A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

• Klíčová slova
• auditory behavior, auditory maps, auditory nuclei, inferior colliculus, spiral ganglion neurons,
• MeSH
• ganglion spirale * enzymologie   MeSH
• kochlea embryologie   inervace   MeSH
• myši MeSH
• neurogeneze * genetika   MeSH
• nucleus cochlearis * embryologie   MeSH
• proteiny s homeodoménou LIM * genetika   fyziologie   MeSH
• sluchová dráha * embryologie   MeSH
• transkripční faktory * genetika   fyziologie   MeSH
• vláskové buňky * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• proteiny s homeodoménou LIM * MeSH
• transkripční faktory * MeSH

This review provides an up-to-date source of information on the primary auditory neurons or spiral ganglion neurons in the cochlea. These neurons transmit auditory information in the form of electric signals from sensory hair cells to the first auditory nuclei of the brain stem, the cochlear nuclei. Congenital and acquired neurosensory hearing loss affects millions of people worldwide. An increasing body of evidence suggest that the primary auditory neurons degenerate due to noise exposure and aging more readily than sensory cells, and thus, auditory neurons are a primary target for regenerative therapy. A better understanding of the development and function of these neurons is the ultimate goal for long-term maintenance, regeneration, and stem cell replacement therapy. In this review, we provide an overview of the key molecular factors responsible for the function and neurogenesis of the primary auditory neurons, as well as a brief introduction to stem cell research focused on the replacement and generation of auditory neurons.

• Klíčová slova
• auditory pathways, cochlea, genetic mutations, single-cell RNAseq, transcription factor,
• MeSH
• ganglion spirale embryologie   fyziologie   MeSH
• indukované pluripotentní kmenové buňky cytologie   MeSH
• kochlea embryologie   fyziologie   MeSH
• lidé MeSH
• mozkový kmen MeSH
• mutace MeSH
• myši MeSH
• neurogeneze MeSH
• neurony fyziologie   MeSH
• nucleus cochlearis embryologie   fyziologie   MeSH
• percepční nedoslýchavost patofyziologie   MeSH
• regenerativní lékařství metody   MeSH
• sekvence nukleotidů MeSH
• sluchové kmenové evokované potenciály MeSH
• vláskové buňky fyziologie   MeSH
• vnitřní ucho embryologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

• Klíčová slova
• Neurod1 mutation, auditory pathway, cochlear nucleus, inferior colliculus, plasticity, sensory topographical map,
• MeSH
• chování zvířat fyziologie   MeSH
• colliculus inferior anatomie a histologie   fyziologie   MeSH
• ganglion spirale cytologie   fyziologie   MeSH
• mapování mozku MeSH
• mezencefalon embryologie   fyziologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• nucleus cochlearis anatomie a histologie   fyziologie   MeSH
• sluch fyziologie   MeSH
• sluchová percepce genetika   fyziologie   MeSH
• těhotenství MeSH
• transkripční faktory bHLH genetika   fyziologie   MeSH
• úleková reakce genetika   fyziologie   MeSH
• vestibulární aparát anatomie a histologie   fyziologie   MeSH
• vnímání výšky zvuku fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Neurod1 protein, mouse MeSH Prohlížeč
• transkripční faktory bHLH MeSH