Synaptic activity is not required for establishing heterogeneity of inner hair cell ribbon synapses

Neural sound encoding in the mammalian cochlea faces the challenge of representing audible sound pressures that vary over six orders of magnitude. The cochlea meets this demand through the use of active micromechanics as well as the diversity and adaptation of afferent neurons and their synapses. Mechanisms underlying neural diversity likely include heterogeneous presynaptic input from inner hair cells (IHCs) to spiral ganglion neurons (SGNs) as well as differences in the molecular profile of SGNs and in their efferent control. Here, we tested whether glutamate release from IHCs, previously found to be critical for maintaining different molecular SGN profiles, is required for establishing heterogeneity of active zones (AZs) in IHCs. We analyzed structural and functional heterogeneity of IHC AZs in mouse mutants with disrupted glutamate release from IHCs due to lack of a vesicular glutamate transporter (Vglut3) or impaired exocytosis due to defective otoferlin. We found the variance of the voltage-dependence of presynaptic Ca2+ influx to be reduced in exocytosis-deficient IHCs of otoferlin mutants. Yet, the spatial gradients of maximal amplitude and voltage-dependence of Ca2+ influx along the pillar-modiolar IHC axis were maintained in both mutants. Further immunohistochemical analysis showed an intact spatial gradient of ribbon size in Vglut3–/– mice. These results indicate that IHC exocytosis and glutamate release are not strictly required for establishing the heterogeneity of IHC AZs

Ca2+ Regulates the Kinetics of Synaptic Vesicle Fusion at the Afferent Inner Hair Cell Synapse

The early auditory pathway processes information at high rates and with utmost temporal fidelity. Consequently, the synapses in the auditory pathway are highly specialized to meet the extraordinary requirements on signal transmission. The calyceal synapses in the auditory brainstem feature more than a hundred active zones (AZs) with thousands of releasable synaptic vesicles (SVs). In contrast, the first auditory synapse, the afferent synapse of inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs), typically exhibits a single ribbon-type AZ tethering only tens of SVs resulting in a highly stochastic pattern of transmitter release. Spontaneous excitatory postsynaptic currents (sEPSCs), besides more conventional EPSCs with a single peak, fast rise and decay (compact), also include EPSCs with multiple peaks, variable rise and decay times (non-compact). The strong heterogeneity in size and shape of spontaneous EPSCs has led to the hypothesis of multivesicular release (MVR) that is more (compact) or less (non-compact) synchronized by coordination of release sites. Alternatively, univesicular release (UVR), potentially involving glutamate release through a flickering fusion pore for non-compact EPSCs, has been suggested to underlie IHC exocytosis. Here, we further investigated the mode of release by recording sEPSCs from SGNs of hearing rats while manipulating presynaptic IHC Ca2+ influx by changes in extracellular [Ca2+] ([Ca2+]e) and by application of the Ca2+ channel antagonist, isradipine, or the Ca2+ channel agonist, BayK8644 (BayK). Our data reveal that Ca2+ influx manipulation leaves the distributions of sEPSC amplitude and charge largely unchanged. Regardless the type of manipulation, the rate of sEPSC decreased with the reduction in Ca2+ influx. The fraction of compact sEPSCs was increased in the presence of BayK, an effect that was abolished when combined with decreased [Ca2+]e. In conclusion, we propose that UVR is the prevailing mode of exocytosis at cochlear IHCs of hearing rats, whereby the rate of exocytosis and the kinetics of SV fusion are regulated by Ca2+ influx

Potential of Concentrating Solar Power Plants for the Combined Production of Water and Electricity in MENA Countries

The widening gap between consumption and availability of water poses a serious threat to a sustainable socioeconomic development of the Middle East and North Africa (MENA) countries and calls for an even larger augmentation of water supply using seawater desalination. However, these plants are affected by high specific energy consumption, while the uncertainty about fossil fuel prices in the future represents a severe problem. Within this study long-term scenarios for water and electricity demand based on potential assessment of renewable energies have been developed. The results provide baseline information for decision makers for the establishment of a favourable framework for the deployment of concentrated solar power and desalination plants. Finally, this paper points out the importance to start a paradigm change in water and electricity supply as soon as possible, in order to meet the requirements for low cost water and electricity and to avoid conflicts related to water scarcity

Access-Based Services for the Base of the Pyramid

One key challenge for consumers at the base of the pyramid (BoP) is access to products that could transform their livelihood, leading to nonconsumption as the dominant pattern. Previous studies have claimed that nonconsumption could be addressed with services offering access to goods without ownership. Drawing on expected utility theory, we conduct two experimental studies in rural India that provide the first empirical support for the idea that the availability of access-based services reduces nonconsumption at the BoP. Additionally, we show that this effect is explained by BoP consumers’ expected utility assessment as reflected in their perception of access being more affordable and entailing less financial risk than ownership. We also demonstrate that access temporality, an important configurational variable for access-based service providers, affects the degree to which nonconsumption can be decreased. Compared to short-term access, BoP consumers perceive long-term access to be too similar to ownership in terms of affordability and financial risk, which causes them to refrain from purchasing. Overall, the results suggest that access-based services represent a viable alternative for addressing nonconsumption at the BoP. However, service providers should be aware that short-term access is required to gain acceptance among BoP consumers

A Voting Approach for Explainable Classification with Rule Learning

State-of-the-art results in typical classification tasks are mostly achieved by unexplainable machine learning methods, like deep neural networks, for instance. Contrarily, in this paper, we investigate the application of rule learning methods in such a context. Thus, classifications become based on comprehensible (first-order) rules, explaining the predictions made. In general, however, rule-based classifications are less accurate than state-of-the-art results (often significantly). As main contribution, we introduce a voting approach combining both worlds, aiming to achieve comparable results as (unexplainable) state-of-the-art methods, while still providing explanations in the form of deterministic rules. Considering a variety of benchmark data sets including a use case of significant interest to insurance industries, we prove that our approach not only clearly outperforms ordinary rule learning methods, but also yields results on a par with state-of-the-art outcomes.Comment: 34 pages, 10 figure

Disruption of Otoferlin Alters the Mode of Exocytosis at the Mouse Inner Hair Cell Ribbon Synapse

Sound encoding relies on Ca2+-mediated exocytosis at the ribbon synapse between cochlear inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs). Otoferlin, a multi-C2 domain protein, is proposed to regulate Ca2+-triggered exocytosis at this synapse, but the precise mechanisms of otoferlin function remain to be elucidated. Here, performing whole-cell voltage-clamp recordings of excitatory postsynaptic currents (EPSCs) from SGNs in otoferlin mutant mice, we investigated the impact of Otof disruption at individual synapses with single release event resolution. Otof deletion decreased the spontaneous release rate and abolished the stimulus-secretion coupling. This was evident from failure of potassium-induced IHC depolarization to stimulate release and supports the proposed role of otoferlin in Ca2+ sensing for fusion. A missense mutation in the Otof gene (pachanga), in which otoferlin level at the IHC plasma membrane was lowered without changing its Ca2+ binding, also reduced the spontaneous release rate but spared the stimulus-secretion coupling. The slowed stimulated release rate supports the hypothesis that a sufficient abundance of otoferlin at the plasma membrane is crucial for the vesicle supply. Large-sized monophasic EPSCs remained present upon Otof deletion despite the drastic reduction of the rate of exocytosis. However, EPSC amplitude, on average, was modestly decreased. Moreover, a reduced contribution of multiphasic EPSC was observed in both Otof mutants. We argue that the presence of large monophasic EPSCs despite the exocytic defect upon Otof deletion supports the uniquantal hypothesis of transmitter release at the IHC ribbon synapse. Based upon the reduced contribution of multiphasic EPSC, we propose a role of otoferlin in regulating the mode of exocytosis in IHCs

Patient perspectives on the need for improved hearing rehabilitation: A qualitative survey study of German cochlear implant users

BackgroundThe electrical cochlear implant (eCI) partially restores hearing in individuals affected by profound hearing impairment (HI) or deafness. However, the limited resolution of sound frequency coding with eCIs limits hearing in daily situations such as group conversations. Current research promises future improvements in hearing restoration which may involve gene therapy and optical stimulation of the auditory nerve, using optogenetics. Prior to the potential clinical translation of these technologies, it is critical that patients are engaged in order to align future research agendas and technological advancements with their needs.MethodsHere, we performed a survey study with hearing impaired, using an eCI as a means of hearing rehabilitation. We distributed a questionnaire to 180 adult patients from the University Medical Center Göttingen’s Department of Otolaryngology who were actively using an eCI for 6 months or more during the time of the survey period. Questions revolved around patients needs, and willingness to accept hypothetical risks or drawbacks associated with an optical CI (oCI).ResultsEighty-one participants responded to the questionnaire; 68% were greater than 60 years of age and 26% had bilateral eCIs. Participants expressed a need for improving the performance beyond that experienced with their current eCI. Primarily, they desired improved speech comprehension in background noise, greater ability to appreciate music, and more natural sound impression. They expressed a willingness for engaging with new technologies for improved hearing restoration. Notably, participants were least concerned about hypothetically receiving a gene therapy necessary for the oCI implant; but expressed greater reluctance to hypothetically receiving an implant that had yet to be evaluated in a human clinical trial.ConclusionThis work provides a preliminary step in engaging patients in the development of a new technology that has the potential to address the limitations of electrical hearing rehabilitation

Does a single session of theta-burst transcranial magnetic stimulation of inferior temporal cortex affect tinnitus perception?

<p>Abstract</p> <p>Background</p> <p>Cortical excitability changes as well as imbalances in excitatory and inhibitory circuits play a distinct pathophysiological role in chronic tinnitus. Repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex was recently introduced to modulate tinnitus perception. In the current study, the effect of theta-burst stimulation (TBS), a novel rTMS paradigm was investigated in chronic tinnitus. Twenty patients with chronic tinnitus completed the study. Tinnitus severity and loudness were monitored using a tinnitus questionnaire (TQ) and a visual analogue scale (VAS) before each session. Patients received 600 pulses of continuous TBS (cTBS), intermittent TBS (iTBS) and intermediate TBS (imTBS) over left inferior temporal cortex with an intensity of 80% of the individual active or resting motor threshold. Changes in subjective tinnitus perception were measured with a numerical rating scale (NRS).</p> <p>Results</p> <p>TBS applied to inferior temporal cortex appeared to be safe. Although half of the patients reported a slight attenuation of tinnitus perception, group analysis resulted in no significant difference when comparing the three specific types of TBS. Converting the NRS into the VAS allowed us to compare the time-course of aftereffects. Only cTBS resulted in a significant short-lasting improvement of the symptoms. In addition there was no significant difference when comparing the responder and non-responder groups regarding their anamnestic and audiological data. The TQ score correlated significantly with the VAS, lower loudness indicating less tinnitus distress.</p> <p>Conclusion</p> <p>TBS does not offer a promising outcome for patients with tinnitus in the presented study.</p