Synaptic plasticity of inhibitory synapses onto medial olivocochlear efferent neurons

The descending auditory system modulates the ascending system at every level. The final descending, or efferent stage, is comprised of lateral olivocochlear (LOC) and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC-mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention, and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB-MOC synapses exhibit short-term depression, suggesting reduced MNTB-MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound-evoked activity in MNTB neurons in vivo, MNTB-MOC synapses may be tonically depressed. To probe this, we characterized short-term plasticity of MNTB-MOC synapses in mouse brain slices. We mimicked in vivo-like temperature and extracellular calcium conditions, and in vivo-like activity patterns of fast synaptic activation rates, sustained activation, and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, post-synaptic currents (PSCs) in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression.

Immunohistochemistry localises myosin-7a to cochlear efferent boutons

Background: Myosin 7a is an actin-binding motor protein involved in the formation of hair-cell stereocilia both in the cochlea and in the vestibular system. Mutations in myosin 7a are linked to congenital hearing loss and are present in 50% of Type-1 Usher syndrome patients who suffer from progressive hearing loss and vestibular system dysfunction. Methods: Myosin 7a is often used to visualise sensory hair cells due to its well characterised and localised expression profile. We thus conducted myosin-7a immunostaining across all three turns of the adult rat organ of Corti to visualise hair cells. Results: As expected, we observed myosin 7a staining in both inner and outer hair cells. Unexpectedly, we also observed strong myosin 7a staining in the medial olivocochlear efferent synaptic boutons contacting the outer hair cells. Efferent bouton myosin-7a staining was present across all three turns of the cochlea. We verified this localisation by co-staining with a known efferent bouton marker, the vesicular acetylcholine transporter. Conclusions: In addition to its role in stereocilia formation and maintenance, myosin 7a or certain myosin-7a expression variants might play a role in efferent synaptic transmission in the cochlea and thus ultimately influence cochlear gain regulation. Our immunohistochemistry results should be validated with other methods to confirm these serendipitous findings.

The Strength of the Medial Olivocochlear Reflex in Chinchillas Is Associated With Delayed Response Performance in a Visual Discrimination Task With Vocalizations as Distractors

The ability to perceive the world is not merely a passive process but depends on sensorimotor loops and interactions that guide and actively bias our sensory systems. Understanding which and how cognitive processes participate in this active sensing is still an open question. In this context, the auditory system presents itself as an attractive model for this purpose as it features an efferent control network that projects from the cortex to subcortical nuclei and even to the sensory epithelium itself. This efferent system can regulate the cochlear amplifier sensitivity through medial olivocochlear (MOC) neurons located in the brainstem. The ability to suppress irrelevant sounds during selective attention to visual stimuli is one of the functions that have been attributed to this system. MOC neurons are also directly activated by sounds through a brainstem reflex circuit, a response linked to the ability to suppress auditory stimuli during visual attention. Human studies have suggested that MOC neurons are also recruited by other cognitive functions, such as working memory and predictability. The aim of this research was to explore whether cognitive processes related to delayed responses in a visual discrimination task were associated with MOC function. In this behavioral condition, chinchillas held their responses for more than 2.5 s after visual stimulus offset, with and without auditory distractors, and the accuracy of these responses was correlated with the magnitude of the MOC reflex. We found that the animals’ performance decreased in presence of auditory distractors and that the results observed in MOC reflex could predict this performance. The individual MOC strength correlated with behavioral performance during delayed responses with auditory distractors, but not without them. These results in chinchillas, suggest that MOC neurons are also recruited by other cognitive functions, such as working memory.

A Time-Course-Based Estimation of the Human Medial Olivocochlear Reflex Function Using Clicks

The auditory efferent system, especially the medial olivocochlear reflex (MOCR), is implicated in both typical auditory processing and in auditory disorders in animal models. Despite the significant strides in both basic and translational research on the MOCR, its clinical applicability remains under-utilized in humans due to the lack of a recommended clinical method. Conventional tests employ broadband noise in one ear while monitoring change in otoacoustic emissions (OAEs) in the other ear to index efferent activity. These methods, (1) can only assay the contralateral MOCR pathway and (2) are unable to extract the kinetics of the reflexes. We have developed a method that re-purposes the same OAE-evoking click-train to also concurrently elicit bilateral MOCR activity. Data from click-train presentations at 80 dB peSPL at 62.5 Hz in 13 young normal-hearing adults demonstrate the feasibility of our method. Mean MOCR magnitude (1.7 dB) and activation time-constant (0.2 s) are consistent with prior MOCR reports. The data also suggest several advantages of this method including, (1) the ability to monitor MEMR, (2) obtain both magnitude and kinetics (time constants) of the MOCR, (3) visual and statistical confirmation of MOCR activation.

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.

Behavioral Measures of Cochlear Gain Reduction Depend on Precursor Frequency, Bandwidth, and Level

Sensory systems adjust to the environment to maintain sensitivity to change. In the auditory system, the medial olivocochlear reflex (MOCR) is a known physiological mechanism capable of such adjustment. The MOCR provides efferent feedback between the brainstem and cochlea, reducing cochlear gain in response to sound. The perceptual effects of the MOCR are not well understood, such as how gain reduction depends on elicitor characteristics in human listeners. Physiological and behavioral data suggest that ipsilateral MOCR tuning is only slightly broader than it is for afferent fibers, and that the fibers feed back to the frequency region of the cochlea that stimulated them. However, some otoacoustic emission (OAE) data suggest that noise is a more effective elicitor than would be consistent with sharp tuning, and that a broad region of the cochlea may be involved in elicitation. If the elicitor is processed in a cochlear channel centered at the signal frequency, the growth of gain reduction with elicitor level would be expected to depend on the frequency content of the elicitor. In the current study, the effects of the frequency content and level of a preceding sound (called a precursor) on signal threshold was examined. The results show that signal threshold increased with increasing precursor level at a shallower slope for a tonal precursor at the signal frequency than for a tonal precursor nearly an octave below the signal frequency. A broadband noise was only slightly more effective than a tone at the signal frequency, with a relatively shallow slope similar to that of the tonal precursor at the signal frequency. Overall, these results suggest that the excitation at the signal cochlear place, regardless of elicitor frequency, determines the magnitude of ipsilateral cochlear gain reduction, and that it increases with elicitor level.

Olivocochlear Changes Associated With Aging Predominantly Affect the Medial Olivocochlear System

Age-related hearing loss (ARHL) is a public health problem that has been associated with negative health outcomes ranging from increased frailty to an elevated risk of developing dementia. Significant gaps remain in our knowledge of the underlying central neural mechanisms, especially those related to the efferent auditory pathways. Thus, the aim of this study was to quantify and compare age-related alterations in the cholinergic olivocochlear efferent auditory neurons. We assessed, in young-adult and aged CBA mice, the number of cholinergic olivocochlear neurons, auditory brainstem response (ABR) thresholds in silence and in presence of background noise, and the expression of excitatory and inhibitory proteins in the ventral nucleus of the trapezoid body (VNTB) and in the lateral superior olive (LSO). In association with aging, we found a significant decrease in the number of medial olivocochlear (MOC) cholinergic neurons together with changes in the ratio of excitatory and inhibitory proteins in the VNTB. Furthermore, in old mice we identified a correlation between the number of MOC neurons and ABR thresholds in the presence of background noise. In contrast, the alterations observed in the lateral olivocochlear (LOC) system were less significant. The decrease in the number of LOC cells associated with aging was 2.7-fold lower than in MOC and in the absence of changes in the expression of excitatory and inhibitory proteins in the LSO. These differences suggest that aging alters the medial and lateral olivocochlear efferent pathways in a differential manner and that the changes observed may account for some of the symptoms seen in ARHL.

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.