The structural and functional properties of the visual system are disrupted in mutant animals lacking the 2 subunit of the nicotinic acetylcholine receptor. In particular, eye-specific retinogeniculate projections do not develop normally in these mutants. It is widely thought that the developing retinas of 2 ؊/؊ mutants do not manifest correlated activity, leading to the notion that retinal waves play an instructional role in the formation of eye-specific retinogeniculate projections. By multielectrode array recordings, we show here that the 2 ؊/؊ mutants have robust retinal waves during the formation of eye-specific projections. Unlike in WT animals, however, the mutant retinal waves are propagated by gap junctions rather than cholinergic circuitry. These results indicate that lack of retinal waves cannot account for the abnormalities that have been documented in the retinogeniculate pathway of the 2 ؊/؊ mutants and suggest that other factors must contribute to the deficits in the visual system that have been noted in these animals.lateral geniculate nucleus ͉ multielectrode array ͉ retinal ganglion cells ͉ retinogeniculate segregation ͉ gap junction T he precise connections that characterize the mature nervous system often arise from an early exuberant pattern that becomes refined through a combination of molecular and activity-dependent cues. In the case of the visual system, the projections of the two eyes to the dorsal lateral geniculate nucleus (dLGN) are initially intermingled before gradually becoming segregated into separate layers in animals with a laminated dLGN such as ferret, cat, and monkey or to different regions of the geniculate as in the mouse and rat (1-3). During the developmental period when eye-specific retinogeniculate projections are being established the retina manifests a remarkable pattern of activity. Immature retinal ganglion cells (RGCs) discharge periodic bursts of action potentials, with adjacent cells firing in a temporally correlated manner, resulting in waves of activity sweeping across the retinal surface (4-7). These retinal waves have been considered to be essential for the formation of eye-specific retinogeniculate projections through a Hebbiantype mechanism where the connections stemming from one eye are strengthened and maintained, whereas those of the other eye become eliminated based on which set of inputs is more capable of activating dLGN neurons (8, 9). Evidence in support of this prevalent notion has been provided by studies that have relied on pharmacological agents to alter the normal activity patterns of the developing retina. Several studies have shown that blocking or perturbing retinal activity prevents the formation of segregated retinogeniculate projections (9-11). These observations have led to the conclusion that retinal waves instruct the formation of eye-specific domains (8,(12)(13)(14).Studies that have used mutant mice have also supported a linkage between retinal waves and development of segregated retinogeniculate projections. In particular, anim...
Despite the need for special fitting strategies and the appearance of complications, facial nerve stimulation, and tinnitus, improvements in speech discrimination tests support the use of cochlear implantation for patients with otosclerosis.
Long-term treatment with low-dose clarithromycin may reduce the incidence of surgical site infections.
Introduction: Constant histological changes in otosclerosis lead to progressive hearing loss which may end up in a profound hearing loss and then be treated by means of cochlear implants. These progressive changes could be followed by changes in cochlear implants fitting and speech discrimination results over the years. Objectives: The aim of the study is to correlate the progressive histological changes to the cochlear implant clinical outcomes (fitting and speech discrimination results). Also main complications (facial nerve stimulation and difficulties at insertion) and new complications will be discussed. Design: A 5-year prospective case-control study was performed in order to compare cochlear implant results in otosclerosis patients to those in a matched-pair control group. Materials and Methods: Fifteen otosclerosis patients were followed throughout the study. Preoperatively temporal bone high-resolution computed tomography, electrically evoked auditory brainstem responses and speech discrimination tests were performed in order to select the patients to be implanted. Results: Not only difficulties with electrode guide insertion were reported, but also difficulties with fitting over the years, due to increasing difficulties to spread the electrical stimuli, which provokes increasing thresholds, maximum comfort levels and charges needed to stimulate hearing cells in basal and medial turn electrodes (p < 0.05), which required deactivating some basal and medial turn electrodes in order to improve cochlear implant effectiveness. The results demonstrated no statistical differences in speech discrimination in otosclerosis patients compared to the control group (p > 0.05). Several complications were reported: facial nerve stimulation (7.14%) and sudden episodes of tinnitus and headaches (14.28%). Conclusions: Although progressive histological changes in otosclerosis lead to increasing thresholds, maximum comfort levels and charges needed to stimulate hearing cells, speech discrimination results support the cochlear implantation in otosclerosis.
Mice lacking expression of the ß2 subunit of the neuronal nicotinic acetylcholine receptor (CHRNB2) display abnormal retinal waves and a dispersed projection of retinal ganglion cell (RGC) axons to their dorsal lateral geniculate nuclei (dLGNs). Transcriptomes of LGN tissue from two independently generated Chrnb2−/− mutants and from wildtype mice were obtained at postnatal day 4 (P4), during the normal period of segregation of eye-specific afferents to the LGN. Microarray analysis reveals reduced expression of genes located on the cell membrane or in extracellular space, and of genes active in cell adhesion and calcium signaling. In particular, mRNA for cadherin 1 (Cdh1), a known axon growth regulator, is reduced to nearly undetectable levels in the LGN of P4 mutant mice and Lypd2 mRNA is similarly suppressed. Similar analysis of retinal tissue shows increased expression of crumbs 1 (Crb1) and chemokine (C-C motif) ligand 21 (Ccl21) mRNAs in Chrnb2−/− mutant animals. Mutations in these genes are associated with retinal neuronal degeneration. The retinas of Chrnb2−/− mutants are normal in appearance, but the increased expression of these genes may also be involved in the abnormal projection patterns of RGC to the LGN. These data may provide the tools to distinguish the interplay between neural activity and molecular expression. Finally, comparison of the transcriptomes of the two different Chrnb2−/− mutant strains reveals the effects of genetic background upon gene expression.
We compared the developmental periods in the mouse when projections from the two eyes become segregated in the dorsal lateral geniculate nucleus with the time when this nucleus becomes innervated by cholinergic fibers from the brainstem. Changes in labeling patterns of different tracers injected into each eye revealed that segregation of retinogeniculate inputs commences at postnatal day five (P5) and is largely complete by P8. Immunocytochemical staining showed that cholinergic neurons are present in the parabrachial region of the brain stem on the day of birth. However, cholinergic fibers are not evident in the geniculate until P5, and these are sparse at this age, increasing in density to form well-defined clusters by P12. These results indicate that segregation of eye-specific projections during normal development is unlikely to be regulated by cholinergic inputs from the brainstem.
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