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.

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Unravelling the molecular players at the cholinergic efferent synapse of the zebrafish lateral line

10.1101/2020.07.09.196246 ◽

2020 ◽

Author(s):

Agustín E. Carpaneto Freixas ◽

Marcelo J. Moglie ◽

Tais Castagnola ◽

Lucia Salatino ◽

Sabina Domene ◽

...

Keyword(s):

Potassium Channels ◽

Lateral Line ◽

Sensory System ◽

Cholinergic Receptor ◽

Sk Channels ◽

Efferent Neurons ◽

Subsequent Activation ◽

Main Components ◽

External Stimuli

AbstractThe lateral line (LL) is a sensory system that allows fish and amphibians to detect water currents. LL responsiveness to external stimuli is modulated by descending efferent neurons. LL efferent modulation aids the animal to distinguish between external and self-generated stimuli, maintaining sensitivity to relevant cues. One of the main components of the efferent system is cholinergic, the activation of which inhibits afferent activity. Since LL hair cells (HC) share structural, functional and molecular similarities with those of the cochlea, one could propose that the receptor at the LL efferent synapse is a α9α10 nicotinic cholinergic one (nAChR). However, the identity of the molecular players underlying acetylcholine (ACh)-mediated inhibition in the LL remain unknown. Surprisingly, through the analysis of single-cell expression data and in situ hybridization, we describe that α9, but not α10 subunits, are enriched in zebrafish HC. Moreover, the heterologous expression of zebrafish α9 subunits indicates that α9 homomeric receptors are functional and exhibit robust ACh-gated currents which are blocked by α-Bungarotoxin (α-Btx). In addition, in vivo Ca2+ imaging on mechanically-stimulated zebrafish LL HC showed that ACh elicits a decrease in evoked Ca2+ signals, irrespective of HC polarity. This effect was blocked by both α-Btx and apamin, indicating coupling of ACh mediated effects to SK potassium channels. Collectively, our results indicate that an α9-containing (α9*) nAChR operates at the zebrafish LL efferent synapse. Moreover, the activation of α9* nAChRs most likely leads to LL HC hyperpolarization served by the ACh-dependent activation of Ca2+-dependent SK potassium channels.Significance StatementFishes and amphibians have a mechanosensory system, the lateral line (LL), which serves to detect hydromechanical variations around the animal’s body. The LL receives descending efferent innervation from the brain that modulates its responsiveness to external stimuli. LL efferent inhibition is mediated by ACh, however the identity of the molecular players at the LL efferent synapse is unknown. Here we demonstrate that a nicotinic cholinergic receptor (nAChR) composed of α9 subunits operates at the LL efferent synapse. Activation of α9-containing (α9*) nAChRs leads to LL hair cell hyperpolarization. The inhibitory signature of this process is brought about by the subsequent activation of Ca2+-dependent potassium SK channels, functionally coupled to α9* nAChRs.

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

eLife ◽

10.7554/elife.66396 ◽

2021 ◽

Vol 10 ◽

Author(s):

Gabriel E Romero ◽

Laurence O Trussell

Keyword(s):

Dynamic Range ◽

Short Term ◽

Wide Dynamic Range ◽

Efferent System ◽

Short Term Plasticity ◽

Ventral Cochlear Nucleus ◽

Brainstem Nucleus ◽

Reflex Arc ◽

Efferent Neurons ◽

Medial Olivocochlear

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.

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Efferent modulation of spontaneous lateral line activity during and after zebrafish motor commands

Journal of Neurophysiology ◽

10.1152/jn.00594.2019 ◽

2019 ◽

Vol 122 (6) ◽

pp. 2438-2448 ◽

Cited By ~ 6

Author(s):

Elias T. Lunsford ◽

Dimitri A. Skandalis ◽

James C. Liao

Keyword(s):

Motor Activity ◽

Lateral Line ◽

Spike Frequency ◽

Corollary Discharge ◽

Lateral Line System ◽

Afferent Neurons ◽

Afferent Activity ◽

Larval Zebrafish ◽

Efferent Neurons ◽

First Time

Accurate sensory processing during movement requires the animal to distinguish between external (exafferent) and self-generated (reafferent) stimuli to maintain sensitivity to biologically relevant cues. The lateral line system in fishes is a mechanosensory organ that experiences reafferent sensory feedback, via detection of fluid motion relative to the body generated during behaviors such as swimming. For the first time in larval zebrafish ( Danio rerio), we employed simultaneous recordings of lateral line and motor activity to reveal the activity of afferent neurons arising from endogenous feedback from hindbrain efferent neurons during locomotion. Frequency of spontaneous spiking in posterior lateral line afferent neurons decreased during motor activity and was absent for more than half of swimming trials. Targeted photoablation of efferent neurons abolished the afferent inhibition that was correlated to swimming, indicating that inhibitory efferent neurons are necessary for modulating lateral line sensitivity during locomotion. We monitored calcium activity with Tg(elav13:GCaMP6s) fish and found synchronous activity between putative cholinergic efferent neurons and motor neurons. We examined correlates of motor activity to determine which may best predict the attenuation of afferent activity and therefore what components of the motor signal are translated through the corollary discharge. Swim duration was most strongly correlated to the change in afferent spike frequency. Attenuated spike frequency persisted past the end of the fictive swim bout, suggesting that corollary discharge also affects the glide phase of burst and glide locomotion. The duration of the glide in which spike frequency was attenuated increased with swim duration but decreased with motor frequency. Our results detail a neuromodulatory mechanism in larval zebrafish that adaptively filters self-generated flow stimuli during both the active and passive phases of locomotion. NEW & NOTEWORTHY For the first time in vivo, we quantify the endogenous effect of efferent activity on afferent gain control in a vertebrate hair cell system during and after locomotion. We believe that this pervasive effect has been underestimated when afferent activity of octavolateralis systems is characterized in the current literature. We further identify a refractory period out of phase with efferent control and place this gain mechanism in the context of gliding behavior of freely moving animals.

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Visually mediated inhibition of lateral line primary afferent activity by the octavolateralis efferent system during predation in the free-swimming toadfish, Opsanus tau

Experimental Brain Research ◽

10.1007/bf00232215 ◽

1990 ◽

Vol 83 (1) ◽

Cited By ~ 26

Author(s):

T.C. Tricas ◽

S.M. Highstein

Keyword(s):

Lateral Line ◽

Afferent Activity ◽

Free Swimming ◽

Primary Afferent ◽

Efferent System ◽

Opsanus Tau

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

10.1101/2021.03.02.433557 ◽

2021 ◽

Author(s):

Gabriel E. Romero ◽

Laurence O. Trussell

Keyword(s):

Dynamic Range ◽

Short Term ◽

Wide Dynamic Range ◽

Efferent System ◽

Short Term Plasticity ◽

Ventral Cochlear Nucleus ◽

Brainstem Nucleus ◽

Reflex Arc ◽

Efferent Neurons ◽

Medial Olivocochlear

AbstractActivity 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.

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Influence of contralateral noise on distortion product latency in humans: Is the medial olivocochlear efferent system involved?

The Journal of the Acoustical Society of America ◽

10.1121/1.419635 ◽

1997 ◽

Vol 102 (4) ◽

pp. 2219-2227 ◽

Cited By ~ 12

Author(s):

Anne Lise Giraud ◽

Jocelyne Wable ◽

André Chays ◽

Lionel Collet ◽

Sylviane Chéry-Croze

Keyword(s):

Contralateral Noise ◽

Efferent System ◽

Distortion Product ◽

Medial Olivocochlear ◽

Medial Olivocochlear Efferent System

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Fast, Slow, and Steady-State Effects of Contralateral Acoustic Activation of the Medial Olivocochlear Efferent System in Awake Guinea Pigs: Action of Gentamicin

Journal of Neurophysiology ◽

10.1152/jn.1997.78.4.1826 ◽

1997 ◽

Vol 78 (4) ◽

pp. 1826-1836 ◽

Cited By ~ 29

Author(s):

Deise Lima da Costa ◽

Anne Chibois ◽

Jean-Paul Erre ◽

Christophe Blanchet ◽

RENAUD CHARLET de Sauvage ◽

...

Keyword(s):

Steady State ◽

Time Constant ◽

Decay Time ◽

Guinea Pigs ◽

Round Window ◽

Broadband Noise ◽

Decay Time Constant ◽

Efferent System ◽

Medial Olivocochlear ◽

Medial Olivocochlear Efferent System

Lima da Costa, Deise, Anne Chibois, Jean-Paul Erre, Christophe Blanchet, Renaud Charlet de Sauvage, and Jean-Marie Aran. Fast, slow, and steady-state effects of contralateral acoustic activation of the medial olivocochlear efferent system in awake guinea pigs: action of gentamicin. J. Neurophysiol. 78: 1826–1836, 1997. The function of the medial olivocochlear efferent system was observed in awake guinea pigs by recording, in the absence of ipsilateral external acoustic stimulation, the ensemble background activity (EBA) of the VIIIth nerve from an electrode chronically implanted on the round window of one ear. The EBA was measured by calculating the power value of the round window signal in the 0.5- to 2.5-kHz band after digital or analog (active) filtering. This EBA was compared with and without the addition of a low-level broadband noise to the opposite ear. The contralateral broadband noise (CLBN, 55 dB SPL) induced, via the efferent system, a decrease (suppression) of this EBA. With the use of noise bursts of different durations, two components in this suppression could be observed. After the onset of a 1-s CLBN, the power value of the EBA decreased rapidly by 38.0 ± 4.2% (mean ± SD, n = 3), with a latency of <10 ms and a decay time constant of 13.1 ± 1.0 ms (fast effect). At the offset of the 1-s CLBN, EBA came back to prestimulation values with a similar latency and a time constant of 15.5 ± 2.9 ms. During longer CLBN stimulation (≥1 min), EBA presented, after the fast decrease, an additional, slower decrease of 15.6 ± 3.1%, with a delay of 9.8 ± 1.3 s and a decay time constant of 16.1 ± 5.0 s ( n = 12, slow effect), and then remained remarkably constant for as long as observed, i.e., >2 h (steady state). The average global suppression was thus up to 47.8 ± 5.8% of the basal, pre-CLBN-stimulation EBA value. At the offset of the CLBN, EBA returned to pre-CLBN level with fast and slow phases, with, for the slow phase, no delay and a time constant of 32.1 ± 8.1 s. Fast and slow changes in EBA power values were observed after a single injection of gentamicin (GM) at different doses (150, 200, and 250 mg/kg). At 150 and 200 mg/kg, GM progressively and reversibly blocked the rapid effect, but the slow component of the efferent medial suppression remained remarkably unchanged. However, at higher doses both the fast and slow suppressions were totally yet still reversibly blocked. These observations indicate that the medial olivocochlear efferent system exerts sustained influences on outer hair cells and that this effect develops in two different steps that may have different basic cellular mechanisms.

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The Activity of Lateral-Line Efferent Neurones in Stationary and Swimming Dogfish

Journal of Experimental Biology ◽

10.1242/jeb.57.2.435 ◽

1972 ◽

Vol 57 (2) ◽

pp. 435-448 ◽

Cited By ~ 1

Author(s):

B. L. ROBERTS ◽

I. J. RUSSELL

Keyword(s):

Lateral Line ◽

Body Movement ◽

Cranial Nerves ◽

Regulatory System ◽

The Body ◽

Muscle Fibres ◽

Sense Organs ◽

Efferent System ◽

Natural Stimulation ◽

Stimulation Of

1. The activity of efferent neurones innervating lateral-line organs on the body of dogfish was followed by recording from filaments of cranial nerve X in 41 decerebrate preparations. 2. The efferent nerves were not spontaneously active. 3. Tactile stimulation to the head and body, vestibular stimulation and noxious chemical stimulation were followed by activity of the efferent nerves. 4. In contrast, natural stimulation of lateral-line organs (water jets) did not reflexly evoke discharges from the efferent fibres. 5. Reflex efferent responses were still obtained to mechanical stimulation even after the lateral-line organs had been denervated. 6. Electrical stimulation of cranial nerves innervating lateral-lines organs was followed by reflex activity of the efferent fibres. But similar stimuli applied to other cranial nerves were equally effective in exciting the efferent system. 7. Vigorous movements of the fish, involving the white musculature, were preceded and accompanied by activity of the efferent fibres which persisted as long as the white muscle fibres were contracting. 8. Rhythmical swimming movements were accompanied by a few impulses in the efferent fibres grouped in bursts at the same frequency as the swimming movements. 9. It is concluded that the efferent neurones cannot contribute to a feedback regulatory system because they are not excited by natural stimulation of the lateral-line sense organs. The close correlation found between efferent activity and body movement suggests that the efferent system might operate in a protective manner to prevent the sense organs from being over-stimulated when the fish makes vigorous movements.

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