Acoustic communication between animals requires them to detect, discriminate, and categorize conspecific or heterospecific vocalizations in their natural environment. Laboratory studies of the auditory-processing abilities that facilitate these tasks have typically employed a broad range of acoustic stimuli, ranging from natural sounds like vocalizations to “artificial” sounds like pure tones and noise bursts. However, even when using vocalizations, laboratory studies often test abilities like categorization in relatively artificial contexts. Consequently, it is not clear whether neural and behavioral correlates of these tasks (1) reflect extensive operant training, which drives plastic changes in auditory pathways, or (2) the innate capacity of the animal and its auditory system. Here, we review a number of recent studies, which suggest that adopting more ethological paradigms utilizing natural communication contexts are scientifically important for elucidating how the auditory system normally processes and learns communication sounds. Additionally, since learning the meaning of communication sounds generally involves social interactions that engage neuromodulatory systems differently than laboratory-based conditioning paradigms, we argue that scientists need to pursue more ethological approaches to more fully inform our understanding of how the auditory system is engaged during acoustic communication.
Mutations in GJB2, which codes for the gap junction protein connexin26, are the most common causes of human nonsyndromic hereditary deafness. We inoculated modified adeno-associated viral vectors into the scala media of early postnatal conditional Gjb2 knockout mice to drive exogenous connexin26 expression. We found extensive virally-expressed connexin26 in cells lining the scala media, and intercellular gap junction network was re-established in the organ of Corti of mutant mouse cochlea. Widespread ectopic connexin26 expression neither formed ectopic gap junctions nor affected normal hearing thresholds in wild type mice, suggesting that autonomous cellular mechanisms regulate proper membrane trafficking of exogenously-expressed connexin26 and govern the functional manifestation of them. Functional recovery of gap-junction-mediated coupling among the supporting cells was observed. We found that both cell death in the organ of Corti and degeneration of spiral ganglion neurons in the cochlea of mutant mice were substantially reduced, although auditory brainstem responses did not show significant hearing improvement. This is the first report demonstrating that virally-mediated gene therapy restored extensive gap junction intercellular network among cochlear non-sensory cells in vivo. Such a treatment performed at early postnatal stages resulted in a partial rescue of disease phenotypes in the cochlea of the mutant mice.
Listeners infer which object in a visual scene a speaker refers to from the systematic variation of the speaker’s tone of voice (ToV). We examined whether ToV also guides word learning. During exposure, participants heard novel adjectives (e.g., “daxen”) spoken with a ToV representing hot, cold, strong, weak, big, or small while viewing picture pairs representing the meaning of the adjective and its antonym (e.g., elephant-ant for big-small). Eye fixations were recorded to monitor referent detection and learning. During test, participants heard the adjectives spoken with a neutral ToV, while selecting referents from familiar and unfamiliar picture pairs. Participants were able to learn the adjectives’ meanings, and, even in the absence of informative ToV, generalise them to new referents. A second experiment addressed whether ToV provides sufficient information to infer the adjectival meaning or needs to operate within a referential context providing information about the relevant semantic dimension. Participants who saw printed versions of the novel words during exposure performed at chance during test. ToV, in conjunction with the referential context, thus serves as a cue to word meaning. ToV establishes relations between labels and referents for listeners to exploit in word learning.
Objective: To evaluate pediatric otolaryngologists, neurotologists, and otologists on awareness and knowledge of congenital cytomegalovirus (cCMV).
Study Design: Pilot cross-sectional online survey.
Setting: Otolaryngology practices.
Subjects and Methods: An electronic multiple-choice questionnaire was sent email listserv to physician members of the American Society of Pediatric Otolaryngology and American Otological Society. The survey assessed demographics, physician awareness, and practice patterns. Data were collected and analyzed.
Results: Seventy (14.5%) pediatric otolaryngologists and otologists responded. All responded that they are familiar with cCMV. Most were familiar with symptoms associated with cCMV with the exception of petechia/purpura. Less than 50% knew the incidence/natural history of cCMV-induced hearing loss. Only 63% knew that saliva or urine polymerase chain reaction/culture should be performed prior to 3 weeks of age. Less than half knew the indications for dry blood spot testing, and many incorrectly recommended serologic saliva or urine testing in a child >3 weeks old. Most respondents do not offer any diagnostic testing for cCMV or referral for antiviral therapy for those who may benefit from this treatment. Most either did not know the cCMV screening policy or did not have one at their institution.
Conclusion: Despite a relatively low overall response rate, this study suggests several knowledge gaps and underutilization of cCMV testing by physicians who frequently encounter pediatric hearing loss. The findings from this pilot study demonstrate the need for further educational directives focused on cCMV to improve knowledge and incorporation of cCMV best practices.
Introduction:
Sensorineural hearing loss (SNHL) has been reported to occur at increased frequency in the pediatric sickle cell disease (SCD) population, likely secondary to ototoxic medication regimens and repeat sickling events that lead to end organ damage. Risk and protective factors of SNHL in this population are not fully characterized. The objective of this study was to describe audiology results in children with SCD and the prevalence and sequelae of SNHL.
Methods:
A comprehensive clinical database of 2600 pediatric SCD patients treated at 1 institution from 2010-16 was retrospectively reviewed to identify all patients who were referred for audiologic testing. Audiologic test results, patient characteristics, and SCD treatments were reviewed.
Results:
181 SCD children (97 male, 153 HbSS) underwent audiologic testing, with 276 total audiology encounters, ranging 1–9 per patient. Mean age at first audiogram was 8.9 ± 5.2 years. 29.8% had prior cerebrovascular infarct and an additional 25.4% had prior abnormal transcranial Doppler screens documented at time of first audiogram. Overall, 13.3% had documented hearing loss, with 6.6% SNHL. Mean pure tone average (PTA) among patients with SNHL ranged from mild to profound hearing loss (Right: 43.3 ± 28.9, Left: 40.8 ± 29.7), sloping to more severe hearing loss at higher frequencies.
Conclusions:
Hearing loss was identified in a significant subset of children with SCD and the hearing loss ranged from normal to profound. Though the overall prevalence of SNHL in SCD patients was low, baseline audiology screening should be considered.
Mutations in connexin (Cx) genes are responsible for a large proportion of human inherited prelingual deafness cases. The most commonly found human Cx mutations are either Cx26 or Cx30 deletions. Histological observations made in the organ of Corti of homozygous Cx26 and Cx30 gene knockout mice show that cochlear hair cells degenerate after the onset of hearing. However, it is unclear whether vestibular hair cells undergo similar degeneration in connexin knockout mice. To address this question, we first examined expression patterns of Cx26 and Cx30 in the saccule, utricle, and ampulla by immunolabeling. In wild-type mice, Cx26 and Cx30 immunoreactivity was found extensively in vestibular supporting cells and connective tissue cells, and the two Cxs were co-localized in most gap junction (GJ) plaques. Targeted deletion of the Cx30 gene, which caused little change in Cx26 expression pattern, resulted in a significant and age-related loss of vestibular hair cells only in the saccule. dUTP nick end labeling (TUNEL) staining also revealed on-going apoptosis specifically in saccular hair cells of Cx30−/− mice. These results indicated that hair cell survival in the utricle and ampulae does not require Cx30. Importantly, over-expressing the Cx26 gene from a modified bacterial artificial chromosome in the Cx30−/− background rescued the saccular hair cells. These results suggest that it is the reduction in the total amount of GJs rather than the specific loss of Cx30 that underlies saccular hair cell death in Cx30−/− mice. Hybrid GJs co-assembled from Cx26 and Cx30 were not essential for the survival of saccular hair cells.
Mutations in connexins (Cxs), the constitutive protein subunits of gap junction (GJ) intercellular channels, are one of the most common human genetic defects that cause severe prelingual non-syndromic hearing impairments. Many subtypes of Cxs (e.g., Cxs 26, 29, 30, 31, 43) and pannexins (Panxs) are expressed in the cochlea where they contribute to the formation of a GJ-based intercellular communication network. Cx26 and Cx30 are the predominant cochlear Cxs and they co-assemble in most GJ plaques to form hybrid GJs. The cellular localization of specific Cx subtypes provides a basis for understanding the molecular structure of GJs and hemichannels in the cochlea. Information about the interactions among the various co-assembled Cx partners is critical to appreciate the functional consequences of various types of genetic mutations. In vitro studies of reconstituted GJs in cell lines have yielded surprisingly heterogeneous mechanisms of dysfunction caused by various Cx mutations. Availability of multiple lines of Cx-mutant mouse models has provided some insight into the pathogenesis processes in the cochlea of deaf mice. Here we summarize recent advances in understanding the structure and function of cochlear GJs and give a critical review of current findings obtained from both in vitro studies and mouse models on the mechanisms of Cx mutations that lead to cell death in the cochlea and hearing loss.
The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7AWT/WT; C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders.
Background
Genetic factors play an important role in hearing loss, contributing to approximately 60 % of cases of congenital hearing loss. Autosomal dominant deafness accounts for approximately 20 % of cases of hereditary hearing loss. Diseases with autosomal dominant inheritance often show pleiotropy, different degrees of penetrance, and variable expressivity.
Methods
A three-generation Chinese family with autosomal dominant nonsyndromic hearing impairment (ADNSHI) was enrolled in this study. Audiometric data and blood samples were collected from the family. In total, 129 known human deafness genes were sequenced using next-generation sequencing (NGS) to identify the responsible gene mutation in the family. Whole Exome Sequencing (WES) was performed to exclude any other variant that cosegregated with the phenotype.
Results
The age of onset of the affected family members was the second decade of life. The condition began with high-frequency hearing impairment in all family members excluding III:2. The novel ACTG1 c.638A > G (p.K213R) mutation was found in all affected family members and was not found in the unaffected family members. A heterozygous c.638A > G mutation in ACTG1 and homozygous c.109G > A (p.V37I) mutation in GJB2 were found in III:2, who was born with hearing loss. The WES result concurred with that of targeted sequencing of known deafness genes.
Conclusions
The novel mutation p.K213R in ACTG1 was found to be co-segregated with hearing loss and the genetic cause of ADNSHI in this family. A homozygous mutation associated with recessive inheritance only rarely co-acts with a dominant mutation to result in hearing loss in a dominant family. In such cases, the mutations in the two genes, as in ACTG1 and GJB2 in the present study, may result in a more severe phenotype. Targeted sequencing of known deafness genes is one of the best choices to identify the genetic cause in hereditary hearing loss families.
P2X purinergic receptors are plasma membrane ATP-dependent cation channels that are broadly distributed in the mammalian tissues. P2RX2 is a modulator of auditory sensory hair cell mechanotransduction and plays an important role in hair cell tolerance to noise. In this study, we demonstrate for the first time in vitro and in cochlear neuroepithelium, that P2RX2 possesses the ATPase activity. We observed that the P2RX2 V60L human deafness mutation alters its ability to bind ATP, while the G353R has no effect on ATP binding or hydrolysis. A non-hydrolysable ATP assay using HEK293 cells suggests that ATP hydrolysis plays a significant role in the opening and gating of the P2RX2 ion channel. Moreover, the results of structural modeling of the molecule was in agreement with our experimental observations. These novel findings suggest the intrinsic ATPase activity of P2RX2 and provide molecular insights into the channel opening.