Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.

• MeSH
• Humans MeSH
• Brain metabolism   growth & development   MeSH
• Hearing * physiology   MeSH
• Auditory Pathways * physiology   MeSH
• Auditory Cortex metabolism   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

A gene cadre orchestrates the normal development of sensory and non-sensory cells in the inner ear, segregating the cochlea with a distinct tonotopic sound frequency map, similar brain projection, and five vestibular end-organs. However, the role of genes driving the ear development is largely unknown. Here, we show double deletion of the Iroquois homeobox 3 and 5 transcription factors (Irx3/5 DKO) leads to the fusion of the saccule and the cochlear base. The overlying otoconia and tectorial membranes are absent in the Irx3/5 DKO inner ear, and the primary auditory neurons project fibers to both the saccule and cochlear hair cells. The central neuronal projections from the cochlear apex-base contour are not fully segregated into a dorsal and ventral innervation in the Irx3/5 DKO cochlear nucleus, obliterating the characteristic tonotopic auditory map. Additionally, Irx3/5 deletion reveals a pronounced cochlear-apex-vestibular "vestibular-cochlear" nerve (VCN) bilateral connection that is less noticeable in wild-type control mice. Moreover, the incomplete segregation of apex and base projections that expands fibers to connect with vestibular nuclei. The results suggest the mammalian cochlear apex is a derived lagena reminiscent of sarcopterygians. Thus, Irx3 and 5 are potential evolutionary branch-point genes necessary for balance-sound segregation, which fused into a saccule-cochlea organization.

• MeSH
• Homeodomain Proteins * genetics   metabolism   MeSH
• Cochlea * physiology   MeSH
• Mice, Knockout * MeSH
• Mice MeSH
• Saccule and Utricle * physiology   MeSH
• Auditory Pathways physiology   MeSH
• Transcription Factors * genetics   metabolism   deficiency   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The two types of spiral ganglion neurons (SGNs), types I and II, innervate inner hair cells and outer hair cells, respectively, within the mammalian cochlea and send another process back to cochlear nuclei in the hindbrain. Studying these two neuronal types has been made easier with the identification of unique molecular markers. One of these markers, peripherin, was shown using antibodies to be present in all SGNs initially but becomes specific to type II SGNs during maturation. We used mice with fluorescently labeled peripherin (Prph-eGFP) to examine peripherin expression in SGNs during development and in aged mice. Using these mice, we confirm the initial expression of Prph-eGFP in both types I and II neurons and eventual restriction to only type II perikarya shortly after birth. However, while Prph-eGFP is uniquely expressed within type II cell bodies by P8, both types I and II peripheral and central processes continue to express Prph-eGFP for some time before becoming downregulated. Only at P30 was there selective type II Prph-eGFP expression in central but not peripheral processes. By 9 months, only the type II cell bodies and more distal central processes retain Prph-eGFP expression. Our results show that Prph-eGFP is a reliable marker for type II SGN cell bodies beyond P8; however, it is not generally a suitable marker for type II processes, except for central processes beyond P30. How the changes in Prph-eGFP expression relate to subsequent protein expression remains to be explored.

• Publication type
• Journal Article MeSH

We review the molecular basis of three related basic helix-loop-helix (bHLH) genes (Neurog1, Neurod1, and Atoh1) and upstream regulators Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires early expression of Neurog1, followed by its downstream target Neurod1, which downregulates Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 and Neurog1 expression for various aspects of development. Several experiments show a partial uncoupling of Atoh1/Neurod1 (spiral ganglia and cochlea) and Atoh1/Neurog1/Neurod1 (cochlear nuclei). In this review, we integrate the cellular and molecular mechanisms that regulate the development of auditory system and provide novel insights into the restoration of hearing loss, beyond the limited generation of lost sensory neurons and hair cells.

• Publication type
• Journal Article MeSH
• Review MeSH

We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix-loop-helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons' fate into "hair cells", highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of "intraganglionic" HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

• MeSH
• Cochlea cytology   metabolism   MeSH
• Humans MeSH
• Neurogenesis genetics   physiology   MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Hair Cells, Auditory metabolism   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review 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
• Spiral Ganglion embryology   physiology   MeSH
• Induced Pluripotent Stem Cells cytology   MeSH
• Cochlea embryology   physiology   MeSH
• Humans MeSH
• Brain Stem MeSH
• Mutation MeSH
• Mice MeSH
• Neurogenesis MeSH
• Neurons physiology   MeSH
• Cochlear Nucleus embryology   physiology   MeSH
• Hearing Loss, Sensorineural physiopathology   MeSH
• Regenerative Medicine methods   MeSH
• Base Sequence MeSH
• Evoked Potentials, Auditory, Brain Stem MeSH
• Hair Cells, Auditory physiology   MeSH
• Ear, Inner embryology   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

To examine whether exposure to sodium salicylate disrupts expression of vesicular glutamate transporter 3 (VGLUT3) and whether the alteration in expression corresponds to increased risk for tinnitus. Rats were treated with saline (control) or sodium salicylate (treated) Rats were examined for tinnitus by monitoring gap-pre-pulse inhibition of the acoustic startle reflex (GPIAS). Auditory brainstem response (ABR) was applied to evaluate hearing function after treatment. Rats were sacrificed after injection to obtain the cochlea, cochlear nucleus (CN), and inferior colliculus (IC) for examination of VGLUT3 expression. No significant differences in hearing thresholds between groups were identified (p>0.05). Tinnitus in sodium salicylate-treated rats was confirmed by GPIAS. VGLUT3 encoded by solute carrier family 17 members 8 (SLC17a8) expression was significantly increased in inner hair cells (IHCs) of the cochlea in treated animals, compared with controls (p<0.01). No significant differences in VGLUT3 expression between groups were found for the cochlear nucleus (CN) or IC (p>0.05). Exposure to sodium salicylate may disrupt SLC17a8 expression in IHCs, leading to alterations that correspond to tinnitus in rats. However, the CN and IC are unaffected by exposure to sodium salicylate, suggesting that enhancement of VGLUT3 expression in IHCs may contribute to the pathogenesis of tinnitus.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal adverse effects   MeSH
• Inferior Colliculi drug effects   metabolism   MeSH
• Cochlear Nucleus drug effects   metabolism   MeSH
• Rats, Wistar MeSH
• Sodium Salicylate adverse effects   MeSH
• Auditory Threshold drug effects   MeSH
• Tinnitus chemically induced   MeSH
• Vesicular Glutamate Transport Proteins metabolism   MeSH
• Hair Cells, Auditory, Inner drug effects   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article 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
• Behavior, Animal physiology   MeSH
• Inferior Colliculi anatomy & histology   physiology   MeSH
• Spiral Ganglion cytology   physiology   MeSH
• Brain Mapping MeSH
• Mesencephalon embryology   physiology   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Cochlear Nucleus anatomy & histology   physiology   MeSH
• Hearing physiology   MeSH
• Auditory Perception genetics   physiology   MeSH
• Pregnancy MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   physiology   MeSH
• Reflex, Startle genetics   physiology   MeSH
• Vestibule, Labyrinth anatomy & histology   physiology   MeSH
• Pitch Perception physiology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Tone at moderate levels presented to young rats at a stage (postnatal week-4) presumably that has passed the cortical critical period still can enlarge neurons in the auditory cortex. It remains unclear whether this delayed plastic change occurs only in the cortex, or reflects a change taking place in the auditory brainstem. Here we compared sound-exposure effects on neuronal size in the auditory cortex and the midbrain. Starting from postnatal day 22, young rats were exposed to a low-frequency tone (4 kHz at 65 dB SPL) for a period of 3 (postnatal day 22-25) or 7 (postnatal day 22-29) days before sacrifice. Neurons were analyzed morphometrically from 7 μm-thick histological sections. A marked increase in neuronal size (32%) was found at the cortex in the high-frequency region distant from the exposing tone. The increase in the midbrain was even larger (67%) and was found in both the low and high frequency regions. While cell enlargements were clear at day 29, only in the high frequency region of the cortex a slight enlargement was found at day 22, suggesting that the cortical and subcortical changes are synchronized, if not slightly preceded by the cortex. In contrast, no changes in neuronal size were found in the cochlear nucleus or the visual midbrain. Such differential effects of sound-exposure at the auditory centers across cortical and subcortical levels cannot be explained by a simple activity-driven change occurring earlier in the brainstem, and might involve function of other structures as for example the descending auditory system.

• MeSH
• Acoustic Stimulation MeSH
• Time Factors MeSH
• Bone and Bones MeSH
• Rats MeSH
• Mesencephalon physiology   MeSH
• Brain Stem physiology   MeSH
• Neurons metabolism   physiology   MeSH
• Neuronal Plasticity MeSH
• Cochlear Nucleus metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Hearing MeSH
• Auditory Pathways physiology   MeSH
• Auditory Cortex physiology   MeSH
• Animals MeSH
• Sound * MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Monografie se zabývá mezi odborníky velmi diskutovaným tématem týkajícím se současné situace v oblasti kochleárních implantací u dětí s těžkým sluchovým postižením. Především sleduje možnosti vzdělávání těchto dětí v ČR a tyto údaje doplňujeo popis téže situace v dalších třech vybraných zemích : Velké Británii, Austrálii a USA. Obsah publikace je rozčleněn do pěti samostatných kapitol, které s tématem úzce souvisejí. Každá kapitola je doplněna výzkumnými údaji konkrétně ilustrujícími popisovanou problematiku. Mimo jiné je sledována efektivita kochleárního implantátu z pohledu předem stanovených faktorů (věk při implantaci, délka trvání hluchoty, rodinné prostředí, eventuální výskyt souběžného postižení v podobě vývojové dysfázie či dyslálie), z pohledu možnosti rozvoje komunikačních kompetencí u jedinců s kochleárním implantátem, a dále pak korelaci mezi rozvojem těchto kompetencí a možnostmi začlenění těchto jedinců do škol hlavního vzdělávacího proudu. Nakladatelská anotace. Kráceno; Publikace představuje aktuální poznatky z oblasti problematiky sluchového postižení a kochleárních implantací spolu s výsledky výzkumné činnosti autorky z let 1996 - 2010.

• MeSH
• Cochlear Implants MeSH
• Persons with Hearing Disabilities MeSH
• Education, Special MeSH
• Education of Persons with Hearing Disabilities MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Výchova a vzdělávání zvláštních skupin osob
• NML Fields
• zdravotně postižení
• pedagogika