Different types of spiral ganglion neurons (SGNs) are essential for auditory perception by transmitting complex auditory information from hair cells (HCs) to the brain. Here, we use deep, single cell transcriptomics to study the molecular mechanisms that govern their identity and organization in mice. We identify a core set of temporally patterned genes and gene regulatory networks that may contribute to the diversification of SGNs through sequential binary decisions and demonstrate a role for NEUROD1 in driving specification of a Ic-SGN phenotype. We also find that each trajectory of the decision tree is defined by initial co-expression of alternative subtype molecular controls followed by gradual shifts toward cell fate resolution. Finally, analysis of both developing SGN and HC types reveals cell-cell signaling potentially playing a role in the differentiation of SGNs. Our results indicate that SGN identities are drafted prior to birth and reveal molecular principles that shape their differentiation and will facilitate studies of their development, physiology, and dysfunction.

• MeSH
• buněčná diferenciace genetika   MeSH
• ganglion spirale * MeSH
• myši MeSH
• neurony * metabolismus   MeSH
• RNA metabolismus   MeSH
• vláskové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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.

• 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

Ear development requires the transcription factors ATOH1 for hair cell differentiation and NEUROD1 for sensory neuron development. In addition, NEUROD1 negatively regulates Atoh1 gene expression. As we previously showed that deletion of the Neurod1 gene in the cochlea results in axon guidance defects and excessive peripheral innervation of the sensory epithelium, we hypothesized that some of the innervation defects may be a result of abnormalities in NEUROD1 and ATOH1 interactions. To characterize the interdependency of ATOH1 and NEUROD1 in inner ear development, we generated a new Atoh1/Neurod1 double null conditional deletion mutant. Through careful comparison of the effects of single Atoh1 or Neurod1 gene deletion with combined double Atoh1 and Neurod1 deletion, we demonstrate that NEUROD1-ATOH1 interactions are not important for the Neurod1 null innervation phenotype. We report that neurons lacking Neurod1 can innervate the flat epithelium without any sensory hair cells or supporting cells left after Atoh1 deletion, indicating that neurons with Neurod1 deletion do not require the presence of hair cells for axon growth. Moreover, transcriptome analysis identified genes encoding axon guidance and neurite growth molecules that are dysregulated in the Neurod1 deletion mutant. Taken together, we demonstrate that much of the projections of NEUROD1-deprived inner ear sensory neurons are regulated cell-autonomously.

• MeSH
• apoptóza genetika   MeSH
• axony metabolismus   MeSH
• biologické modely MeSH
• buněčná diferenciace genetika   MeSH
• Cortiho orgán patologie   MeSH
• delece genu MeSH
• epitel metabolismus   MeSH
• ganglion spirale metabolismus   MeSH
• mutace genetika   MeSH
• myši knockoutované MeSH
• nervová vlákna metabolismus   MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• stanovení celkové genové exprese MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• transkripční faktory SOXB1 metabolismus   MeSH
• vláskové buňky metabolismus   patologie   ultrastruktura   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články 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.

• 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

The development, maturation, and maintenance of the inner ear are governed by temporal and spatial expression cascades of transcription factors that form a gene regulatory network. ISLET1 (ISL1) may be one of the major players in this cascade, and in order to study its role in the regulation of inner ear development, we produced a transgenic mouse overexpressing Isl1 under the Pax2 promoter. Pax2-regulated ISL1 overexpression increases the embryonic ISL1(+) domain and induces accelerated nerve fiber extension and branching in E12.5 embryos. Despite these gains in early development, the overexpression of ISL1 impairs the maintenance and function of hair cells of the organ of Corti. Mutant mice exhibit hyperactivity, circling behavior, and progressive age-related decline in hearing functions, which is reflected in reduced otoacoustic emissions (DPOAEs) followed by elevated hearing thresholds. The reduction of the amplitude of DPOAEs in transgenic mice was first detected at 1 month of age. By 6-9 months of age, DPOAEs completely disappeared, suggesting a functional inefficiency of outer hair cells (OHCs). The timing of DPOAE reduction coincides with the onset of the deterioration of cochlear efferent terminals. In contrast to these effects on efferents, we only found a moderate loss of OHCs and spiral ganglion neurons. For the first time, our results show that the genetic alteration of the medial olivocochlear (MOC) efferent system induces an early onset of age-related hearing loss. Thus, the neurodegeneration of the MOC system could be a contributing factor to the pathology of age-related hearing loss.

• MeSH
• analýza přežití MeSH
• embryo savčí metabolismus   patologie   MeSH
• ganglion spirale patologie   MeSH
• kochlea inervace   patologie   patofyziologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• molekulární motory metabolismus   MeSH
• myši transgenní MeSH
• nedoslýchavost patologie   patofyziologie   MeSH
• neurony eferentní MeSH
• otoakustické emise spontánní MeSH
• počet buněk MeSH
• proteiny s homeodoménou LIM metabolismus   MeSH
• sluchový práh MeSH
• stárnutí patologie   MeSH
• transkripční faktor PAX2 metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• vnější vláskové buňky patologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

It is automatically assumed that the accuracy with which a stimulus can be decoded is entirely determined by the properties of the neuronal system. We challenge this perspective by showing that the identification of pure tone intensities in an auditory nerve fiber depends on both the stochastic response model and the arbitrarily chosen stimulus units. We expose an apparently paradoxical situation in which it is impossible to decide whether loud or quiet tones are encoded more precisely. Our conclusion reaches beyond the topic of auditory neuroscience, however, as we show that the choice of stimulus scale is an integral part of the neural coding problem and not just a matter of convenience.

• MeSH
• akustická stimulace metody   MeSH
• algoritmy * MeSH
• lidé MeSH
• modely neurologické * MeSH
• nervová vlákna fyziologie   MeSH
• nervové vedení fyziologie   MeSH
• nervus cochlearis fyziologie   MeSH
• počítačová simulace využití   MeSH
• stochastické procesy MeSH
• vnímání hlasitosti fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The aim of this study was to analyze the effect of vestibular schwannoma microsurgery via the retrosigmoid-transmeatal approach with special reference to the postoperative tinnitus outcome. MATERIAL AND METHODS: A prospective study was performed in 89 consecutive patients with unilateral vestibular schwannoma indicated for microsurgery. Patient and tumor related parameters, pre- and postoperative hearing level, intraoperative findings, and hearing and tinnitus handicap inventory scores were analyzed. RESULTS: Cochlear nerve integrity was achieved in 44% corresponding to preservation of preoperatively serviceable hearing in 47% and useful hearing in 21%. Main prognostic factors of hearing preservation were grade/size of tumor, preoperative hearing level, intraoperative neuromonitoring, tumor consistency, and adhesion to neurovascular structures. Microsurgery led to elimination of tinnitus in 66% but also new-onset of the symptom in 14% of cases. Preservation of useful hearing and neurectomy of the eighth cranial nerve were main prognostic factors of tinnitus elimination. Preservation of cochlear nerve but loss of preoperative hearing emerged as the main factor for tinnitus persistence and new onset tinnitus. Decrease of THI scores was observed postoperatively. CONCLUSIONS: Our results underscore the importance of proper pre- and intraoperative decision making about attempt at hearing preservation versus potential for tinnitus elimination/risk of new onset of tinnitus.

• MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrochirurgie škodlivé účinky   MeSH
• nervus cochlearis chirurgie   MeSH
• neurochirurgické výkony škodlivé účinky   MeSH
• pooperační komplikace etiologie   MeSH
• prospektivní studie MeSH
• sluch fyziologie   MeSH
• tinnitus etiologie   MeSH
• vestibulární schwannom chirurgie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Endoscopy-assisted microsurgery represents modern trend of treatment of the cerebellopontine angle (CPA) pathologies including vestibular schwannoma (VS). Endoscopes are used in adjunct to microscope to achieve better functional results with less morbidity. Angled optics, magnification and illumination enable superior view in the operative field. Consecutive 89 patients with untreated unilateral sporadic vestibular schwannoma undergoing tumor resection via a retrosigmoid approach during 2008-2010 were prospectively analysed. Endoscopy-assisted microsurgical (EA-MS) removal was performed in 39 cases (Grade 1: 2, Grade 2: 5, Grade 3: 9, Grade 4: 22, Grade 5: 1) and microsurgical (MS) removal was performed in 50 cases (Grade 1: 1, Grade 2: 3, Grade 3: 9, Grade 4: 34, Grade 5: 3). Minimally invasive approach with craniotomy ≤ 2.5 cm was employed for small tumors (Grade 1 and 2) in the EA-MS group. Endoscopic technique was used for monitoring of neuro-vascular anatomy in CPA, during dissection of the meatal portion of tumors, assessment of radicality and for identification of potential pathways for CSF leak formation. All cases in MS group were deemed as radically removed. In the EA-MS group, residual tumor tissue in the fundus of internal auditory canal not observable with microscope was identified with endoscope in four cases. Such cases were radicalized. Tumor recurrence was not observed during the follow-up in EA-MS group. There is a suspicious intrameatal tumor recurrence on the repeated MRI scan in one patient in the MS group. Neither mortality nor infection was observed. The most common complication was pseudomeningocele (EA-MS 20 cases; MS 23). It was managed with aspiration with or without tissue-gluing in all cases without the need for any surgical revision. Adjunctive use of endoscope in the EA-MS group identified potential pathways for CSF leak formation, which was not observable with the microscope in five patients. Improved cochlear nerve (EA-MS: 22, MS: 14; p = 0.012), brainstem auditory evoked potentials (EA-MS: 3 of 8, MS: 0 of 4) and hearing (EA-MS: 14 of 36, MS: 4 of 45; p = 0.001) preservation were observed in EA-MS group. Despite the trend for better useful hearing (Gardner-Robertson class 1 and 2) preservation (EA-MS: 8 of 26, MS: 1 of 16) there were no significant differences in the postoperative hearing handicap inventory in both groups. There were no differences in the postoperative tinnitus in both groups. Better facial nerve preservation (EA-MS: 39, MS: 44; p = 0.027) and excellent-very good (House-Brackmann 1 or 2) facial nerve function (EA-MS: 31, MS: 29; p = 0.035) were observed in EA-MS group. Postoperative compensation of vestibular lesion, symptoms typical for VS, patients assessed by dizziness handicap inventory, facial disability index were comparable in both studied groups. Adjunctive use of endoscope during the VS surgery due to its magnification and illumination enable superior view in the operative field. It is valuable for assessment of radicality of resection in the region of internal auditory meatus. Improved information about critical structures and tumor itself helps the surgeon to preserve facial nerve and in selected cases also hearing. These techniques can help to decrease incidence of postoperative complications.

• MeSH
• audiovizuální záznam metody   MeSH
• dospělí MeSH
• endoskopie metody   MeSH
• kraniotomie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mikrochirurgie metody   MeSH
• mladý dospělý MeSH
• nervus cochlearis patofyziologie   MeSH
• nervus vestibularis patofyziologie   MeSH
• pooperační komplikace diagnóza   etiologie   patofyziologie   MeSH
• prospektivní studie MeSH
• senioři MeSH
• sluchové kmenové evokované potenciály fyziologie   MeSH
• vestibulární schwannom diagnóza   chirurgie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Direct drug delivery to the cochlea is associated with the risk of irreversible damage to the ear. In this study, liposome and polymersome nanoparticles (NPs), both formed from amphiphilic molecules (lipids in liposomes and block copolymers in polymersomes), were tested as potential tools for drug delivery to the cochlea via application onto the round window membrane in adult mice (strain C3H). One day after round window membrane application, both types of NPs labeled with fluorescent markers were identified in the spiral ganglion in all cochlear turns without producing any distinct morphological or functional damage to the inner ear. NPs were detected, although to a lesser extent, in the organ of Corti and the lateral wall. The potential of liposome and polymersome NPs as therapeutic delivery systems into the cochlea via the round window membrane was evaluated using disulfiram, a neurotoxic agent, as a model payload. Disulfiram-loaded NP delivery resulted in a significant decrease in the number of spiral ganglion cells starting 2 days postapplication, with associated pronounced hearing loss reaching 20-35 dB 2 weeks postapplication as assessed through auditory brainstem responses. No changes in hair cell morphology and function (as assessed by recording otoacoustic emissions) were detected after disulfiram-loaded NP application. No effects were observed in controls where solution of free disulfiram was similarly administered. The results demonstrate that liposome and polymersome NPs are capable of carrying a payload into the inner ear that elicits a biological effect, with consequences measurable by a functional readout.

• MeSH
• apoptóza účinky léků   MeSH
• Cortiho orgán účinky léků   ultrastruktura   MeSH
• cytotoxiny aplikace a dávkování   farmakologie   MeSH
• disulfiram aplikace a dávkování   farmakologie   MeSH
• fenestra rotunda účinky léků   metabolismus   ultrastruktura   MeSH
• ganglion spirale cytologie   účinky léků   MeSH
• kaspasa 3 metabolismus   MeSH
• kochlea účinky léků   metabolismus   ultrastruktura   MeSH
• lékové transportní systémy metody   MeSH
• liposomy analýza   MeSH
• myši MeSH
• nanočástice analýza   MeSH
• povrchově aktivní látky chemie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Interaural time difference (ITD) is a major cue for sound azimuth localization at lower sound frequencies. We review two theories of how the sound localization neural circuit works. One of them proposes labeling of sound direction in the array of delay lines by maximal response of the tuning curve (Jeffress model). The other proposes detection of the direction by calculating the maximum slope of tuning curves. We formulate a simple hypothesis from this that stochastic neural response infers sound direction from this maximum slope, which supports the second theory. We calculate the output spike time density used in the readout of sound direction analytically. We show that the numerical implementation of the model yields results similar to those observed in experiments in mammals. We then go one step further and show that our model also gives similar results when a detailed implementation of the cochlear implant processor and simulation of implant to auditory nerve transduction are used, instead of the simplified model of auditory nerve input. Our results are useful in explaining some recent puzzling observations on the binaural cochlear implantees.

• MeSH
• akční potenciály fyziologie   MeSH
• akustická stimulace MeSH
• kochleární implantáty MeSH
• lidé MeSH
• lokalizace zvuku fyziologie   MeSH
• modely neurologické MeSH
• nervový přenos fyziologie   MeSH
• nervus cochlearis fyziologie   MeSH
• sluchová dráha fyziologie   MeSH
• stochastické procesy MeSH
• teoretické modely MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH