A primary cause of deafness is damage of receptor cells in the inner ear. Clinically, it has been demonstrated that effective functionality can be provided by electrical stimulation of the auditory nerve, thus bypassing damaged receptor cells. However, subsequent to sensory cell loss there is a secondary degeneration of the afferent nerve fibers, resulting in reduced effectiveness of such cochlear prostheses. The effects of neurotrophic factors were tested in a guinea pig cochlear prosthesis model. After chemical deafening to mimic the clinical situation, the neurotrophic factors brain-derived neurotrophic factor and an analogue of ciliary neurotrophic factor were infused directly into the cochlea of the inner ear for 26 days by using an osmotic pump system. An electrode introduced into the cochlea was used to elicit auditory responses just as in patients implanted with cochlear prostheses. Intervention with brainderived neurotrophic factor and the ciliary neurotrophic factor analogue not only increased the survival of auditory spiral ganglion neurons, but significantly enhanced the functional responsiveness of the auditory system as measured by using electrically evoked auditory brainstem responses. This demonstration that neurotrophin intervention enhances threshold sensitivity within the auditory system will have great clinical importance for the treatment of deaf patients with cochlear prostheses. The findings have direct implications for the enhancement of responsiveness in deafferented peripheral nerves. Hearing impairment is the most frequent disability of people in industrialized countries, affecting more than one in seven individuals. Most hearing loss is caused by destruction of the sensory cells within the cochlea of the inner ear. In mammals, the auditory cells do not regenerate, nor are there currently effective interventions for their repair. Moreover, in the auditory system, as in other afferent systems, degeneration of the auditory nerve occurs secondary to the loss of the inner ear sensory cells (hair cells), thus aggravating the functional impairment. In the severely and profoundly deaf, the cochlear implant (prosthesis) has been shown to provide an effective habilitative intervention. The cochlear prosthesis consists of one or more electrodes inserted into the fluid space of the inner ear. The implant operates by directly electrically stimulating the auditory nerve, bypassing damaged or missing sensory receptor cells. This device now provides significant speech understanding, with a score for everyday sentence understanding of about 80% without lip reading in the majority of patients implanted (so far more than 40,000 worldwide) (1-3). However, the cochlear prosthesis depends on remaining excitable auditory nerve fibers, and their loss severely compromises the effectiveness of the implant and the hearing benefits it provides. Studies show a clear relationship between the total number of viable auditory neurons available for stimulation and the performance of subjects receiving cochlear implant...

The dynamic responses of the hearing organ to acoustic overstimulation were investigated using the guinea pig isolated temporal bone preparation. The organ was loaded with the f luorescent Ca 2؉ indicator Fluo-3, and the cochlear electric responses to low-level tones were recorded through a microelectrode in the scala media. After overstimulation, the amplitude of the cochlear potentials decreased significantly. In some cases, rapid recovery was seen with the potentials returning to their initial amplitude. ] changes were not seen in preparations that were stimulated at levels that did not cause an amplitude change in the cochlear potentials. The overstimulation also gave rise to a contraction, evident as a decrease of the width of the organ of Corti. The average contraction in 10 preparations was 9 m (SE 2 m). Partial or complete recovery was seen within 30-45 min after the overstimulation. The [Ca 2؉ ] changes and the contraction are likely to produce major functional alterations and consequently are suggested to be a factor contributing strongly to the loss of function seen after exposure to loud sounds.Noise-induced hearing loss is a common condition that leads to considerable communication problems for affected individuals. Recent research on the physiology of this condition (reviewed in ref. 1) has been mainly focused on damage to the stereocilia (SC) of the sensory cells in the inner ear, important because this is the location of the ion channels converting mechanic vibrations into electric currents. Damage to the SC correlates well with alterations of the tuning curves of auditory nerve fibres (2). A capacity for repair of the SC after acoustic trauma also has been implicated (3), but the mechanisms underlying the stereociliary changes as well as the repair process remain unknown.Acoustic trauma also may cause degeneration of the sensory cells, resulting in an irreversible elevation in hearing thresholds (4). The degeneration most likely involves not only stereociliary changes but also alterations at the cell body level. The events taking place in these cells during and after overstimulation remain largely obscure. Cody and Russell (5) have shown that sustained depolarizations of the outer hair cells (OHCs) occur after moderately intense acoustic overstimulation and that repolarization parallels the recovery of auditory sensitivity. The underlying mechanisms are unclear.In isolated OHCs, mechanical overstimulation results in cytoplasmic [Ca 2ϩ ] increase (6). To investigate how this finding relates to reduced hearing sensitivity after acoustic trauma, the guinea pig isolated temporal bone preparation (7) was used to perform simultaneous investigations of calcium-dependent fluorescence, stimulus-evoked cochlear potentials and cochlear morphology. The sensory cells were visualized in situ in an almost native environment, and the cochlear electric responses were recorded. The preparation was used previously to study changes of organ of Corti mechanics following acoustic trauma (8) and has now been ...

No abstract

PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel −/−). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel −/− melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.

Isolated outer hair cells were found to slowly shorten when subjected to a solution that would induce contraction in a muscle fibre. Two possible mechanisms underlying this behaviour emerge from ultrastructural and immunocytochemical investigations. Antibody labelling at the electron microscopic level demonstrates that actin is present not only in the stereocilia and in the cuticular plate but also along the wall of outer hair cells, between the plasma membrane and the subsurface fenestrated cisternae. The latter are interconnected by regularly spaced pillars, resembling those seen between the T-tubules and sarcoplasmic reticulum in muscle fibres. Contraction also results from the application of positively charged macromolecules to the bathing solution. This implies sensitivity of the membrane-associated complex (the cortex system) to an electrical current. A second contractile system may reside in the cytoplasm, where calmodulin is present in contracted hair cells. This protein is a calcium-binding control protein for contraction-like events in smooth muscle and non-muscle cells. The unique presence of the cortex system in outer hair cells, and its absence in inner hair cells, indicates a functional significance that relates to a motor function of outer hair cells in hearing.