Efferent neurons control hearing sensitivity and protect hearing from noise through the regulation of gap junctions between cochlear supporting cells

It is critical for hearing that the descending cochlear efferent system provide a negative feedback to hair cells to regulate hearing sensitivity and provide the protection of hearing from noise. Here, we report that the medial olivocochlear (MOC) efferent nerves, which project to outer hair cells (OHCs), also could innervate OHC surrounding supporting cells (SCs) to regulate hearing sensitivity. MOC nerve fibers are cholinergic and acetylcholine (ACh) is a primary neurotransmitter. MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChT), and postsynaptic ACh receptors were visible in SCs and the SC area. Application of ACh in the SC could evoke a typical inward current, which reduced gap junctions (GJs) between SCs and consequently declined OHC electromotility, which is an active cochlear amplification and can increase hearing sensitivity. This indirect, GJ-mediated inhibition enhanced the direct inhibition of ACh on OHC electromotility but had long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway declined the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion production otoacoustic emission (DPOAE) showed a delayed reduction after noise exposure. Our findings reveal a new pathway for the MOC efferent system via innervating SCs to control active cochlear amplification and hearing sensitivity. These data also suggest that this GJ-mediated efferent pathway may play a critical role in the long-term efferent inhibition and is required for protecting hearing from noise trauma.

The Cholinergic Lateral Line Efferent Synapse: Structural, Functional and Molecular Similarities With Those of the Cochlea

Vertebrate hair cell (HC) systems are innervated by efferent fibers that modulate their response to external stimuli. In mammals, the best studied efferent-HC synapse, the cholinergic medial olivocochlear (MOC) efferent system, makes direct synaptic contacts with HCs. The net effect of MOC activity is to hyperpolarize HCs through the activation of α9α10 nicotinic cholinergic receptors (nAChRs) and the subsequent activation of Ca2+-dependent SK2 potassium channels. A serious obstacle in research on many mammalian sensory systems in their native context is that their constituent neurons are difficult to access even in newborn animals, hampering circuit observation, mapping, or controlled manipulation. By contrast, fishes and amphibians have a superficial and accessible mechanosensory system, the lateral line (LL), which circumvents many of these problems. LL responsiveness is modulated by efferent neurons which aid to distinguish between external and self-generated stimuli. One component of the LL efferent system is cholinergic and its activation inhibits LL afferent activity, similar to what has been described for MOC efferents. The zebrafish (Danio rerio) has emerged as a powerful model system for studying human hearing and balance disorders, since LL HC are structurally and functionally analogous to cochlear HCs, but are optically and pharmacologically accessible within an intact specimen. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of HC biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired HC dysfunction. With the rise of the zebrafish LL as a model in which to study auditory system function and disease, there has been an increased interest in studying its efferent system and evaluate the similarity between mammalian and piscine efferent synapses. Advances derived from studies in zebrafish include understanding the effect of the LL efferent system on HC and afferent activity, and revealing that an α9-containing nAChR, functionally coupled to SK channels, operates at the LL efferent synapse. In this review, we discuss the tools and findings of these recent investigations into zebrafish efferent-HC synapse, their commonalities with the mammalian counterpart and discuss several emerging areas for future studies.

Effects of Multisession Anodal Electrical Stimulation of the Auditory Cortex on Temporary Noise-Induced Hearing Loss in the Rat

The protective effect of the efferent system against acoustic trauma (AT) has been shown by several experimental approaches, including damage to one ear, sectioning of the olivocochlear bundle (OCB) in the floor of the IV ventricle, and knock-in mice overexpressing outer hair cell (OHC) cholinergic receptors, among others. Such effects have been related to changes in the regulation of the cholinergic efferent system and in cochlear amplification, which ultimately reverse upon protective hearing suppression. In addition to well-known circuits of the brainstem, the descending corticofugal pathway also regulates efferent neurons of the olivary complex. In this study, we applied our recently developed experimental paradigm of multiple sessions of electrical stimulation (ES) to activate the efferent system in combination with noise overstimulation. ABR thresholds increased 1 and 2 days after AT (8–16 kHz bandpass noise at 107 dB for 90 min) recovering at AT + 14 days. However, after multiple sessions of epidural anodal stimulation, no changes in thresholds were observed following AT. Although an inflammatory response was also observed 1 day after AT in both groups, the counts of reactive macrophages in both experimental conditions suggest decreased inflammation in the epidural stimulation group. Quantitative immunocytochemistry for choline acetyltransferase (ChAT) showed a significant decrease in the size and optical density of the efferent terminals 1 day after AT and a rebound at 14 days, suggesting depletion of the terminals followed by a long-term compensatory response. Such a synthesis recovery was significantly higher upon cortical stimulation. No significant correlation was found between ChAT optical density and size of the buttons in sham controls (SC) and ES/AT + 1day animals; however, significant negative correlations were shown in all other experimental conditions. Therefore, our comparative analysis suggests that cochleotopic cholinergic neurotransmission is also better preserved after multisession epidural stimulation.

Distinct forms of synaptic plasticity during ascending vs descending control of medial olivocochlear efferent neurons

Activity in each brain region is shaped by the convergence of ascending and descending axonal pathways, and the balance and characteristics of these determine neural output. The medial olivocochlear (MOC) efferent system is part of a reflex arc that critically controls auditory sensitivity. Multiple central pathways contact MOC neurons, raising the question of how a reflex arc could be engaged by diverse inputs. We examined functional properties of synapses onto brainstem MOC neurons from ascending (ventral cochlear nucleus, VCN), and descending (inferior colliculus, IC) sources in mice using an optogenetic approach. We found that these pathways exhibited opposing forms of short-term plasticity, with VCN input showing depression and IC input showing marked facilitation. By using a conductance clamp approach, we found that combinations of facilitating and depressing inputs enabled firing of MOC neurons over a surprisingly wide dynamic range, suggesting an essential role for descending signaling to a brainstem nucleus.

Auditory Efferent System Influences the Auditory Overshoot Phenomenon- An Auditory Brainstem Response Study in Guinea Pigs

Introduction: Detection of a brief tonal signal at the beginning of a longer masking noise is difficult, but it becomes easier when the onset of signal is delayed. This phenomenon is known as overshoot or temporal effect. Aiming of our study was to investigate the effect of the auditory efferent nerves (AENs) function on the auditory electrophysiological overshoot, further introducing an objective tool examining one of the AENs performances. Therefore, the effect and the trend of changes induced by low and high-frequency stimuli on electrophysiological overshoot in different delay onset time (DOTs) between the signal and the noise before and after dissecting the AENs were studied. Methods: Right internal auditory canals were exposed in 16 young male guinea pigs weighing 250 to 350 g. The inferior and posterior vestibular nerves that are known to carry AENs were transected in half of the subjects. Then, the ABR waveforms were recorded at 16 & 8 kHz tone burst stimuli at 0, 30, 60, 100 ms DOTs relative to wide-band noise. The value of latency of ABR waves I and III were compared among the different DOTs and five signal-to-noise ratios (SNRs) before and after the surgery. Results: By increasing DOTs, the latency of ABR waves I& III decreased in the control group before and after the surgery and the case group before surgery at 16 kHz. However, the observed overshoot-like effect disappeared after the surgery in the case group. The wave's latency I& III increased from 0 to 30 ms, remained approximately constant from 30 to 60ms, and then began to decrease toward 100 ms DOTs. However, none of the measurements at 8 kHz, before and after surgery at both groups showed an overshoot effect. Conclusion(s): By using the ABR paradigm, the overshoot phenomenon disappeared after the transection of AENs. The results confirmed the role of the efferent system on auditory overshoot. Therefore, an objective tool to measure auditory efferent function is provided.

Differences in the Structure and Function of the Vestibular Efferent System Among Vertebrates

The role of the mammalian vestibular efferent system in everyday life has been a long-standing mystery. In contrast to what has been reported in lower vertebrate classes, the mammalian vestibular efferent system does not appear to relay inputs from other sensory modalities to the vestibular periphery. Furthermore, to date, the available evidence indicates that the mammalian vestibular efferent system does not relay motor-related signals to the vestibular periphery to modulate sensory coding of the voluntary self-motion generated during natural behaviors. Indeed, our recent neurophysiological studies have provided insight into how the peripheral vestibular system transmits head movement-related information to the brain in a context independent manner. The integration of vestibular and extra-vestibular information instead only occurs at next stage of the mammalian vestibular system, at the level of the vestibular nuclei. The question thus arises: what is the physiological role of the vestibular efferent system in mammals? We suggest that the mammalian vestibular efferent system does not play a significant role in short-term modulation of afferent coding, but instead plays a vital role over a longer time course, for example in calibrating and protecting the functional efficacy of vestibular circuits during development and aging in a role analogous the auditory efferent system.

Distinct forms of synaptic plasticity during ascending vs. descending control of medial olivocochlear efferent neurons

Activity in each brain region is shaped by the convergence of ascending and descending axonal pathways, and the balance and characteristics of these determine neural output. The medial olivocochlear (MOC) efferent system is part of a reflex arc that critically controls auditory sensitivity. Multiple central pathways contact MOC neurons, raising the question of how a reflex arc could be engaged by diverse inputs. We examined functional properties of synapses onto brainstem MOC neurons from ascending (ventral cochlear nucleus, VCN), and descending (inferior colliculus, IC) sources in mice using an optogenetic approach. We found that these pathways exhibited opposing forms of short-term plasticity, with VCN input showing depression and IC input showing marked facilitation. By using a conductance clamp approach, we found that combinations of facilitating and depressing inputs enabled firing of MOC neurons over a surprisingly wide dynamic range, suggesting an essential role for descending signaling to a brainstem nucleus.