RNA microarray analysis in prenatal mouse cochlea reveals novel IGF-I target genes: implication of MEF2 and FOXM1 transcription factors

Background: Insulin-like growth factor-I (IGF-I) provides pivotal cell survival and differentiation signals during inner ear development throughout evolution. Homozygous mutations of human IGF1 cause syndromic sensorineural deafness, decreased intrauterine and postnatal growth rates, and mental retardation. In the mouse, deficits in IGF-I result in profound hearing loss associated with reduced survival, differentiation and maturation of auditory neurons. Nevertheless, little is known about the molecular basis of IGF-I activity in hearing and deafness. Methodology/Principal Findings: A combination of quantitative RT-PCR, subcellular fractionation and Western blotting, along with in situ hybridization studies show IGF-I and its high affinity receptor to be strongly expressed in the embryonic and postnatal mouse cochlea. The expression of both proteins decreases after birth and in the cochlea of E18.5 embryonic Igf1(-/-) null mice, the balance of the main IGF related signalling pathways is altered, with lower activation of Akt and ERK1/2 and stronger activation of p38 kinase. By comparing the Igf1(-/-) and Igf1(+/+) transcriptomes in E18.5 mouse cochleae using RNA microchips and validating their results, we demonstrate the up-regulation of the FoxM1 transcription factor and the misexpression of the neural progenitor transcription factors Six6 and Mash1 associated with the loss of IGF-I. Parallel, in silico promoter analysis of the genes modulated in conjunction with the loss of IGF-I revealed the possible involvement of MEF2 in cochlear development. E18.5 Igf1(+/+) mouse auditory ganglion neurons showed intense MEF2A and MEF2D nuclear staining and MEF2A was also evident in the organ of Corti. At P15, MEF2A and MEF2D expression were shown in neurons and sensory cells. In the absence of IGF-I, nuclear levels of MEF2 were diminished, indicating less transcriptional MEF2 activity. By contrast, there was an increase in the nuclear accumulation of FoxM1 and a corresponding decrease in the nuclear cyclin-dependent kinase inhibitor p27(Kip1). Conclusions/Significance: We have defined the spatiotemporal expression of elements involved in IGF signalling during inner ear development and reveal novel regulatory mechanisms that are modulated by IGF-I in promoting sensory cell and neural survival and differentiation. These data will help us to understand the molecular bases of human sensorineural deafness associated to deficits in IGF-I

Sound Recognition System Using Spiking and MLP Neural Networks

In this paper, we explore the capabilities of a sound classification system that combines a Neuromorphic Auditory System for feature extraction and an artificial neural network for classification. Two models of neural network have been used: Multilayer Perceptron Neural Network and Spiking Neural Network. To compare their accuracies, both networks have been developed and trained to recognize pure tones in presence of white noise. The spiking neural network has been implemented in a FPGA device. The neuromorphic auditory system that is used in this work produces a form of representation that is analogous to the spike outputs of the biological cochlea. Both systems are able to distinguish the different sounds even in the presence of white noise. The recognition system based in a spiking neural networks has better accuracy, above 91 %, even when the sound has white noise with the same power.Ministerio de Economía y Competitividad TEC2012-37868-C04-02Junta de Andalucía P12-TIC-130

Electrical vestibular stimulation in humans. A narrative review

Background: In patients with bilateral vestibulopathy, the regular treatment options, such as medication, surgery, and/ or vestibular rehabilitation, do not always suffice. Therefore, the focus in this field of vestibular research shifted to electri- cal vestibular stimulation (EVS) and the development of a system capable of artificially restoring the vestibular func- tion. Key Message: Currently, three approaches are being investigated: vestibular co-stimulation with a cochlear im- plant (CI), EVS with a vestibular implant (VI), and galvanic vestibular stimulation (GVS). All three applications show promising results but due to conceptual differences and the experimental state, a consensus on which application is the most ideal for which type of patient is still missing. Summa- ry: Vestibular co-stimulation with a CI is based on “spread of excitation,” which is a phenomenon that occurs when the currents from the CI spread to the surrounding structures and stimulate them. It has been shown that CI activation can indeed result in stimulation of the vestibular structures. Therefore, the question was raised whether vestibular co- stimulation can be functionally used in patients with bilat- eral vestibulopathy. A more direct vestibular stimulation method can be accomplished by implantation and activa- tion of a VI. The concept of the VI is based on the technology and principles of the CI. Different VI prototypes are currently being evaluated regarding feasibility and functionality. So far, all of them were capable of activating different types of vestibular reflexes. A third stimulation method is GVS, which requires the use of surface electrodes instead of an implant- ed electrode array. However, as the currents are sent through the skull from one mastoid to the other, GVS is rather unspe- cific. It should be mentioned though, that the reported spread of excitation in both CI and VI use also seems to in- duce a more unspecific stimulation. Although all three ap- plications of EVS were shown to be effective, it has yet to be defined which option is more desirable based on applicabil- ity and efficiency. It is possible and even likely that there is a place for all three approaches, given the diversity of the pa- tient population who serves to gain from such technologies

Two adaptation processes in auditory hair cells together can provide an active amplifier

The hair cells of the vertebrate inner ear convert mechanical stimuli to electrical signals. Two adaptation mechanisms are known to modify the ionic current flowing through the transduction channels of the hair bundles: a rapid process involves calcium ions binding to the channels; and a slower adaptation is associated with the movement of myosin motors. We present a mathematical model of the hair cell which demonstrates that the combination of these two mechanisms can produce `self-tuned critical oscillations', i.e. maintain the hair bundle at the threshold of an oscillatory instability. The characteristic frequency depends on the geometry of the bundle and on the calcium dynamics, but is independent of channel kinetics. Poised on the verge of vibrating, the hair bundle acts as an active amplifier. However, if the hair cell is sufficiently perturbed, other dynamical regimes can occur. These include slow relaxation oscillations which resemble the hair bundle motion observed in some experimental preparations.Comment: 13 pages, 6 figures,REVTeX 4, To appear in Biophysical Journa

Computation of Interaural Time Difference in the Owl's Coincidence Detector Neurons

Both the mammalian and avian auditory systems localize sound sources by computing the interaural time difference (ITD) with submillisecond accuracy. The neural circuits for this computation in birds consist of axonal delay lines and coincidence detector neurons. Here, we report the first in vivo intracellular recordings from coincidence detectors in the nucleus laminaris of barn owls. Binaural tonal stimuli induced sustained depolarizations (DC) and oscillating potentials whose waveforms reflected the stimulus. The amplitude of this sound analog potential (SAP) varied with ITD, whereas DC potentials did not. The amplitude of the SAP was correlated with firing rate in a linear fashion. Spike shape, synaptic noise, the amplitude of SAP, and responsiveness to current pulses differed between cells at different frequencies, suggesting an optimization strategy for sensing sound signals in neurons tuned to different frequencies