Publications by authors named "Richard Salvi"

217 Publications

High-frequency Noise-induced Hearing Loss Disrupts Functional Connectivity in Non-auditory Areas with Cognitive Disturbances.

Neurosci Bull 2021 Mar 27. Epub 2021 Mar 27.

Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.

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http://dx.doi.org/10.1007/s12264-021-00663-2DOI Listing
March 2021

Emerging Topics in the Behavioral Neuroscience of Tinnitus.

Curr Top Behav Neurosci 2021 Mar 5. Epub 2021 Mar 5.

Eisdell Moore Centre, The University of Auckland, Auckland, New Zealand.

This volume has highlighted the many recent advances in tinnitus theory, models, diagnostics, therapies, and therapeutics. But tinnitus knowledge is far from complete. In this chapter, contributors to the Behavioral Neuroscience of Tinnitus consider emerging topics and areas of research needed in light of recent findings. New research avenues and methods to explore are discussed. Issues pertaining to current assessment, treatment, and research methods are outlined, along with recommendations on new avenues to explore with research.
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http://dx.doi.org/10.1007/7854_2020_217DOI Listing
March 2021

Temporal characteristics of the cochlear response after noise exposure.

Hear Res 2021 May 18;404:108208. Epub 2021 Feb 18.

Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, New York 14214, USA.

The effect of intense noise on cochlear sensitivity has been extensively studied, but its influence on the temporal characteristics of the cochlear response is still unclear. This study investigated the effects of noise exposure on the latency of cochlear response and cochlear forward masking. Rats were exposed to an octave band noise (8-16 kHz) at 90 dB SPL for 5 days. Cochlear compound action potentials (CAPs) induced by single- and double-tone stimuli and distortion product otoacoustic emissions (DPOAE) were recorded 1 day or 2 months after the noise exposure. The latency of the CAP and its forward masking were compared between the noise-exposed rats and normal control rats. The noise exposure significantly reduced DPOAE and elevated CAP threshold in the noise band region, but not in the other areas. Even in the noise band area, the noise did not reduce CAP-amplitude at the high stimulation level (80 dB SPL). Correspondingly, about one-third of the outer hair cells (OHC) in the noise band area disappeared, while the inner hair cells (IHC) did not. However, the noise exposure in the frequency range of 4-24 kHz significantly prolonged CAP latency and increased its variability, while the CAP forward masking effect was significantly enhanced in the frequency range of 16-30 kHz. The frequency-dependent changes in CAP latency and forward masking after noise exposure may reflect different types of synaptic subinjury in the cochlea, which may lead to psychophysical consequences of sound localization and speech recognition.
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http://dx.doi.org/10.1016/j.heares.2021.108208DOI Listing
May 2021

Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal).

Prog Brain Res 2021 1;260:1-25. Epub 2021 Feb 1.

Department of Psychiatry and Psychotherapy, Bezirksklinikum, University of Regensburg, Regensburg, Germany.

As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO's ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association's DSM-V doesn't mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: "Tinnitus" for the former and "Tinnitus Disorder" for the latter. The proposed definition then becomes "Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder "when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.". In other words "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder.
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http://dx.doi.org/10.1016/bs.pbr.2020.12.002DOI Listing
February 2021

Neuroplastic changes in auditory cortex induced by long-duration "non-traumatic" noise exposures are triggered by deficits in the neural output of the cochlea.

Hear Res 2021 May 12;404:108203. Epub 2021 Feb 12.

Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, 137 Cary Hall, 3435 Main Street, NY 14214, USA.

Long-term exposure to moderate intensity noise that does not cause measureable hearing loss can cause striking changes in sound-evoked neural activity in auditory cortex.  It is unclear if these changes originate in the cortex or result from functional deficits in the neural output of the cochlea.  To explore this issue, rats were exposed for 6-weeks to 18-24 kHz noise at 45, 65 or 85 dB SPL and then compared the noise-induced changes in the cochlear compound action potential (CAP) with the neurophysiological alterations in the anterior auditory field (AAF) of auditory cortex. The 45-dB exposure, which had no effect on the cochlear CAP also had no effect on the AAF. In contrast, the 85-dB exposure greatly reduced CAP amplitudes at high frequencies, but had little or no effect on low frequencies. Despite the large reduction in high-frequency CAP neural responses, high frequency AAF neural responses (spike rate and local field potential amplitude) remained largely within normal limits, evidence of central gain compensation. AAF responses were also enhanced at the low frequencies even though CAP responses were normal; this AAF hyperactivity only occurred at low-moderate intensities (level-dependent enhanced central gain). The 65-dB exposure also caused a moderate reduction in high-frequency CAP amplitudes. Notwithstanding this cochlear loss, AAF responses were boosted into the normal range, evidence of homeostatic gain compensation. Our results suggest that the noise-induced neuroplastic changes in the auditory cortex from so-called "non-traumatic" exposures are triggered from functional deficits in the neural output of the cochlea.
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http://dx.doi.org/10.1016/j.heares.2021.108203DOI Listing
May 2021

Review: Neural Mechanisms of Tinnitus and Hyperacusis in Acute Drug-Induced Ototoxicity.

Am J Audiol 2021 Jan 19:1-15. Epub 2021 Jan 19.

Center for Hearing & Deafness, Department of Communicative Disorders and Sciences, The State University of New York at Buffalo.

Purpose Tinnitus and hyperacusis are debilitating conditions often associated with age-, noise-, and drug-induced hearing loss. Because of their subjective nature, the neural mechanisms that give rise to tinnitus and hyperacusis are poorly understood. Over the past few decades, considerable progress has been made in deciphering the biological bases for these disorders using animal models. Method Important advances in understanding the biological bases of tinnitus and hyperacusis have come from studies in which tinnitus and hyperacusis are consistently induced with a high dose of salicylate, the active ingredient in aspirin. Results Salicylate induced a transient hearing loss characterized by a reduction in otoacoustic emissions, a moderate cochlear threshold shift, and a large reduction in the neural output of the cochlea. As the weak cochlear neural signals were relayed up the auditory pathway, they were progressively amplified so that the suprathreshold neural responses in the auditory cortex were much larger than normal. Excessive central gain (neural amplification), presumably resulting from diminished inhibition, is believed to contribute to hyperacusis and tinnitus. Salicylate also increased corticosterone stress hormone levels. Functional imaging studies indicated that salicylate increased spontaneous activity and enhanced functional connectivity between structures in the central auditory pathway and regions of the brain associated with arousal (reticular formation), emotion (amygdala), memory/spatial navigation (hippocampus), motor planning (cerebellum), and motor control (caudate/putamen). Conclusion These results suggest that tinnitus and hyperacusis arise from aberrant neural signaling in a complex neural network that includes both auditory and nonauditory structures.
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http://dx.doi.org/10.1044/2020_AJA-20-00023DOI Listing
January 2021

Switching Tinnitus-On: Maps and source localization of spontaneous EEG.

Clin Neurophysiol 2021 Feb 23;132(2):345-357. Epub 2020 Nov 23.

Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai 200233, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai 200233, China.

Objective: To identify the spectrotemporal changes and sources in patients that could "turn on" tinnitus with multichannel electroencephalography (EEG) system.

Methods: Multichannel EEG was recorded from six patients during the Tinnitus-On and Tinnitus-Off states. The EEG power spectrum and eLORETA-based sources were measured.

Results: There was a global increase in delta and theta during Tinnitus-On plus large changes in alpha 1 and alpha 2. During the Tinnitus-On state, many new sources in delta, theta, alpha 1 and gamma bands emerged in the opposite hemisphere in the inferior temporal gyrus (Brodmann area, BA 20), middle temporal gyrus (BA 21), lateral perirhinal cortex (BA 36), ventral entorhinal cortex (BA 28) and anterior pole of the temporal gyrus (BA 38).

Conclusions: The emergence of new delta, theta and gamma band sources in the inferior temporal gyrus (BA 20), middle temporal gyrus (BA 21) and lateral perirhinal cortex (BA 36) plus the appearance of new delta and theta sources in the ventral entorhinal cortex (BA28) and anterior pole of the temporal lobe (BA 38) may comprise a network capable of evoking the phantom sound of tinnitus by simultaneously engaging brain regions involved in memory, sound recognition, and distress which together contribute to tinnitus severity.

Significance: The sudden appearance of new sources of activity in the opposite hemisphere within the inferior temporal gyrus, middle temporal gyrus and perirhinal cortex may initiate the perception of tinnitus perception.
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http://dx.doi.org/10.1016/j.clinph.2020.10.023DOI Listing
February 2021

Cochlear spiral ganglion neuron degeneration following cyclodextrin-induced hearing loss.

Hear Res 2021 Feb 27;400:108125. Epub 2020 Nov 27.

Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY 14221, USA. Electronic address:

Because cyclodextrins are capable of removing cholesterol from cell membranes, there is growing interest in using these compounds to treat diseases linked to aberrant cholesterol metabolism. One compound, 2-hydroxypropyl-beta-cyclodextrin (HPβCD), is currently being evaluated as a treatment for Niemann-Pick Type C1 disease, a rare, fatal neurodegenerative disease caused by the buildup of lipids in endosomes and lysosomes. HPβCD can reduce some debilitating symptoms and extend life span, but the therapeutic doses used to treat the disease cause hearing loss. Initial studies in rodents suggested that HPβCD selectively damaged only cochlear outer hair cells during the first week post-treatment. However, our recent in vivo and in vitro studies suggested that the damage could become progressively worse and more extensive over time. To test this hypothesis, we treated rats subcutaneously with 1, 2, 3 or 4 g/kg of HPβCD and waited for 8-weeks to assess the long-term histological consequences. Our new results indicate that the two highest doses of HPβCD caused extensive damage not only to OHC, but also to inner hair cells, pillar cells and other support cells resulting in the collapse and flattening of the sensory epithelium. The 4 g/kg dose destroyed all the outer hair cells and three-fourths of the inner hair cells over the basal two-thirds of the cochlea and more than 85% of the nerve fibers in the habenula perforata and more than 80% of spiral ganglion neurons in the middle of basal turn of the cochlea. The mechanisms that lead to the delayed degeneration of inner hair cells, pillar cells, nerve fibers and spiral ganglion neurons remain poorly understood, but may be related to the loss of trophic support caused by the degeneration of sensory and/or support cells in the organ of Corti. Despite the massive damage to the cochlear sensory epithelium, the blood vessels in the stria vascularis and the vestibular hair cells in the utricle and saccule remained normal.
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http://dx.doi.org/10.1016/j.heares.2020.108125DOI Listing
February 2021

Occupational Noise: Auditory and Non-Auditory Consequences.

Int J Environ Res Public Health 2020 12 2;17(23). Epub 2020 Dec 2.

Department of Communicative Disorders and Sciences and Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14221, USA.

Occupational noise exposure accounts for approximately 16% of all disabling hearing losses, but the true value and societal costs may be grossly underestimated because current regulations only identify hearing impairments in the workplace if exposures result in audiometric threshold shifts within a limited frequency region. Research over the past several decades indicates that occupational noise exposures can cause other serious auditory deficits such as tinnitus, hyperacusis, extended high-frequency hearing loss, and poor speech perception in noise. Beyond the audiogram, there is growing awareness that hearing loss is a significant risk factor for other debilitating and potentially life-threatening disorders such as cardiovascular disease and dementia. This review discusses some of the shortcomings and limitations of current noise regulations in the United States and Europe.
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http://dx.doi.org/10.3390/ijerph17238963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729999PMC
December 2020

Adenosine A2B receptor: A pathogenic factor and a therapeutic target for sensorineural hearing loss.

FASEB J 2020 Dec 1;34(12):15771-15787. Epub 2020 Nov 1.

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Over 466 million people worldwide are diagnosed with hearing loss (HL). About 90% of HL cases are sensorineural HL (SNHL) with treatments limited to hearing aids and cochlear implants with no FDA-approved drugs. Intriguingly, ADA-deficient patients have been reported to have bilateral SNHL, however, its underlying cellular and molecular basis remain unknown. We report that Ada mice, phenocopying ADA-deficient humans, displayed SNHL. Ada mice cochlea with elevated adenosine caused substantial nerve fiber demyelination and mild hair cell loss. ADA enzyme therapy in these mice normalized cochlear adenosine levels, attenuated SNHL, and prevented demyelination. Additionally, ADA enzyme therapy rescued SNHL by restoring nerve fiber structure in Ada mice post two-week drug withdrawal. Moreover, elevated cochlear adenosine in untreated mice was associated with enhanced Adora2b gene expression. Preclinically, ADORA2B-specific antagonist treatment in Ada mice significantly improved HL, nerve fiber density, and myelin compaction. We also provided genetic evidence that ADORA2B is detrimental for age-related SNHL by impairing cochlear myelination in WT aged mice. Overall, understanding purinergic molecular signaling in SNHL in Ada mice allows us to further discover that ADORA2B is also a pathogenic factor underlying aged-related SNHL by impairing cochlear myelination and lowering cochlear adenosine levels or blocking ADORA2B signaling are effective therapies for SNHL.
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http://dx.doi.org/10.1096/fj.202000939RDOI Listing
December 2020

Accelerated age-related decline in hippocampal neurogenesis in mice with noise-induced hearing loss is associated with hippocampal microglial degeneration.

Aging (Albany NY) 2020 Oct 11;12(19):19493-19519. Epub 2020 Oct 11.

Department of Physiology, Medical College, Southeast University, Nanjing 210009, China.

Large-scale epidemiological surveys suggest that hearing loss (HL) is a significant risk factor for dementia. We previously showed that noise-induced HL (NIHL) impairs hippocampal cognitive function and decreases hippocampal neurogenesis and neuronal complexity, suggesting a causal role of HL in dementia. To further investigate the influence of acquired peripheral HL on hippocampal neurogenesis with the aging process as well as the underlying mechanism, we produced NIHL in male CBA/J mice and assessed hippocampal neurogenesis and microglial morphology in the auditory brain and hippocampus at 4 days post-noise exposure (DPN) or 1, 3, 6, or 12 months post-noise exposure (MPN) by immunofluorescence labeling. We found that the age-related decline in hippocampal neurogenesis was accelerated in mice with NIHL. Furthermore, in mice with NIHL, prolonged microglial activation occurred from 1 MPN to 12 MPN across multiple auditory nuclei, while aggravated microglial deterioration occurred in the hippocampus and correlated with the age-related decline in hippocampal neurogenesis. These results suggest that acquired peripheral HL accelerates the age-related decline in hippocampal neurogenesis and that hippocampal microglial degeneration may contribute to the development of neurodegeneration following acquired peripheral HL.
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http://dx.doi.org/10.18632/aging.103898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732316PMC
October 2020

Can auditory brain stem response accurately reflect the cochlear function?

J Neurophysiol 2020 12 7;124(6):1667-1675. Epub 2020 Oct 7.

Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, New York.

Auditory brain stem response (ABR) and compound action potential (CAP) recordings have been used in animal research to determine hearing sensitivity. Because of the relative ease of testing, the ABR test has been more commonly used in assessing cochlear lesions than the CAP test. The purpose of this experiment is to examine the difference between these two methods in monitoring the dynamic changes in auditory function after cochlear damage and in detecting asymmetric hearing loss due to unilateral cochlear damage. ABR and CAP were measured in two models of cochlear damage: acoustic trauma induced by exposure to a narrowband noise centered at 4 kHz (2,800-5,600 Hz) at 105 dB sound pressure level for 5 h in chinchillas and unilateral cochlear damage induced by surgical destruction of one cochlea in guinea pigs. Cochlear hair cells were quantified after completing the evoked potential testing. In the noise-damaged model, we found different recovery patterns between ABR and CAP. At 1 day after noise exposure, the ABR and CAP assessment revealed a similar level of threshold shifts. However, at 30 days after noise exposure, ABR thresholds displayed an average of 20-dB recovery, whereas CAP thresholds showed no recovery. Notably, the CAP threshold signifies the actual condition of sensory cell pathogenesis in the cochlea because sensory cell death is known to be irreversible in mammals. After unilateral cochlear damage, we found that both CAP and ABR were affected by cross-hearing when testing the damaged ear with the testing stimuli delivered directly into the canal of the damaged ear. When cross-hearing occurred, ABR testing was not able to reveal the presence of cross-hearing because the ABR waveform generated by cross-stimulation was indistinguishable from that generated by the test ear (damaged ear), should the test ear be intact. However, CAP testing can provide a warning sign, since the typical CAP waveform became an ABR-like waveform when cross-hearing occurred. Our study demonstrates two advantages of the CAP test over the ABR test in assessing cochlear lesions: contributing evidence for the occurrence of cross-hearing when subjects have asymmetric hearing loss and providing a better assessment of the progression of cochlear pathogenesis. Auditory brain stem response (ABR) is more commonly used to evaluate cochlear lesions than cochlear compound action potential (CAP). In a noise-induced cochlear damage model, we found that the reduced CAP and enhanced ABR caused the threshold difference. In a unilateral cochlear destruction model, a shadow curve of the ABR from the contralateral healthy ear masked the hearing loss in the destroyed ear.
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http://dx.doi.org/10.1152/jn.00233.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814896PMC
December 2020

Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence.

Proc Natl Acad Sci U S A 2020 10 5;117(42):26460-26469. Epub 2020 Oct 5.

Department of Pharmacology and Toxicology, Program in Neuroscience, Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214;

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-β (TGF-β) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.
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http://dx.doi.org/10.1073/pnas.2006133117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585028PMC
October 2020

Hydroxypropyl-β-cyclodextrin causes massive damage to the developing auditory and vestibular system.

Hear Res 2020 10 4;396:108073. Epub 2020 Sep 4.

Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY 14214, United States. Electronic address:

2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator used to treat Niemann-Pick C1 (NPC1) lysosomal storage disease, causes hearing loss in mammals by preferentially destroying outer hair cells. Because cholesterol plays an important role in early neural development, we hypothesized that HPβCD would cause more extensive damage to postnatal cochlear and vestibular structures in than adult rats. This hypothesis was tested by administering HPβCD to adult rats and postnatal day 3 (P3) cochlear and vestibular organ cultures. Adult rats treated with HPβCD developed hearing impairment and outer hair cell loss 3-day post-treatment; damage increased with dose from the high frequency base toward the low-frequency apex. The HPβCD-induced histopathologies were more severe and widespread in cochlear and vestibular cultures at P3 than in adults. HPβCD destroyed both outer and inner hair cells, auditory nerve fibers and spiral ganglion neurons as well as type I and type II vestibular hair cells and vestibular ganglion neurons. The early stage of HPβCD damage involved disruption of hair cell mechanotransduction and destruction of stereocilia. HPβCD-mediated apoptosis in P3 cultures was most-strongly initiated by activation of the extrinsic caspase-8 cell death pathway in cochlear and vestibular hair cells and neurons followed by activation of executioner caspase-3. Thus, HPβCD is toxic to all types of postnatal cochlear and vestibular hair cells and neurons in vitro whereas in vivo it only appears to destroy outer hair cells in adult cochleae. The more severe HPβCD-induced damage in postnatal cultures could be due to greater drug bioavailability in vitro and/or greater vulnerability of the developing inner ear.
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http://dx.doi.org/10.1016/j.heares.2020.108073DOI Listing
October 2020

Txn2 haplodeficiency does not affect cochlear antioxidant defenses or accelerate the progression of cochlear cell loss or hearing loss across the lifespan.

Exp Gerontol 2020 11 28;141:111078. Epub 2020 Aug 28.

Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA. Electronic address:

Thioredoxin 2 (TXN2) is a small redox protein found in nearly all organisms. As a mitochondrial member of the thioredoxin antioxidant defense system, TXN2 interacts with peroxiredoxin 3 (PRDX3) to remove hydrogen peroxide. Accordingly, TXN2 is thought to play an important role in maintaining the appropriate mitochondrial redox environment and protecting the mitochondrial components against oxidative stress. In the current study, we investigated the effects of Txn2 haplodeficiency on cochlear antioxidant defenses, auditory function, and cochlear cell loss across the lifespan in wild-type (WT) and Txn2 heterozygous knockout (Txn2) mice backcrossed onto CBA/CaJ mice, a well-established model of age-related hearing loss. Txn2 mice displayed a 58% decrease in TXN2 protein levels in the mitochondria of the inner ears compared to WT mice. However, Txn2 haplodeficiency did not affect the thioredoxin or glutathione antioxidant defense in both the mitochondria and cytosol of the inner ears of young mice. There were no differences in the levels of mitochondrial biogenesis markers, mitochondrial DNA content, or oxidative DNA and protein damage markers in the inner ears between young WT and Txn2 mice. In a mouse inner ear cell line, knockdown of Txn2 did not affect cell viability under hydrogen peroxide treatment. Consistent with the tissue and cell line results, there were no differences in hair cell loss or spiral ganglion neuron density between WT and Txn2 mice at 3-5 or 23-25 months of age. Furthermore, Txn2 haplodeficiency did not affect auditory brainstem response threshold, wave I latency, or wave I amplitude at 3-5, 15-16, or 23-25 months of age. Therefore, Txn2 haplodeficiency does not affect cochlear antioxidant defenses, accelerate degeneration of cochlear cells, or affect auditory function in mice across the lifespan.
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http://dx.doi.org/10.1016/j.exger.2020.111078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680416PMC
November 2020

Gap Detection Deficits in Chinchillas with Selective Carboplatin-Induced Inner Hair Cell Loss.

J Assoc Res Otolaryngol 2020 12 17;21(6):475-483. Epub 2020 Aug 17.

Center for Hearing and Deafness, The State University of New York at Buffalo, Buffalo, NY, USA.

Temporal resolution is essential for processing complex auditory information such as speech. In hearing impaired persons, temporal resolution, often assessed by detection of brief gaps in continuous sound stimuli, is typically poorer than in individuals with normal hearing. At low stimulus presentation levels, hearing impaired individuals perform poorly but the deficits are greatly reduced when the sensation level of the stimuli are adjusted to match their normal hearing peers. In the present study, we evaluated the effect of selective inner hair cell loss on gap detection in chinchillas treated with carboplatin, an anticancer drug that selectively damages inner hair cells and afferents in this species. Treatment with carboplatin-induced inner hair cell loss of ~ 70 % but had little effect on audiometric thresholds in quiet and produced no evidence of outer hair cell loss. In contrast, selective inner hair cell loss had a significant effect on gap detection ability across a wide range of presentation levels. These results suggest that gap detection tasks are more sensitive to inner hair cell pathology than audiometric thresholds.
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http://dx.doi.org/10.1007/s10162-020-00744-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644605PMC
December 2020

Using auditory reaction time to measure loudness growth in rats.

Hear Res 2020 09 8;395:108026. Epub 2020 Jul 8.

Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, NY, 14214, USA. Electronic address:

Previous studies have demonstrated that auditory reaction time (RT) is a reliable surrogate of loudness perception in humans. Reaction time-intensity (RT-I) functions faithfully recapitulate equal loudness contours in humans while being easier to obtain than equal loudness judgments, especially in animals. In humans, loudness estimation not only depends on sound intensity, but on a variety of other acoustic factors. Stimulus duration and bandwidth are known to impact loudness perception. In addition, the presence of background noise mimics loudness recruitment; loudness growth is rapid near threshold, but growth becomes normal at suprathreshold levels. Therefore, to evaluate whether RT-I functions are a reliable measure of loudness growth in rats, we obtained auditory RTs across a range of stimulus intensities, durations, and bandwidths, in both quiet and in the presence of background/masking noise. We found that reaction time patterns across stimulus parameters were repeatable over several months in rats and generally consistent with human loudness perceptual data. Our results provide important building blocks for future animal model studies of loudness perception and loudness perceptual disorders.
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http://dx.doi.org/10.1016/j.heares.2020.108026DOI Listing
September 2020

Blast-induced hearing loss suppresses hippocampal neurogenesis and disrupts long term spatial memory.

Hear Res 2020 09 8;395:108022. Epub 2020 Jul 8.

Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY, 14214, USA. Electronic address:

Acoustic information transduced by cochlear hair cells is continuously relayed from the auditory pathway to other sensory, motor, emotional and cognitive centers in the central nervous system. Human epidemiological studies have suggested that hearing loss is a risk factor for dementia and cognitive decline, but the mechanisms contributing to these memory and cognitive impairments are poorly understood. To explore these issues in a controlled experimental setting, we exposed adult rats to a series of intense blast wave exposures that significantly reduced the neural output of the cochlea. Several weeks later, we used the Morris Water Maze test, a hippocampal-dependent memory task, to assess the ability of Blast Wave and Control rats to learn a spatial navigation task (memory acquisition) and to remember what they had learned (spatial memory retention) several weeks earlier. The elevated plus maze and open field arena were used to test for anxiety-like behaviors. Afterwards, hippocampal cell proliferation and neurogenesis were evaluated using bromodeoxyuridine (BrdU), doublecortin (DCX), and Neuronal Nuclei (NeuN) immunolabeling. The Blast Wave and Control rats learned the spatial navigation task equally well and showed no differences on tests of anxiety. However, the Blast Wave rats performed significantly worse on the spatial memory retention task, i.e., remembering where they had been two weeks earlier. Deficits on the spatial memory retention task were associated with significant decreases in hippocampal cell proliferation and neurogenesis. Our blast wave results are consistent with other experimental manipulations that link spatial memory retention deficits (long term memory) with decreased cell proliferation and neurogenesis in the hippocampus. These results add to the growing body of knowledge linking blast-induced cochlear hearing loss with the cognitive deficits often seen in combat personnel and provide mechanistic insights into these extra auditory disorders that could lead to therapeutic interventions.
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http://dx.doi.org/10.1016/j.heares.2020.108022DOI Listing
September 2020

Functional Neuroanatomy of Salicylate- and Noise-Induced Tinnitus and Hyperacusis.

Curr Top Behav Neurosci 2020 Jul 12. Epub 2020 Jul 12.

Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, USA.

Tinnitus and hyperacusis are debilitating conditions often associated with aging or exposure to intense noise or ototoxic drugs. One of the most reliable methods of inducing tinnitus is with high doses of sodium salicylate, the active ingredient in aspirin. High doses of salicylate have been widely used to investigate the functional neuroanatomy of tinnitus and hyperacusis. High doses of salicylate have been used to develop novel behavioral methods to detect the presence of tinnitus and hyperacusis in animal models. Salicylate typically induces a hearing loss of approximately 20 dB which greatly reduces the neural output of the cochlea. As this weak neural signal emerging from the cochlea is sequentially relayed to the cochlear nucleus, inferior colliculus, medial geniculate, and auditory cortex, the neural response to suprathreshold sounds is progressively amplified by a factor of 2-3 by the time the signal reaches the auditory cortex, a phenomenon referred to as enhanced central gain. Sound-evoked hyperactivity also occurred in the amygdala, a region that assigns emotional significance to sensory stimuli. Resting state functional magnetic imaging of the BOLD signal revealed salicylate-induced increases in spontaneous neural activity in the inferior colliculus, medial geniculate body, and auditory cortex as well as in non-auditory areas such as the amygdala, reticular formation, cerebellum, and other sensory areas. Functional connectivity of the BOLD signal revealed increased neural coupling between several auditory areas and non-auditory areas such as the amygdala, cerebellum, reticular formation, hippocampus, and caudate/putamen; these strengthened connections likely contribute to the multifaceted dimensions of tinnitus. Taken together, these results suggest that salicylate-induced tinnitus disrupts a complex neural network involving many auditory centers as well as brain regions involved with emotion, arousal, memory, and motor planning. These extra-auditory centers embellish the basic auditory percepts that results in tinnitus and which may also contribute to hyperacusis.
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http://dx.doi.org/10.1007/7854_2020_156DOI Listing
July 2020

2-Hydroxypropyl-β-cyclodextrin Ototoxicity in Adult Rats: Rapid Onset and Massive Destruction of Both Inner and Outer Hair Cells Above a Critical Dose.

Neurotox Res 2020 Oct 30;38(3):808-823. Epub 2020 Jun 30.

Center for Hearing and Deafness, 137 Cary Hall, University at Buffalo, Buffalo, NY, 14214, USA.

2-Hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator, is being used to treat diseases associated with abnormal cholesterol metabolism such as Niemann-Pick C1 (NPC1). However, the high doses of HPβCD needed to slow disease progression may cause hearing loss. Previous studies in mice have suggested that HPβCD ototoxicity results from selective outer hair cell (OHC) damage. However, it is unclear if HPβCD causes the same type of damage or is more or less toxic to other species such as rats, which are widely used in toxicity research. To address these issues, rats were given a subcutaneous injection of HPβCD between 500 and 4000 mg/kg. Distortion product otoacoustic emissions (DPOAE), the cochlear summating potential (SP), and compound action potential (CAP) were used to assess cochlear function followed by quantitative analysis of OHC and inner hair cell (IHC) loss. The 3000- and 4000-mg/kg doses abolished DPOAE and greatly reduced SP and CAP amplitudes. These functional deficits were associated with nearly complete loss of OHC as well as ~ 80% IHC loss over the basal two thirds of the cochlea. The 2000-mg/kg dose abolished DPOAE and significantly reduced SP and CAP amplitudes at the high frequencies. These deficits were linked to OHC and IHC losses in the high-frequency region of the cochlea. Little or no damage occurred with 500 or 1000 mg/kg of HPβCD. The HPβCD-induced functional and structural deficits in rats occurred suddenly, involved damage to both IHC and OHC, and were more severe than those reported in mice.
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http://dx.doi.org/10.1007/s12640-020-00252-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484207PMC
October 2020

Interaction of auditory and pain pathways: Effects of stimulus intensity, hearing loss and opioid signaling.

Hear Res 2020 08 4;393:108012. Epub 2020 Jun 4.

Center for Hearing and Deafness, 137 Cary Hall, University at Buffalo, Buffalo, NY, 14214, USA. Electronic address:

Moderate intensity sounds can reduce pain sensitivity (i.e., audio-analgesia) whereas intense sounds can induce aural pain, evidence of multisensory interaction between auditory and pain pathways. To explore auditory-pain pathway interactions, we used the tail-flick (TF) test to assess thermal tail-pain sensitivity by measuring the latency of a rat to remove its tail from 52 °C water. In Experiment 1, TF latencies were measured in ambient noise and broadband noise (BBN) presented from 80 to 120 dB SPL. TF latencies gradually increased from ambient to 90 dB SPL (audio-analgesia), but then declined. At 120 dB, TF latencies were significantly shorter than normal, evidence for audio-hyperalgesia near the aural threshold for pain. In Experiment II, the opioid pain pathway was modified by treating rats with a high dose of fentanyl known to induce post-treatment hyperalgesia. TF latencies in ambient noise were normal 10-days post-fentanyl. However, TF latencies became shorter than normal from 90 to 110 dB indicating that fentanyl pre-treatment had converted audio-analgesia to audio-hyperalgesia. In Experiment III, we tested the hypothesis that hearing loss could alter pain sensitivity by unilaterally exposing rats to an intense noise that induced a significant hearing loss. TF latencies in ambient noise gradually declined from 1- to 4-weeks post-exposure indicating that noise-induced hearing loss had increased pain sensitivity. Our results suggest that auditory and pain pathways interact in ways that depend on intensity, hearing loss and opioid pain signaling, results potentially relevant to pain hyperacusis.
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http://dx.doi.org/10.1016/j.heares.2020.108012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338237PMC
August 2020

New insights on repeated acoustic injury: Augmentation of cochlear susceptibility and inflammatory reaction resultant of prior acoustic injury.

Hear Res 2020 08 18;393:107996. Epub 2020 May 18.

Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY, 14214, USA. Electronic address:

In industrial and military settings, individuals who suffer from one episode of acoustic trauma are likely to sustain another episode of acoustic stress, creating an opportunity for a potential interaction between the two stress conditions. We previously demonstrated that acoustic overstimulation perturbs the cochlear immune environment. However, how the cochlear immune system responds to repeated acoustic overstimulation is unknown. Here, we used a mouse model to investigate the cochlear immune response to repeated stress. We reveal that exposure to an intense noise at 120 dB SPL for 1 h activates the cochlear immune response in a time-dependent fashion with substantial expansion and activation of the macrophage population in the cochlea at 2-days post-exposure. At 20-days post-exposure, the number and pro-inflammatory phenotypes of cochlear macrophages have significantly subsided, but have yet to return to homeostatic levels. Monocytes with anti-inflammatory phenotypes are recruited into the cochlea. With the presence of this residual immune activation, a second exposure to the same noise provokes an exaggerated inflammatory response as evidenced by exacerbated maturation of macrophages. Furthermore, the second noise causes greater sensory cell pathogenesis. Unlike the first noise-induced damage that occurs mainly between 0 and 2 days post-exposure, the second noise-induced damage occurs more frequently between 2 and 20 days post-exposure, the period when secondary damage takes place. These observations suggest that repeated acoustic overstimulation exacerbates cochlear inflammation and secondary sensory cell pathogenesis. Together, our results suggest that the cochlear immune system plays an important role in modulating cochlear responses to repeated acoustic stress.
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http://dx.doi.org/10.1016/j.heares.2020.107996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359731PMC
August 2020

How low must you go? Effects of low-level noise on cochlear neural response.

Hear Res 2020 07 29;392:107980. Epub 2020 Apr 29.

Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, 14214, USA.

Prolonged exposure to low-level noise has often been used scientifically as well as clinically to induce neuroplastic changes within the central auditory pathway in order to reduce central gain, suppress tinnitus and hyperacusis, and modulate different features of central auditory processing. A fundamental assumption underling these studies is that the noise exposure levels are so low that they have no effect on the neural output of the cochlea. Therefore, functional changes occurring in the central auditory pathway must be the results of central rather than peripheral changes. In an attempt to identify long-term noise exposures that did not cause peripheral changes, we measured the compound action potential (CAP) input/output functions from control rats and rats exposed for 6-weeks to 18-24 kHz noise presented at 25, 45, 55, 65, 75 or 85 dB SPL. Exposures >65 dB SPL significantly increased CAP thresholds; the critical intensity (Ct) below which no threshold shift occurred was estimated to be 55 dB SPL. Exposures >55 dB SPL significantly reduced suprathreshold CAP amplitudes; the critical intensity (Ca) below which no amplitude change was predicted to occur was a remarkably low level of 19 dB SPL. These results demonstrate that even extremely low-intensity long duration exposures can disrupt the neural output of the cochlea; these peripheral modifications are likely to contribute to the extensive compensatory changes observed at multiple levels of the central auditory pathway, neural network changes aimed at re-establishing homeostasis.
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http://dx.doi.org/10.1016/j.heares.2020.107980DOI Listing
July 2020

Dynamic Changes in Synaptic Plasticity Genes in Ipsilateral and Contralateral Inferior Colliculus Following Unilateral Noise-induced Hearing Loss.

Neuroscience 2020 06 9;436:136-153. Epub 2020 Apr 9.

Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA. Electronic address:

Unilateral noise-induced hearing loss reduces the input to the central auditory pathway disrupting the excitatory and inhibitory inputs to the inferior colliculus (IC), an important binaural processing center. Little is known about the compensatory synaptic changes that occur in the IC as a consequence of unilateral noise-induced hearing loss. To address this issue, Sprague-Dawley rats underwent unilateral noise exposure resulting in severe unilateral hearing loss. IC tissues from the contralateral and ipsilateral IC were evaluated for acute (2-d) and chronic (28-d) changes in the expression of 84 synaptic plasticity genes on a PCR array. Arc and Egr1 genes were further visualized by in situ hybridization to validate the PCR results. None of the genes were upregulated, but many were downregulated post-exposure. At 2-d post-exposure, more than 75% of the genes were significantly downregulated in the contralateral IC, while only two were downregulated in the ipsilateral IC. Many of the downregulated genes were related to long-term depression, long-term potentiation, cell adhesion, immediate early genes, neural receptors and postsynaptic density. At 28-d post-exposure, the gene expression pattern was reversed with more than 85% of genes in the ipsilateral IC now downregulated. Most genes previously downregulated in the contralateral IC 2-d post-exposure had recovered; less than 15% remained downregulated. These time-dependent, asymmetric changes in synaptic plasticity gene expression could shed new light on the perceptual deficits associated with unilateral hearing loss and the dynamic structural and functional changes that occur in the IC days and months following unilateral noise-induced hearing loss.
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http://dx.doi.org/10.1016/j.neuroscience.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225073PMC
June 2020

Low-grade albuminuria is associated with hearing loss in non-diabetic US males: A cross-sectional analysis of 1999-2004 national health and nutrition examination survey.

Medicine (Baltimore) 2020 Mar;99(11):e19284

School of Medicine, College of Medicine, China Medical University, Taichung.

High levels of albuminuria have been demonstrated to associate with hearing loss in non-diabetic people, while the clinical impact of low-grade albuminuria has attracted less attention. This cross-sectional population-based study aimed to examine whether hearing loss in non-diabetic United States (US) adults is independently associated with low-grade albuminuria or reduced estimated glomeruli filtration rate (eGFR).A total of 2518 participants aged 20 to 69 years were selected from the US National Health and Nutritional Examination Survey database. Participants with diabetes or high-grade albuminuria were excluded. Hearing loss was assessed using low-frequency pure-tone average (LFPTA) thresholds (0.5, 1.0, 2.0 kHz) and high-frequency pure-tone average (HFPTA) thresholds (3.0, 4.0, 6.0, 8.0 kHz). Logistic and linear regression analyses were used to evaluate associations between renal function indicators and hearing loss.The median age of included participants was 37.4 years, and 55% of them were female. Multivariate analysis revealed that participants with urinary albumin-to-creatinine ratio (UACR) in the highest tertile had a significantly higher risk of hearing loss (OR, 1.79; 95% CI, 1.01-3.19) and higher HFPTA thresholds (β: 2.23; SE: 0.77). Participants with eGFR <60 mL/min/1.73 m had higher LFPTA thresholds (β: 4.31; SE: 1.79). After stratification by sex, a significant risk remained only for males in the highest UACR tertile, with 2.18 times the risk of hearing loss (95% CI, 1.06-4.48).Non-diabetic US males with low-grade albuminuria are at increased risk of hearing loss, independent of eGFR.
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http://dx.doi.org/10.1097/MD.0000000000019284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220087PMC
March 2020

Antioxidative stress-induced damage in cochlear explants.

J Otol 2020 Mar 3;15(1):36-40. Epub 2019 Dec 3.

Center for Hearing and Deafness, State University of New York at Buffalo, United States.

The imbalance of reactive oxygen species and antioxidants is considered to be an important factor in the cellular injury of the inner ear. At present, great attention has been placed on oxidative stress. However, little is known about fighting oxidative stress. In the current study, we evaluated antioxidant-induced cochlear damage by applying several different additional antioxidants. To determine whether excessive antioxidants can cause damage to cochlear cells, we treated cochlear explants with 50 μM M40403, a superoxide dismutase mimetic, 50 μM coenzyme Q-10, a vitamin-like antioxidant, or 50 μM d-methionine, an essential amino acid and the important antioxidant glutathione for 48 h. Control cochlear explants without the antioxidant treatment maintained their normal structures after incubation in the standard serum-free medium for 48 h, indicating the maintenance of the inherent oxidative and antioxidant balance in these cochlear explants. In contrast, M40403 and coenzyme Q-10-treated cochlear explants displayed significant hair cell damage together with slight damage to the auditory nerve fibers. Moreover, d-methiodine-treated explants exhibited severe damage to the surface structure of hair cells and the complete loss of the spiral ganglion neurons and their peripheral fibers. These results indicate that excessive antioxidants are detrimental to cochlear cells, suggesting that inappropriate dosages of antioxidant treatments can interrupt the balance of the inherent oxidative and antioxidant capacity in the cell.
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http://dx.doi.org/10.1016/j.joto.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033592PMC
March 2020

Functional magnetic resonance imaging of enhanced central auditory gain and electrophysiological correlates in a behavioral model of hyperacusis.

Hear Res 2020 04 6;389:107908. Epub 2020 Feb 6.

Department of Physics, City University of Hong Kong, Hong Kong, China. Electronic address:

Hyperacusis is a debilitating hearing condition in which normal everyday sounds are perceived as exceedingly loud, annoying, aversive or even painful. The prevalence of hyperacusis approaches 10%, making it an important, but understudied medical condition. To noninvasively identify the neural correlates of hyperacusis in an animal model, we used sound-evoked functional magnetic resonance imaging (fMRI) to locate regions of abnormal activity in the central nervous system of rats with behavioral evidence of hyperacusis induced with an ototoxic drug (sodium salicylate, 250 mg/kg, i.p.). Reaction time-intensity measures of loudness-growth revealed behavioral evidence of salicylate-induced hyperacusis at high intensities. fMRI revealed significantly enhanced sound-evoked responses in the auditory cortex (AC) to 80 dB SPL tone bursts presented at 8 and 16 kHz. Sound-evoked responses in the inferior colliculus (IC) were also enhanced, but to a lesser extent. To confirm the main results, electrophysiological recordings of spike discharges from multi-unit clusters were obtained from the central auditory pathway. Salicylate significantly enhanced tone-evoked spike-discharges from multi-unit clusters in the AC from 4 to 30 kHz at intensities ≥60 dB SPL; less enhancement occurred in the medial geniculate body (MGB), and even less in the IC. Our results demonstrate for the first time that non-invasive sound-evoked fMRI can be used to identify regions of neural hyperactivity throughout the brain in an animal model of hyperacusis.
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http://dx.doi.org/10.1016/j.heares.2020.107908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080601PMC
April 2020

Effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss in mice.

Exp Gerontol 2020 05 7;133:110872. Epub 2020 Feb 7.

Department of Aging and Geriatric Research, University of Florida, Gainesville, FL 32611, USA. Electronic address:

The glutathione transferase (GST) detoxification system converts exogenous and endogenous toxins into a less toxic form by conjugating the toxic compound to reduced glutathione (GSH) by a variety of GST enzymes. Of the ~20 GST isoforms, GSTA4 exhibits high catalytic efficiency toward 4-hydroxynonenal (4-HNE), one of the most abundant end products of lipid peroxidation that contributes to neurodegenerative diseases and age-related disorders. Conjugation to GSH by GSTA4 is thought to be a major route of 4-HNE elimination. In the current study, we investigated the effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss using young (3-5 months old) and old (24-25 months old) Gsta4 and Gsta4 mice that were backcrossed onto the CBA/CaJ mouse strain, a well-established model of age-related hearing loss (AHL). At 3-5 months of age, loss of Gsta4 resulted in decreased total GSTA activity toward 4-HNE in the inner ears of young mice. However, there were no differences in the levels of 4-HNE in the inner ears between Gsta4 and Gsta4 mice at 3-5 or 24-25 months of age. No histological abnormalities were observed in the cochlea and no hearing impairments were observed in young Gsta4 mice. At 24-25 months of age, both Gsta4 and Gsta4 mice showed elevated ABR thresholds compared to 3-month-old mice, but there were no differences in ABR thresholds, cochlear spiral ganglion neuron densities, or stria vascularis thickness between Gsta4 and Gsta4 mice. Together, these results suggest that under normal physiological conditions or during normal aging, GSTA4 is not essential for removal of 4-HNE in mouse inner ears.
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http://dx.doi.org/10.1016/j.exger.2020.110872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062562PMC
May 2020

Some Ototoxic Drugs Destroy Cochlear Support Cells Before Damaging Sensory Hair Cells.

Neurotox Res 2020 Mar 29;37(3):743-752. Epub 2020 Jan 29.

Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY, 14214, USA.

A wide variety of ototoxic drugs are capable of damaging the sensory hair cells in the mammalian cochlea resulting in permanent hearing loss. However, the toxic properties of these drugs suggest that some could potentially damage cochlear support cells as well. To test the hypothesis, we treated postnatal day three rat cochlear cultures with toxic doses of gentamicin, cisplatin, mefloquine, and cadmium. Gentamicin primarily destroyed the hair cells and disrupted the intercellular connection with the surrounding support cells. Gentamicin-induced hair cell death was initiated through the caspase-9 intrinsic apoptotic pathway followed by activation of downstream executioner caspase-3. In contrast, cisplatin, mefloquine, and cadmium initially damaged the support cells and only later damaged the hair cells. Support cell death was initiated through the caspase-8 extrinsic apoptotic pathway followed later by downstream activation of caspase-3. Cisplatin, mefloquine, and cadmium significantly reduced the expression of actin and laminin, in the extracellular matrix, leading to significant disarray of the sensory epithelium.
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http://dx.doi.org/10.1007/s12640-020-00170-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065960PMC
March 2020

A Novel Mouse Model of USH1B Reveals Auditory and Visual System Haploinsufficiencies.

Front Neurosci 2019 22;13:1255. Epub 2019 Nov 22.

Department of Ophthalmology, University of Florida, Gainesville, FL, United States.

Usher's syndrome is the most common combined blindness-deafness disorder with USH1B, caused by mutations in , resulting in the most severe phenotype. The existence of numerous, naturally occurring mice harboring variable mutations on different genetic backgrounds has complicated the characterization of MYO7A knockout (KO) and heterozygote mice. We generated a novel MYO7A KO mouse () that is easily genotyped, maintained, and confirmed to be null for MYO7A in both the eye and inner ear. Like USH1B patients, mice are profoundly deaf, and display near complete loss of inner and outer cochlear hair cells (HCs). No gross structural changes were observed in vestibular HCs. mice exhibited modest declines in retinal function but, unlike patients, no loss of retinal structure. We attribute the latter to differential expression of MYO7A in mouse vs. primate retina. Interestingly, heterozygous mice had reduced numbers of cochlear HCs and concomitant reductions in auditory function relative to controls. Notably, this is the first report that loss of a single allele significantly alters auditory structure and function and suggests that audiological characterization of USH1B carriers is warranted. Maintenance of vestibular HCs in mice suggests that gene replacement could be used to correct the vestibular dysfunction in USH1B patients. While mice do not exhibit sufficiently robust retinal phenotypes to be used as a therapeutic outcome measure, they can be used to assess expression of vectored on a null background and generate valuable pre-clinical data toward the treatment of USH1B.
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http://dx.doi.org/10.3389/fnins.2019.01255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883748PMC
November 2019