3D morphology of an outer-hair-cell hair bundle increases its displacement and dynamic range.

In mammals, outer-hair-cell hair bundles (OHBs) transduce sound-induced forces into receptor currents and are required for the wide dynamic range and high sensitivity of hearing. OHBs differ conspicuously in morphology from other types of bundles. Here, we show that the 3D morphology of an OHB greatly impacts its mechanics and transduction. An OHB comprises rod-like stereocilia, which pivot on the surface of its sensory outer hair cell. Stereocilium pivot positions are arranged in columns and form a V shape. We measure the pivot positions and determine that OHB columns are far from parallel. To calculate the consequences of an OHB's V shape and far-from-parallel columns, we develop a mathematical model of an OHB that relates its pivot positions, 3D morphology, mechanics, and receptor current. We find that the 3D morphology of the OHB can halve its stiffness, can double its damping coefficient, and causes stereocilium displacements driven by stimulus forces to differ substantially across the OHB. Stereocilium displacements drive the opening and closing of ion channels through which the receptor current flows. Owing to the stereocilium-displacement differences, the currents passing through the ion channels can peak versus the stimulus frequency and vary considerably across the OHB. Consequently, the receptor current peaks versus the stimulus frequency. Ultimately, the OHB's 3D morphology can increase its receptor-current dynamic range more than twofold. Our findings imply that potential pivot-position changes owing to development, mutations, or location within the mammalian auditory organ might greatly alter OHB function.

Loxhd1 Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells.

Sound detection happens in the inner ear via the mechanical deflection of the hair bundle of cochlear hair cells. The hair bundle is an apical specialization consisting of actin-filled membrane protrusions (called stereocilia) connected by tip links (TLs) that transfer the deflection force to gate the mechanotransduction channels. Here, we identified the hearing loss-associated Loxhd1/DFNB77 gene as being required for the mechanotransduction process. LOXHD1 consists of 15 polycystin lipoxygenase α-toxin (PLAT) repeats, which in other proteins can bind lipids and proteins. LOXHD1 was distributed along the length of the stereocilia. Two LOXHD1 mouse models with mutations in the 10th PLAT repeat exhibited mechanotransduction defects (in both sexes). While mechanotransduction currents in mutant inner hair cells (IHCs) were similar to wild-type levels in the first postnatal week, they were severely affected by postnatal day 11. The onset of the mechanotransduction phenotype was consistent with the temporal progression of postnatal LOXHD1 expression/localization in the hair bundle. The mechanotransduction defect observed in Loxhd1-mutant IHCs was not accompanied by a morphologic defect of the hair bundle or a reduction in TL number. Using immunolocalization, we found that two proteins of the upper and lower TL protein complexes (Harmonin and LHFPL5) were maintained in the mutants, suggesting that the mechanotransduction machinery was present but not activatable. This work identified a novel LOXHD1-dependent step in hair bundle development that is critical for mechanotransduction in mature hair cells as well as for normal hearing function in mice and humans.SIGNIFICANCE STATEMENT Hair cells detect sound-induced forces via the hair bundle, which consists of membrane protrusions connected by tip links. The mechanotransduction machinery forms protein complexes at the tip-link ends. The current study showed that LOXHD1, a multirepeat protein responsible for hearing loss in humans and mice when mutated, was required for hair-cell mechanotransduction, but only after the first postnatal week. Using immunochemistry, we demonstrated that this defect was not caused by the mislocalization of the tip-link complex proteins Harmonin or LHFPL5, suggesting that the mechanotransduction protein complexes were maintained. This work identified a new step in hair bundle development, which is critical for both hair-cell mechanotransduction and hearing.

Using thermographic cameras to investigate eye temperature and clinical severity in depression.

Previous studies suggest that altered corneal temperature may be a feature of schizophrenia, but the association between major depressive disorder (MDD) and corneal temperature has yet to be assessed. The aim of this study is to investigate whether eye temperature is different among MDD patients than among healthy individuals. We used a thermographic camera to measure and compare the temperature profile across the corneas of 16 patients with MDD and 16 age- and sex-matched healthy subjects. We found that the average corneal temperature between the two groups did not differ statistically, although clinical severity correlated positively with right corneal temperature. Corneal temperature may be an indicator of clinical severity in psychiatric disorders, including depression.