Yuan Zhang

Chromosomal localization of three human D5 dopamine receptor genes

It is currently thought that genetic predisposition to imbalances in dopaminergic transmission may underlie several neurological disorders, including schizophrenia, manic depression, Tourette syndrome, Parkinson disease, Huntington disease, and alcohol abuse. Originally two receptors, D1 and D2, were thought to account for all of the pharmacological actions of dopamine. However, through homology screening three additional genes, D3, D4, and D5, and two pseudogenes closely related to D5 have been characterized. To begin our genomic and evolutionary analyses of the human D5 dopamine receptor gene and its two pseudogenes, we have mapped each of them to their respective chromosomes. By combining in situ hybridization results with sequence analysis of PCR products from microdissected chromosomes, somatic cell hybrids, and radiation hybrids, we have assigned DRD5 (the locus containing the functional human D5 receptor gene) to chromosome 4p16.1, DRD5P1 (the locus containing D5 pseudogene 1) to chromosome 2p11.1-p11.2, and DRD5P2 (the locus of D5 pseudogene 2) to chromosome 1q21.1.

Minimal basilar membrane motion in low-frequency hearing

Significance To perceive speech, the brain relies on inputs from sensory cells located near the top of the spiral-shaped cochlea. This low-frequency region of the inner ear is anatomically difficult to access, and it has not previously been possible to study its mechanical response to sound in intact preparations. Here, we used optical coherence tomography to image sound-evoked vibration inside the intact cochlea. We show that low-frequency sound moves a small portion of the basilar membrane, and that the motion declines in an exponential manner across the basilar membrane. Hence, the response of the hearing organ to speech-frequency sounds is different from the one evident in high-frequency cochlear regions. Low-frequency hearing is critically important for speech and music perception, but no mechanical measurements have previously been available from inner ears with intact low-frequency parts. These regions of the cochlea may function in ways different from the extensively studied high-frequency regions, where the sensory outer hair cells produce force that greatly increases the sound-evoked vibrations of the basilar membrane. We used laser interferometry in vitro and optical coherence tomography in vivo to study the low-frequency part of the guinea pig cochlea, and found that sound stimulation caused motion of a minimal portion of the basilar membrane. Outside the region of peak movement, an exponential decline in motion amplitude occurred across the basilar membrane. The moving region had different dependence on stimulus frequency than the vibrations measured near the mechanosensitive stereocilia. This behavior differs substantially from the behavior found in the extensively studied high-frequency regions of the cochlea.

JAK2/STAT3 Inhibition Attenuates Noise-Induced Hearing Loss

Signal transducers and activators of transcription 3 (STAT3) is a stress responsive transcription factor that plays a key role in oxidative stress-mediated tissue injury. As reactive oxygen species (ROS) are a known source of damage to tissues of the inner ear following loud sound exposure, we examined the role of the Janus kinase 2 (JAK2)/STAT3 signaling pathway in noise induce hearing loss using the pathway specific inhibitor, JSI-124. Mice were exposed to a moderately damaging level of loud sound revealing the phosphorylation of STAT3 tyrosine 705 residues and nuclear localization in many cell types in the inner ear including the marginal cells of the stria vascularis, type II, III, and IV fibrocytes, spiral ganglion cells, and in the inner hair cells. Treatment of the mice with the JAK2/STAT3 inhibitor before noise exposure reduced levels of phosphorylated STAT3 Y705. We performed auditory brain stem response and distortion product otoacoustic emission measurements and found increased recovery of hearing sensitivity at two weeks after noise exposure with JAK2/STAT3 inhibition. Performance of cytocochleograms revealed improved outer hair cell survival in JSI-124 treated mice relative to control. Finally, JAK2/STAT3 inhibition reduced levels of ROS detected in outer hair cells at two hours post noise exposure. Together, these findings demonstrate that inhibiting the JAK2/STAT3 signaling pathway is protective against noise-induced cochlear tissue damage and loss of hearing sensitivity.

Minimally invasive surgical method to detect sound processing in the cochlear apex by optical coherence tomography

Abstract. Sound processing in the inner ear involves separation of the constituent frequencies along the length of the cochlea. Frequencies relevant to human speech (100 to 500 Hz) are processed in the apex region. Among mammals, the guinea pig cochlear apex processes similar frequencies and is thus relevant for the study of speech processing in the cochlea. However, the requirement for extensive surgery has challenged the optical accessibility of this area to investigate cochlear processing of signals without significant intrusion. A simple method is developed to provide optical access to the guinea pig cochlear apex in two directions with minimal surgery. Furthermore, all prior vibration measurements in the guinea pig apex involved opening an observation hole in the otic capsule, which has been questioned on the basis of the resulting changes to cochlear hydrodynamics. Here, this limitation is overcome by measuring the vibrations through the unopened otic capsule using phase-sensitive Fourier domain optical coherence tomography. The optically and surgically advanced method described here lays the foundation to perform minimally invasive investigation of speech-related signal processing in the cochlea.

Measurement of in vivo basal-turn vibrations of the organ of Cortiusing phase-sensitive Fourier domain optical coherence tomography

A major reason we can perceive faint sounds and communicate in noisy environments is that the outer hair cells of the organ of Corti enhance the sound-evoked motions inside the cochlea. To understand how the organ of Corti works, we have built and tested the phase-sensitive Fourier domain optical coherence tomography (PSFDOCT) system. This system has key advantages over our previous time domain OCT system [1]. The PSFDOCT system has better signal to noise and simultaneously acquires vibration data from all points along the optical-axis [2]. Feasibility of this system to measure in vitro cochlear vibrations in the apex was demonstrated earlier [3]. In this study, we measure the in vivo vibrations of the organ of Corti via round window in live anaesthetized guinea pigs using PSFDOCT. This region of the guinea pig cochlea responds to very high frequencies (10 - 40 kHz). The current vibration noise floor for native organ of Corti tissue is 0.03 nm in this frequency range. Sound-induced vibrations of the stapes, which delivers input to the cochlea, are also measured. The measured vibrations of the organ of Corti demonstrate non-linear compression and active amplification characteristic of sensitive mammalian cochlea.

Development of a phase-sensitive Fourier domain optical coherence tomography system to measure mouse organ of Corti vibrations in two cochlear turns

In this study, we have developed a phase-sensitive Fourier-domain optical coherence tomography system to simultaneously measure the in vivo inner ear vibrations in the hook area and second turn of the mouse cochlea. This technical development will enable measurement of intra-cochlear distortion products at ideal locations such as the distortion product generation site and reflection site. This information is necessary to un-mix the complex mixture of intra-cochlear waves comprising the DPOAE and thus leads to the non-invasive identification of the local region of cochlear damage.

A mechanoelectrical mechanism for detection of sound envelopes in the hearing organ

To understand speech, the slowly varying outline, or envelope, of the acoustic stimulus is used to distinguish words. A small amount of information about the envelope is sufficient for speech recognition, but the mechanism used by the auditory system to extract the envelope is not known. Several different theories have been proposed, including envelope detection by auditory nerve dendrites as well as various mechanisms involving the sensory hair cells. We used recordings from human and animal inner ears to show that the dominant mechanism for envelope detection is distortion introduced by mechanoelectrical transduction channels. This electrical distortion, which is not apparent in the sound-evoked vibrations of the basilar membrane, tracks the envelope, excites the auditory nerve, and transmits information about the shape of the envelope to the brain.The sound envelope is important for speech perception. Here, the authors look at mechanisms by which the sound envelope is encoded, finding that it arises from distortion produced by mechanoelectrical transduction channels. Surprisingly, the envelope is not present in basilar membrane vibrations.

Two dimensional vibrations of the guinea pig apex organ of Corti measured in vivo using phase sensitive Fourier domain optical coherence tomography

In this study, we measure the in vivo apical-turn vibrations of the guinea pig organ of Corti in both axial and radial directions using phase-sensitive Fourier domain optical coherence tomography. The apical turn in guinea pig cochlea has best frequencies around 100 – 500 Hz which are relevant for human speech. Prior measurements of vibrations in the guinea pig apex involved opening the otic capsule, which has been questioned on the basis of the resulting changes to cochlear hydrodynamics. Here this limitation is overcome by measuring the vibrations through bone without opening the otic capsule. Furthermore, we have significantly reduced the surgery needed to access the guinea pig apex in the axial direction by introducing a miniature mirror inside the bulla. The method and preliminary data are discussed in this article.