scholarly journals alms1 mutant zebrafish do not show hair cell phenotypes seen in other cilia mutants

2020 ◽  
Author(s):  
Lauren Parkinson ◽  
Tamara M. Stawicki
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Intraflagellar Transport ◽  
Cell Loss ◽  
Cell Types ◽  
Mutant Mice ◽  
Alström Syndrome ◽  
Metabolic Defects ◽  
Alstrom Syndrome

ABSTRACTMultiple cilia-associated genes have been shown to affect hair cells in zebrafish (Danio rerio), including the human deafness gene dcdc2, the radial spoke gene rsph9, and multiple intraflagellar transport (IFT) and transition zone genes. Recently a zebrafish alms1 mutant was generated. The ALMS1 gene is the gene mutated in the ciliopathy Alström Syndrome a disease that causes hearing loss among other symptoms. The hearing loss seen in Alström Syndrome may be due in part to hair cell defects as Alms1 mutant mice show stereocilia polarity defects and a loss of hair cells. Hair cell loss is also seen in postmortem analysis of Alström patients. The zebrafish alms1 mutant has metabolic defects similar to those seen in Alström syndrome and Alms1 mutant mice. We wished to investigate if it also had hair cell defects. We, however, failed to find any hair cell related phenotypes in alms1 mutant zebrafish. They had normal lateral line hair cell numbers as both larvae and adults and normal kinocilia formation. They also showed grossly normal swimming behavior, response to vibrational stimuli, and FM1-43 loading. Mutants also showed a normal degree of sensitivity to both short-term neomycin and long-term gentamicin treatment. These results indicate that cilia-associated genes differentially affect different hair cell types.

scholarly journals alms1 mutant zebrafish do not show hair cell phenotypes seen in other cilia mutants

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0246844
Author(s):  
Lauren Parkinson ◽  
Tamara M. Stawicki
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Intraflagellar Transport ◽  
Cell Loss ◽  
Cell Types ◽  
Mutant Mice ◽  
Alström Syndrome ◽  
Metabolic Defects ◽  
Alstrom Syndrome

Multiple cilia-associated genes have been shown to affect hair cells in zebrafish (Danio rerio), including the human deafness gene dcdc2, the radial spoke gene rsph9, and multiple intraflagellar transport (IFT) and transition zone genes. Recently a zebrafish alms1 mutant was generated. The ALMS1 gene is the gene mutated in the ciliopathy Alström Syndrome a disease that causes hearing loss among other symptoms. The hearing loss seen in Alström Syndrome may be due in part to hair cell defects as Alms1 mutant mice show stereocilia polarity defects and a loss of hair cells. Hair cell loss is also seen in postmortem analysis of Alström patients. The zebrafish alms1 mutant has metabolic defects similar to those seen in Alström syndrome and Alms1 mutant mice. We wished to investigate if it also had hair cell defects. We, however, failed to find any hair cell related phenotypes in alms1 mutant zebrafish. They had normal lateral line hair cell numbers as both larvae and adults and normal kinocilia formation. They also showed grossly normal swimming behavior, response to vibrational stimuli, and FM1-43 loading. Mutants also showed a normal degree of sensitivity to both short-term neomycin and long-term gentamicin treatment. These results indicate that cilia-associated genes differentially affect different hair cell types.

scholarly journals Noise-induced and age-related hearing loss:  new perspectives and potential therapies

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 927 ◽  
Author(s):  
M Charles Liberman
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Auditory Nerve ◽  
Cell Loss ◽  
Sensorineural Hearing ◽  
Hair Cell Loss ◽  
Age Related ◽  
Age Related Hearing Loss

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

Neurotrophin gene therapy may be able to treat individuals with noise-induced hearing loss or neural presbyacusis

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Cell Loss ◽  
Cell Populations ◽  
Noise Induced Hearing Loss ◽  
Hair Cell Loss ◽  
Functional Impairments ◽  
Peripheral Axon

Neurotrophin (NT) cochlear gene therapy might perhaps give a single treatment that might greatly enhance neuronal survival, resulting in CI patients, provided the many challenges described above can be adequately addressed and safety concerns allayed by more animal model investigations. This is particularly crucial for juvenile CI patients, who have to rely on electrical hearing for the remainder of their lives, and whose outcomes are quite different. In addition, NT gene therapy may have the potential to treat patients with noise-induced hearing loss or neural presbyacusis (e.g., age-related cochlear synaptopathy), where primary neuronal loss is a key cause of hearing loss. Animal research into noise-induced hearing loss has shown that even exposures that generate only reversible threshold alterations and no hair cell loss can lead to permanent loss of SGN synapses on hair cells, resulting in functional impairments and ultimately SGN degeneration. Cochlear synapses frequently precede both hair cell loss and threshold increases in human ears, according to current studies. Cochlear synaptopathy is characterized by ears with intact hair cell populations and normal audiograms as "hidden" hearing loss. Many frequent perceptual abnormalities, including speech-in-noise difficulties, tinnitus, and hyperacusis, are likely produced by suppressing affected neurons, which radically alters information processing. Thus, in the future, NT gene therapy may be successful in inducing SGN peripheral axon resprouting and synaptic regeneration into residual (or even regenerated) hair cell populations. We have demonstrated compelling evidence that, in this investigation, BDNF gene therapy can boost SGN survival and enhance peripheral axon maintenance or rerouting. NT-3 has been found in adult animals exposed to acoustic damage to induce synaptic regeneration of these fibers, reconnecting them to hair cells and their ribbon synapses, and restoring hearing function. Combining BDNF and NT-3 gene therapy may be the most effective way to maintain/restore a more normal cochlear neuronal substrate.

scholarly journals Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Pengcheng Xu ◽  
Longhao Wang ◽  
Hu Peng ◽  
Huihui Liu ◽  
Hongchao Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Mitochondrial Dysfunction ◽  
Hair Cells ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Inner Hair Cells

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

scholarly journals Osmotic stabilization prevents cochlear synaptopathy after blast trauma

2018 ◽  
Vol 115 (21) ◽  
pp. E4853-E4860 ◽  
Author(s):  
Jinkyung Kim ◽  
Anping Xia ◽  
Nicolas Grillet ◽  
Brian E. Applegate ◽  
John S. Oghalai
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Noise Exposure ◽  
Endolymphatic Hydrops ◽  
Surrogate Marker ◽  
Cell Loss ◽  
Hair Cell Loss ◽  
Blast Trauma

Traumatic noise causes hearing loss by damaging sensory hair cells and their auditory synapses. There are no treatments. Here, we investigated mice exposed to a blast wave approximating a roadside bomb. In vivo cochlear imaging revealed an increase in the volume of endolymph, the fluid within scala media, termed endolymphatic hydrops. Endolymphatic hydrops, hair cell loss, and cochlear synaptopathy were initiated by trauma to the mechanosensitive hair cell stereocilia and were K+-dependent. Increasing the osmolality of the adjacent perilymph treated endolymphatic hydrops and prevented synaptopathy, but did not prevent hair cell loss. Conversely, inducing endolymphatic hydrops in control mice by lowering perilymph osmolality caused cochlear synaptopathy that was glutamate-dependent, but did not cause hair cell loss. Thus, endolymphatic hydrops is a surrogate marker for synaptic bouton swelling after hair cells release excitotoxic levels of glutamate. Because osmotic stabilization prevents neural damage, it is a potential treatment to reduce hearing loss after noise exposure.

scholarly journals Assessment of cochlear toxicity in response to chronic 3,3′-iminodipropionitrile in mice reveals early and reversible functional loss that precedes overt histopathology

2021 ◽  
Vol 95 (3) ◽  
pp. 1003-1021
Author(s):  
Erin A. Greguske ◽  
Jordi Llorens ◽  
Sonja J. Pyott
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Auditory System ◽  
Hair Cells ◽  
Time Course ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Brainstem Response ◽  
Peripheral Auditory System

AbstractThe peripheral auditory and vestibular systems rely on sensorineural structures that are vulnerable to ototoxic agents that cause hearing loss and/or equilibrium deficits. Although attention has focused on hair cell loss as the primary pathology underlying ototoxicity, evidence from the peripheral vestibular system indicates that hair cell loss during chronic exposure is preceded by synaptic uncoupling from the neurons and is potentially reversible. To determine if synaptic pathology also occurs in the peripheral auditory system, we examined the extent, time course, and reversibility of functional and morphological alterations in cochleae from mice exposed to 3,3′-iminodipropionitrile (IDPN) in drinking water for 2, 4 or 6 weeks. Functionally, IDPN exposure caused progressive high- to low-frequency hearing loss assessed by measurement of auditory brainstem response wave I absolute thresholds and amplitudes. The extent of hearing loss scaled with the magnitude of vestibular dysfunction assessed behaviorally. Morphologically, IDPN exposure caused progressive loss of outer hair cells (OHCs) and synapses between the inner hair cells (IHCs) and primary auditory neurons. In contrast, IHCs were spared from ototoxic damage. Importantly, hearing loss consistent with cochlear synaptopathy preceded loss of OHCs and synapses and, moreover, recovered if IDPN exposure was stopped before morphological pathology occurred. Our observations suggest that synaptic uncoupling, perhaps as an early phase of cochlear synaptopathy, also occurs in the peripheral auditory system in response to IDPN exposure. These findings identify novel mechanisms that contribute to the earliest stages of hearing loss in response to ototoxic agents and possibly other forms of acquired hearing loss.

scholarly journals Effects of cochlear hair cell ablation on spatial learning/memory

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Z. Jason Qian ◽  
Anthony J. Ricci
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Spatial Learning ◽  
Hair Cells ◽  
Noise Exposure ◽  
Memory Errors ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Cell Ablation ◽  
Spatial Learning Memory

AbstractCurrent clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30–60 and underwent the RAM assay during P90–120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.

scholarly journals Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss

2021 ◽  
Vol 8 ◽  
Author(s):  
Melanie Holmgren ◽  
Lavinia Sheets
Keyword(s):  
Cell Death ◽  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Lateral Line ◽  
Hair Cells ◽  
High Energy ◽  
Sensorineural Hearing ◽  
Mitochondrial Activity ◽  
Ototoxic Drugs

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans.

Mechanisms of hearing loss and cell death in the cochlea of connexin mutant mice

2020 ◽  
Vol 319 (3) ◽  
pp. C569-C578
Author(s):  
Bei Chen ◽  
Hongen Xu ◽  
Yanfang Mi ◽  
Wei Jiang ◽  
Dan Guo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hearing Loss ◽  
Hair Cell ◽  
Stria Vascularis ◽  
Reactive Oxygen Species Generation ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Spiral Ligament ◽  
Hair Cell Loss ◽  
Auditory Brain Stem Response

Mutations in connexin 30 (Cx30) are known to cause severe congenital hearing impairment; however, the mechanism by which Cx30 mediates homeostasis of endocochlear gap junctions is unclear. We used a gene deletion mouse model to explore the mechanisms of Cx30 in preventing hearing loss. Our results suggest that despite severe loss of the auditory brain-stem response and endocochlear potential at postnatal day 18, Cx30−/− mice only show sporadic loss of the outer hair cells. This inconsistency in the time course and severity of hearing and hair cell losses in Cx30−/− mice might be explained, in part, by an increase in reactive oxygen species generation beginning at postnatal day 10. The expression of oxidative stress genes was increased in Cx30−/− mice in the stria vascularis, spiral ligament, and organ of Corti. Furthermore, Cx30 deficiency caused mitochondrial dysfunction at postnatal day 18, as assessed by decreased ATP levels and decreased expression of mitochondrial complex I proteins, especially in the stria vascularis. Proteomic analysis further identified 444 proteins that were dysregulated in Cx30−/− mice, including several that are involved in mitochondria electron transport, ATP synthesis, or ion transport. Additionally, proapoptotic proteins, including Bax, Bad, and caspase-3, were upregulated at postnatal day 18, providing a molecular basis to explain the loss of hearing that occurs before hair cell loss. Therefore, our results are consistent with an environment of oxidative stress and mitochondrial damage in the cochlea of Cx30−/− mice that is coincident with hearing loss but precedes hair cell loss.

scholarly journals LIN28B/let-7control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

2020 ◽  
Vol 117 (36) ◽  
pp. 22225-22236
Author(s):  
Xiao-Jun Li ◽  
Angelika Doetzlhofer
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Rna Binding ◽  
Mammalian Target Of Rapamycin ◽  
Cell Loss ◽  
Supporting Cell ◽  
Dependent Manner ◽  
Cell Plasticity ◽  
Supporting Cells ◽  
Cochlear Hair Cells

Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mammalian target of rapamycin (mTOR) activity. Employing murine cochlear organoid and explant cultures to model mitotic and nonmitotic mechanisms of hair cell generation, we show that loss of LIN28B function, due to its conditional deletion, or due to overexpression of the antagonistic miRNAlet-7g, suppressed Akt-mTOR complex 1 (mTORC1) activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and nonmitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner.

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