Explore the vast range of titles available.

The neural representations of acoustic features that differ in the location or timbre of the emitter elicit similar perceptions, suggesting the existence of a robust stimulus‐response function between complex sounds and the activity of neural populations at all stages of the auditory system. This hypothesis is tested by decoding a random sound stream, using spike trains from a biophysical model of the auditory nerve and from large‐scale recordings in the inferior colliculus, the auditory thalamus, and the auditory cortex of awake mice. At the level of individual neurons, the reliability of temporal and rate codes is found to decrease along the ascending auditory pathways. Rate coding is progressively favored with increasing independence of neuron frequency tuning. Firing in the auditory cortex is found to be synergistic, whereas that in subcortical areas is more redundant. Finally, combinatorial codes involving neural firing and neural silence within neuron pairs are shown to efficiently encode sound information, particularly in the auditory cortex. Overall, these findings reveal a progressive transformation of the neural code from an individual, redundant, and temporal code at the periphery to a more distributed rate‐based code in the auditory cortex. Decoding sound from neural activity in mice reveals a striking shift in how the brain encodes sound: from precise but redundant timing codes in early auditory areas to efficient, synergistic rate‐based codes in the cortex. This transformation highlights a robust neural strategy for turning complex acoustic input into coherent perception across the auditory pathway.

According to a novel hypothesis (Arnal et al., 2015, Current Biology 25:2051-2056), auditory roughness, or temporal envelope modulations between 30 and 150 Hz, are present in both natural and artificial human alarm signals, which boosts the detection of these alarms in various tasks. These results also shed new light on the unpleasantness of dissonant sounds to humans, which builds upon the high level of roughness present in such sounds. However, it is not clear whether this hypothesis also applies to other species, such as rodents. In particular, whether consonant/dissonant chords, and particularly whether auditory roughness, can trigger unpleasant sensations in mice remains unknown. Using an autonomous behavioral system, which allows the monitoring of mouse behavior over a period of weeks, we observed that C57Bl6J mice did not show any preference for consonant chords. In addition, we found that mice showed a preference for rough sounds over sounds having amplitude modulations in their temporal envelope outside the \"rough\" range. These results suggest that some emotional features carried by the acoustic temporal envelope are likely to be species-specific.

Auditory neuropathies affect the spiral ganglion neurons of the auditory nerve or their synapses with the sensory hair cells, distorting the sound information transmitted from the ear to the brain. Deciphering the underlying pathophysiological mechanisms remains challenging owing to the diversity of spiral ganglion neuron subtypes and associated central auditory circuits. An auditory neuropathy mechanism is unraveled by investigating the origin of auditory hyperexcitability in a mouse model for hereditary congenital deafness. Otogl encodes the large Otogelin‐like protein, which is related to secreted epithelial mucins and is implicated in the mechanical stimulation of cochlear outer hair cells. Heterozygous Otogl+/− mutant mice display auditory hyperexcitability, highlighted by their susceptibility to audiogenic seizures induced by loud sounds. It is shown that Otogl is transiently expressed in a subpopulation of spiral ganglion neurons during cochlear development. Despite their apparently normal hearing, Otogl+/− mice display poor activation of the spiral ganglion neurons processing loud sounds and an elevation of the activation threshold of the middle the ear muscle reflex that attenuates loud sounds. The findings reveal how a neuropathy affecting spiral ganglion neurons specialized in loud sound processing and associated with the middle the ear muscle reflex can manifest itself as auditory hyperexcitability. By investigating auditory hyperexcitability in a mouse model for hereditary deafness, this study identified a subpopulation of afferent neurons of the auditory nerve marked by Otogl expression. Despite their apparently normal hearing, Otogl+/− mice display poor activation of afferent neurons processing loud sounds and an elevation of the middle the ear muscle reflex activation threshold, identifying a mechanism of auditory neuropathy.

Background The autosomal recessive deafness 9 (DFNB9) is caused by mutations in the otoferlin gene that accounts for 2–8% of all inherited deafness cases. In a previous study, we demonstrated that Adeno-associated virus (AAV) gene therapy restored hearing in a preclinical mouse model of profound DFNB9 deafness caused by a frameshift mutation leading to a complete loss of otoferlin expression. However, it remains to be demonstrated that it can address the full spectrum of DFNB9 deafness severity, while also restoring central auditory processing essential for speech understanding. Methods Using homologous recombination in mouse embryonic stem cells, we created a knock-in mouse model carrying the E1799del otoferlin mutation, which mirrors the human E1804del variant linked to DFNB9 deafness, characterized by moderate-to-profound deafness during febrile episodes in affected individuals. A mixture of male and female mice was used at P2, P8, and P30. Some were followed for up to 4 months for longevity monitoring and behavioral tests. Results The mouse model exhibits abnormal otoferlin distribution, failure of synaptic transmission in inner hair cells, and profound hearing loss, all of which is restored to normal through AAV gene therapy. Notably, we conduct objective behavioral testing to provide the first evidence that gene therapy administered to the cochlea, which is part of the peripheral auditory system, can restore frequency discrimination, indicating the recovery of central auditory processing. This is achieved even when treatment is administered late at the end of the critical period. Conclusions These findings indicate that gene therapy can address the entire spectrum of DFNB9 hearing loss, and that profound deafness during critical period may not impede the restoration of central auditory processing. Plain language summary We investigated gene therapy, a technique that introduces a healthy copy of a gene to restore normal cell function, as a potential treatment for an unusual form of inherited deafness caused by mutations in the otoferlin gene. These mutations result in the production of a defective protein, leading to hearing loss during fever episodes. We developed and studied a mouse model with the same genetic alteration observed in affected individuals and discovered that the deafness resulted from the abnormal protein distribution in the inner ear. We use gene therapy to correct this mislocalization and restored normal hearing. Our findings indicate that gene therapy may be an effective approach for treating all forms of otoferlin-related hearing loss. Benamer et al. develop a knock-in mouse model carrying the E1799del otoferlin mutation to study the atypical DFNB9 variant form of deafness. They show the mouse model exhibits abnormal otoferlin distribution, failure of synaptic transmission in inner hair cells, and profound hearing loss, all of which can be restored with AAV gene therapy.

Auditory Circuits The cover illustrates the Research Article by Boris Gourévitch and co‐workers (DOI: 10.1002/advs.202508777) on the neural code of the auditory system. Sound waves, as a physical phenomenon, converge toward the ear before being transduced into a neural code–an internal language in which information is carried by the activity of neural circuits across the brain. This code can be thought of as sequences of “0”s and “1”s, reflecting the firing or silence of neurons. Surrounding the head in the background are spectrograms of complex sounds, showing how acoustic energy unfolds over time and frequency. Image credit: Typhaine Dupont

Auditory Neuropathy Mechanism The frontispiece refers to the peripheral auditory system with its exiting neurons of the auditory nerve. The rainbow appearance of the auditory nerve neurons represents the different sub‐circuits suggested by the results of the study. The audio equalizer points to the relative contribution of these circuits and is reminiscent of a DNA gel reminding the genetic nature of the auditory neuropathy described. More details can be found in article number 2410776 by Nicolas Michalski and co‐workers. Image credits: Sabrina Mechaussier.

Four endemic seasonal human coronaviruses causing common colds circulate worldwide: HKU1, 229E, NL63 and OC43 (ref. 1 ). After binding to cellular receptors, coronavirus spike proteins are primed for fusion by transmembrane serine protease 2 (TMPRSS2) or endosomal cathepsins 2 – 9 . NL63 uses angiotensin-converting enzyme 2 as a receptor 10 , whereas 229E uses human aminopeptidase-N 11 . HKU1 and OC43 spikes bind cells through 9-O-acetylated sialic acid, but their protein receptors remain unknown 12 . Here we show that TMPRSS2 is a functional receptor for HKU1. TMPRSS2 triggers HKU1 spike-mediated cell–cell fusion and pseudovirus infection. Catalytically inactive TMPRSS2 mutants do not cleave HKU1 spike but allow pseudovirus infection. Furthermore, TMPRSS2 binds with high affinity to the HKU1 receptor binding domain (Kd 334 and 137 nM for HKU1A and HKU1B genotypes) but not to SARS-CoV-2. Conserved amino acids in the HKU1 receptor binding domain are essential for binding to TMPRSS2 and pseudovirus infection. Newly designed anti-TMPRSS2 nanobodies potently inhibit HKU1 spike attachment to TMPRSS2, fusion and pseudovirus infection. The nanobodies also reduce infection of primary human bronchial cells by an authentic HKU1 virus. Our findings illustrate the various evolution strategies of coronaviruses, which use TMPRSS2 to either directly bind to target cells or prime their spike for membrane fusion and entry. We demonstrate that the transmembrane protease TMPRSS2 is a receptor for coronavirus HKU1; it triggers HKU1-mediated cell–cell fusion and viral entry by binding to both HKU1A and HKU1B spikes.

Monkeypox virus (MPXV) is the most pathogenic Poxvirus in circulation, yet key viral antigens remain immunologically unexplored. We isolate and characterize a panel of monoclonal antibodies (mAbs) targeting MPXV A28 (OPG153), an important membranal protein present on mature MPXV virions. From male convalescent individuals, we isolate anti-A28 mAbs alongside additional mAbs targeting the A35 and H3 proteins. Anti-A28 mAbs potently neutralize MPXV and Vaccinia virus (VACV) through complement-dependent mechanisms involving C1q and C3 deposition. High-resolution crystal structures of two anti-A28 mAbs, 10M2146 and 8M2110, in complex with VACV A26 reveal two distinct and highly conserved proximal epitopes within the N-terminal domain. Passive transfer of 8M2110 modestly attenuates disease in infected female mice. Moreover, immunization with A28 elicits antigen-specific B cells and robust neutralizing antibody responses and provides protection against lethal VACV challenge. These findings identify MPXV A28 as a promising central target for the induction of neutralizing antibodies and antiviral interventions. Recent MPXV outbreaks underscore the need for better vaccines and treatments. Here, the authors isolate and structurally characterize potent antibodies interacting with A28 that they identify as a key viral surface protein essential for viral entry and that induces strong, protective antibody response in mice.