Platelet-Derived Growth Factor Subunit B Signaling Promotes Pericyte Migration in Response to Loud Sound in the Cochlear Stria Vascularis

Abstract

Normal blood supply to the cochlea is critical for hearing. Noise damages auditory sensory cells and has a marked effect on the microvasculature in the cochlear lateral wall. Pericytes in the stria vascularis (strial pericytes) are particularly vulnerable and sensitive to acoustic trauma. Exposure of NG2DsRedBAC transgenic mice (6–8 weeks old) to wide-band noise at a level of 120 dB for 3 h per day for 2 consecutive days produced a significant hearing threshold shift and caused pericytes to protrude and migrate from their normal endothelial attachment sites. The pericyte migration was associated with increased expression of platelet-derived growth factor beta (PDGF-BB). Blockade of PDGF-BB signaling with either imatinib, a potent PDGF-BB receptor (PDGFR) inhibitor, or APB5, a specific PDGFRβ blocker, significantly attenuated the pericyte migration from strial vessel walls. The PDGF-BB-mediated strial pericyte migration was further confirmed in an in vitro cell migration assay, as well as in an in vivo live animal model used in conjunction with confocal fluorescence microscopy. Pericyte migration took one of two different forms, here denoted protrusion and detachment. The protrusion is characterized by pericytes with a prominent triangular shape, or pericytes extending fine strands to neighboring capillaries. The detachment is characterized by pericyte detachment and movement away from vessels. We also found the sites of pericyte migration highly associated with regions of vascular leakage. In particular, under transmission electron microscopy (TEM), multiple vesicles at the sites of endothelial cells with loosely attached pericytes were observed. These data show that cochlear pericytes are markedly affected by acoustic trauma, causing them to display abnormal morphology. The effect of loud sound on pericytes is mediated by upregulation of PDGF-BB. Normal functioning pericytes are required for vascular stability.

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Psychophysical Tuning Curves as a Correlate of Electrode Position in Cochlear Implant Listeners

ABSTRACT

Speech understanding abilities vary widely among cochlear implant (CI) listeners. A potential source of this variability is the electrode-neuron interface (ENI), which includes peripheral factors such as electrode position and integrity of remaining spiral ganglion neurons. Suboptimal positioning of the electrode array has been associated with poorer speech outcomes; however, postoperative computerized tomography (CT) scans are often not available to clinicians. CT-estimated electrode-to-modiolus distance (distance from the inner wall of the cochlea) has been shown to account for some variability in behavioral thresholds. However, psychophysical tuning curves (PTCs) may provide additional insight into site-specific variation in channel interaction. Thirteen unilaterally implanted adults with the Advanced Bionics HiRes90K device participated. Behavioral thresholds and PTCs were collected for all available electrodes with steered quadrupolar (sQP) configuration, using a modified threshold sweep procedure, used in Bierer et al. (Trends Hear 19:1–12, 2015). PTC bandwidths were quantified to characterize channel interaction across the electrode array, and tip shifts were assessed to identify possible contributions of neural dead regions. Broader PTC bandwidths were correlated with electrodes farther from the modiolus, but not correlated with sQP threshold, though a trend was observed. Both measures were affected by scalar location, and PTC tip shifts were observed for electrodes farther from the modiolus. sQP threshold was the only variable correlated with word recognition. These results suggest PTCs may be used as a site-specific measure of channel interaction that correlates with electrode position in some CI listeners.

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Characterization of Adult Vestibular Organs in 11 CreER Mouse Lines

Abstract

Utricles are vestibular sense organs that encode linear head movements. They are composed of a sensory epithelium with type I and type II hair cells and supporting cells, sitting atop connective tissue, through which vestibular nerves project. We characterized utricular Cre expression in 11 murine CreER lines using the ROSA26^tdTomato reporter line and tamoxifen induction at 6 weeks of age. This characterization included Calbindin2^CreERT2 , Fgfr3-iCreER^T2 , GFAP-A-CreER™, GFAP-B-CreER™, GLAST-CreER^T2 , Id2^CreERT2 , Otoferlin^CreERT2 , Parvalbumin^CreERT2 , Prox1^CreERT2 , Sox2^CreERT2 , and Sox9-CreER^T2 . Otoferlin^CreERT2 mice had inducible Cre activity specific to hair cells. GLAST-CreER^T2 , Id2^CreERT2 , and Sox9-CreER^T2 had inducible Cre activity specific to supporting cells. Sox2^CreERT2 had inducible Cre activity in supporting cells and most type II hair cells. Parvalbumin^CreERT2 mice had small numbers of labeled vestibular nerve afferents. Calbindin2^CreERT2 mice had labeling of most type II hair cells and some type I hair cells and supporting cells. Only rare (or no) tdTomato-positive cells were detected in utricles of Fgfr3-iCreER^T2 , GFAP-A-CreER™, GFAP-B-CreER™, and Prox1^CreERT2 mice. No Cre leakiness (tdTomato expression in the absence of tamoxifen) was observed in Otoferlin^CreERT2 mice. A small degree of leakiness was seen in GLAST-CreER^T2 , Id2^CreERT2 , Sox2^CreERT2 , and Sox9-CreER^T2 lines. Calbindin2^CreERT2 mice had similar tdTomato expression with or without tamoxifen, indicating lack of inducible control under the conditions tested. In conclusion, 5 lines—GLAST-CreER^T2 , Id2^CreERT2 , Otoferlin^CreERT2 , Sox2^CreERT2 , and Sox9-CreER^T2 —showed cell-selective, inducible Cre activity with little leakiness, providing new genetic tools for researchers studying the vestibular periphery.

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