Homma K, Zhou Y, Zuo J, Zheng J, Cheatham MA (2019). Deletion of exons 17 and 18 in prestin’s STAS domain results in loss of function. Sci Rep 9: 6874.
Goodyear RJ, Cheatham MA, Naskar S, Zhou Y, Osgood RT, Zheng J, Richardson GP (2019). Accelerated age-related degradation of the tectorial membrane in the Ceacam16bgal/bgal null mutant mouse, a model for late-onset human hereditary deafness DFNB113. Front Mol Neurosci, 12: 147.