Apoptosis of the fibrocytes type 1 in the spiral ligament and blood labyrinth barrier disturbance cause hearing impairment in murine cerebral malaria

<p>Abstract</p> <p>Background</p> <p>Experimental murine malaria has been shown to result in significant hearing impairment. Microscopic evaluation of the temporal bones of these animals has revealed regular morphology of the cochlea duct. Furthermore, the known vascular pathologic changes being associated with malaria could not be found. Immunohistochemistry for ICAM1 showed a strong marking in the <it>stria vascularis</it>, indicating a disturbance of the endocochlear potential. The aim of this study was to evaluate the role of apoptosis and the disturbance of the blood labyrinth barrier in the murine malaria associated hearing impairment.</p> <p>Methods</p> <p>The temporal bones of seven mice with cerebral malaria-four with hearing impairment, three without hearing impairment-were evaluated with immunohistochemistry for cleaved caspase 3 to detect apoptosis and connexin 26, a gap junction protein being a cornerstone in the endocochlear potassium recirculation. Furthermore five animals with cerebral malaria were treated with Evans blue prior to sacrification to detect disturbances of the blood labyrinth barrier.</p> <p>Results</p> <p>Cleaved caspase 3 could clearly be detected by immunohistochemistry in the fibrocytes of the spiral ligament, more intensively in animals with hearing impairment, less intensively in those without. Apoptosis signal was equally distributed in the spiral ligament as was the connexin 26 gap junction protein. The Evans blue testing revealed a strong signal in the malaria animals and no signal in the healthy control animals.</p> <p>Conclusion</p> <p>Malfunction of the fibrocytes type 1 in the spiral ligament and disruption of the blood labyrinth barrier, resulting in a breakdown of the endocochlear potential, are major causes for hearing impairment in murine cerebral malaria.</p

Murine malaria is associated with significant hearing impairment

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it>malaria has been suspected to cause hearing loss. Developmental, cognitive and language disorders have been observed in children, surviving cerebral malaria. This prospective study aims to evaluate whether malaria influences hearing in mice.</p> <p>Methods</p> <p>Twenty mice were included in a standardized murine cerebral malaria model. Auditory evoked brainstem responses were assessed before infection and at the peak of the illness.</p> <p>Results</p> <p>A significant hearing impairment could be demonstrated in mice with malaria, especially the cerebral form. The control group did not show any alterations. No therapy was used.</p> <p>Conclusion</p> <p>This suggests that malaria itself leads to a hearing impairment in mice.</p

Vascular Supply of the Human Spiral Ganglion : Novel Three-Dimensional Analysis Using Synchrotron Phase-Contrast Imaging and Histology

Human spiral ganglion (HSG) cell bodies located in the bony cochlea depend on a rich vascular supply to maintain excitability. These neurons are targeted by cochlear implantation (CI) to treat deafness, and their viability is critical to ensure successful clinical outcomes. The blood supply of the HSG is difficult to study due to its helical structure and encasement in hard bone. The objective of this study was to present the first three-dimensional (3D) reconstruction and analysis of the HSG blood supply using synchrotron radiation phase-contrast imaging (SR-PCI) in combination with histological analyses of archival human cochlear sections. Twenty-six human temporal bones underwent SR-PCI. Data were processed using volume-rendering software, and a representative three-dimensional (3D) model was created to allow visualization of the vascular anatomy. Histologic analysis was used to verify the segmentations. Results revealed that the HSG is supplied by radial vascular twigs which are separate from the rest of the inner ear and encased in bone. Unlike with most organs, the arteries and veins in the human cochlea do not follow the same conduits. There is a dual venous outflow and a modiolar arterial supply. This organization may explain why the HSG may endure even in cases of advanced cochlear pathology.These authors share last authorship: Hanif M. Ladak, Sumit K. Agrawal and Helge Rask-Andersen.</p

Temporal profiles of transmembrane voltages and extracellular potentials of an extracellularly stimulated feline type I cell.

<p>A small ball electrode simulates the situation of monopolar cathodic stimulation with a cochlear implant for a situation shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079256#pone-0079256-g001" target="_blank">Figure 1C</a>. (A) During application of the 100 µs stimulus pulse the voltage across the membrane is influenced in each compartment. For this electrode placement the threshold is reached in the peripheral terminal and therefore the SGN excitation is similar to natural signaling. The transmembrane voltage lines, shifted vertically according to their distance along the neural path, show AP conductance; myelinated compartment responses in dark gray, compartments with voltage sensitive ion channels in red. (B) The short spike duration is demonstrated with the redrawn transmembrane voltage of the presomatic compartment. (C) Simulated extracellular potential for the position of the center of the stimulating electrode. (D) Simulated recorded signal for natural synaptic excitation, modeled as current injection into the first compartment (E) Simulated (blue, copy of C) and experimentally recorded (black) intracochlear voltage profiles generated with a cochlear implant show similar temporal characteristics although the simulated single cell activity is compared with a compound action potential recording. The black curve is redrawn from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079256#pone.0079256-Miller1" target="_blank">[51]</a> (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079256#pone-0079256-g001" target="_blank">Figure 1</a>, intracochlear recording, cathodic pulse −11.1 dB rel. 1 mA). Simulated situations correspond to scala tympani stimulation in the basal turn. Electrode position and neural path as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079256#pone-0079256-g001" target="_blank">Figure 1C</a>; homogeneous extracellular medium with extracellular resistivity of 300 Ohm.cm and other data as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079256#pone.0079256-Rattay3" target="_blank">[7]</a>.</p

Peripheral and central process diameters of type I neurons based on 3 human specimens and 3 cat specimens.

<p>Data according to their location along the cochlea spiral.</p

Computed SGN spike conduction times with additional delay Δt per 1 µm soma diameter increase.

<p>d1 and d2 represent peripheral and central axon diameters; nmsoma denotes the number of surrounding single membrane layers in the soma region including the pre- and postsomatic segments. t1, t2, t3 and t4 denote postsynaptic delay, spike conduction time in the peripheral axon, presomatic delay and spike conduction time in the central axon, respectively. t_total  = t1+t2+t3+t4, Δt|dsoma+1 µm denotes the enlargement step of the presomatic delay when dsoma is 1 µm increased.</p

Visualization of SGN length measurement (A) and z-projection of a confocal image stack (B) of basal human cochlear neurons.

<p>(A) presents the volume rendered bone of an analyzed individual. The brain is illustrated in a transparent manner (blue) together with the manually segmented brainstem (white star). The starting points of the SGNs from the left and right cochleae are highlighted by the white arrows. The manually segmented Nervuli cochlearum are visualized using surface rendering (green colored). The white arrow in (B) highlights a central process connecting the cell body with the cochlear nucleus. The diameter of this neurite was measured to be 2.54 µm. Scale bar in (A) indicates 5 cm; in (B) it indicates 20 µm.</p

Summary of the detected myelinated and type II spiral ganglion cells.

<p>Presented are the total numbers of counted myelinated type I SGN and type II SGN somata from cat and human cochleae, their percentage as well as the evaluated soma diameters. In contrast to man, the vast majority of cell bodies analyzed from cat cochleae were found to be myelinated.</p

Transmission electron microscopy images of human SGNs.

<p>(A) Cell body of a putative type I SGN completely enwrapped with myelin. Additionally, the process of the SGN shows continuous myelination (white arrow heads). The standard human SGN is shown in B. White arrows highlight an unmyelinated cell body encircled by a satellite glial cell and the myelin lacking process of a SGN. The myelination of the central process starts after about 7 µm pointed by the white arrow head. Scale bar 10 µm.</p