Spike Generators and Cell Signaling in the Human Auditory Nerve: An Ultrastructural, Super-Resolution, and Gene Hybridization Study (original) (raw)
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Upsala journal of medical sciences, 2017
Mutations in the GJB2 gene, which encodes the Connexin26 (Cx26) protein, are the most common cause of childhood hearing loss in American and European populations. The cochlea contains a gap junction (GJ) network in the sensory epithelium and two connective tissue networks in the lateral wall and spiral limbus. The syncytia contain the GJ proteins beta 2 (GJB2/Cx26) and beta 6 (GJB6/Cx30). Our knowledge of their expression in humans is insufficient due to the limited availability of tissue. Here, we sought to establish the molecular arrangement of GJs in the epithelial network of the human cochlea using surgically obtained samples. We analyzed Cx26 and Cx30 expression in GJ networks in well-preserved adult human auditory sensory epithelium using confocal, electron, and super-resolution structured illumination microscopy (SR-SIM). Cx30 plaques (<5 μm) dominated, while Cx26 plaques were subtle and appeared as 'mini-junctions' (2-300 nm). 3-D volume rendering of Z-stacks and ...
Upsala Journal of Medical Sciences, 2019
Background: For the first time the expression of the ion transport protein sodium/potassium-ATPase and its isoforms was analyzed in the human cochlea using light-and confocal microscopy as well as super-resolution structured illumination microscopy. It may increase our understanding of its role in the propagation and processing of action potentials in the human auditory nerve and how electric nerve responses are elicited from auditory prostheses. Material and methods: Archival human cochlear sections were obtained from trans-cochlear surgeries. Antibodies against the Na/K-ATPase b1 isoform together with a1 and a3 were used for immunohistochemistry. An algorithm was applied to assess the expression in various domains. Results: Na/K ATPase b1 subunit was expressed, mostly combined with the a1 isoform. Neurons expressed the b1 subunit combined with a3, while satellite glial cells expressed the a1 isoform without recognized association with b1. Types I and II spiral ganglion neurons and efferent fibers expressed the Na/K-ATPase a3 subunit. Inner hair cells, nerve fibers underneath, and efferent and afferent fibers in the organ of Corti also expressed a1. The highest activity of Na/K-ATPase b1 was at the inner hair cell/nerve junction and spiral prominence. Conclusion: The human auditory nerve displays distinct morphologic features represented in its molecular expression. It was found that electric signals generated via hair cells may not go uninterrupted across the spiral ganglion, but are locally processed. This may be related to particular filtering properties in the human acoustic pathway.
Restoration of auditory evoked responses by human ES-cell-derived otic progenitors
Nature, 2012
Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of a particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells 1 , is responsible for a substantial proportion of patients with hearing impairment 2 . While the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss since poor innervation limits the prospective performance of an implant 3 . Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here, we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory evoked response (ABR) thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness.
Dissecting the circuitry of the auditory system
Trends in Neurosciences, 2003
The brainstem auditory system is a complex system composed of numerous parallel and serial pathways that converge on a common destination in the inferior colliculus (IC). The exact nature of the response transformations that occur in the IC have, however, been elusive -even though the IC has been the subject of numerous studies for more than 30 years. Recent studies have addressed this issue by recording from IC neurons before and during micro-iontophoresis of drugs that selectively block GABA A or glycine receptors (the dominant inhibitory receptors in the IC) or by reversibly inactivating a lower nucleus that provides inhibitory innervation to the IC. These studies have revealed some of the ways that signals, relayed via many different parallel routes, interact in the IC, and suggest some functional advantages that these interactions might have.
Recent advancements in cell-based models for auditory disorders
BioImpacts, 2022
Introduction: Cell-based models play an important role in understanding the pathophysiology and etiology of auditory disorders. For the auditory system, models have primarily focused on restoring inner and outer hair cells. However, they have largely underrepresented the surrounding structures and cells that support the function of the hair cells. Methods: In this article, we will review recent advancements in the evolution of cell-based models of auditory disorders in their progression towards three dimensional (3D) models and organoids that more closely mimic the pathophysiology in vivo. Results: With the elucidation of the molecular targets and transcription factors required to generate diverse cell lines of the components of inner ear, research is starting to progress from two dimensional (2D) models to a greater 3D approach. Of note, the 3D models of the inner ear, including organoids, are relatively new and emerging in the field. As 3D models of the inner ear continue to evolv...
Diseases of the hearing organ and impairment affect a significant fraction of population. Therefore, the hearing organ embedded as a helical structure in the cochlea within the hardest human osseous structure inside the Petrous bone is intensively investigated. Currently, studies of the cochlea with true micrometer resolution or better are destructive. Membranes and three-dimensional vessel structures of post-mortem explanted human cochlea were only visualized with limited spatial resolution or deformed anatomical features resulting from preparation artifacts. We have applied a preparation and staining protocol developed for electron microscopy, which allows the visualization and quantification of a great variety of soft-tissue structures including the Reissner´s membrane, the tectorial membrane, basilar membrane, modiolus, lamina radialis, and Nuel´s space by the use of synchrotron-radiation-based micro computed tomography at the beamline BW 2 (HASYLAB at DESY). The level of detail can be even improved by the application of sophisticated computer vision tools, which enables the extraction of the vascular tree down to the capillaries and of the course of nerve fibers as well as the topology of the osseous lamina radialis, which assembles the nerve fibers from the hair-cells to the ganglia in the center of the cochlea, the modiolus. These non-destructively obtained three-dimensional data are principal for the refined understanding of the hearing process by membranes morphologies and further anatomical features at the cellular level and for teaching purposes in medical curricula.