Efferent Inhibition Research Articles

Virally-Mediated Enhancement of Efferent Inhibition Reduces Acoustic Trauma in Wild Type Murine Cochleas.

Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. In addition, however, the cochlea receives some protection from medial olivocochlear (MOC) efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release ACh (Acetylycholine) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (α9)2(α10)3 nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knock-in mice with a gain-of-function nAChR (α9L9'T) suffer less NIHL. α9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the α9L9'T subunit. In this study, an HA-tagged gain-of-function α9 isoform was expressed in wildtype mice in an attempt to reduce NIHL. Synaptic integration of the virally-expressed nAChR subunit was confirmed by HA-immunopuncta in the postsynaptic membrane of OHCs. After noise exposure, α9L9'T-HA injected mice had less hearing loss (auditory brainstem response (ABR) thresholds and threshold shifts) than did control mice. ABRs of α9L9'T-HA injected mice also had larger wave1 amplitudes and better recovery of wave one amplitudes post noise exposure. Thus, virally-expressed α9L9'T combines effectively with native α9 and α10 subunits to mitigate NIHL in wildtype cochleas.

Co-release of GABA and ACh from medial olivocochlear neurons fine tunes cochlear efferent inhibition.

During development, inner hair cells (IHCs) in the mammalian cochlea are unresponsive to acoustic stimuli but instead exhibit spontaneous activity. During this same period, neurons originating from the medial olivocochlear complex (MOC) transiently innervate IHCs, regulating their firing pattern which is crucial for the correct development of the auditory pathway. Although the MOC-IHC is a cholinergic synapse, previous evidence indicates the widespread presence of gamma-aminobutyric acid (GABA) signaling markers, including presynaptic GABAB receptors (GABABR). In this study, we explore the source of GABA by optogenetically activating either cholinergic or GABAergic fibers. The optogenetic stimulation of MOC terminals from GAD;ChR2-eYFP and ChAT;ChR2-eYFP mice evoked synaptic currents in IHCs that were blocked by α-bungarotoxin. This suggests that GABAergic fibers release ACh and activate α9α10 nicotinic acetylcholine receptors (nAChRs). Additionally, MOC cholinergic fibers release not only ACh but also GABA, as the effect of GABA on ACh response amplitude was prevented by applying the GABAB-R blocker (CGP 36216). Using optical neurotransmitter detection and calcium imaging techniques, we examined the extent of GABAergic modulation at the single synapse level. Our findings suggest heterogeneity in GABA modulation, as only 15 out of 31 recorded synaptic sites were modulated by applying the GABABR specific antagonist, CGP (100-200 μM). In conclusion, we provide compelling evidence that GABA and ACh are co-released from at least a subset of MOC terminals. In this circuit, GABA functions as a negative feedback mechanism, locally regulating the extent of cholinergic inhibition at certain efferent-IHC synapses during an immature stage.

Fast Inhibition Slows and Desynchronizes Mouse Auditory Efferent Neuron Activity.

The encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem arewell suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that reduce MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation ("wedge-slice"). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The "in vivo-like" timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivo-like timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hypersuppression of cochlear activity.

Auditory Deprivation during Development Alters Efferent Neural Feedback and Perception.

Auditory experience plays a critical role in hearing development. Developmental auditory deprivation because of otitis media, a common childhood disease, produces long-standing changes in the central auditory system, even after the middle ear pathology is resolved. The effects of sound deprivation because of otitis media have been mostly studied in the ascending auditory system but remain to be examined in the descending pathway that runs from the auditory cortex to the cochlea via the brainstem. Alterations in the efferent neural system could be important because the descending olivocochlear pathway influences the neural representation of transient sounds in noise in the afferent auditory system and is thought to be involved in auditory learning. Here, we show that the inhibitory strength of the medial olivocochlear efferents is weaker in children with a documented history of otitis media relative to controls; both boys and girls were included in the study. In addition, children with otitis media history required a higher signal-to-noise ratio on a sentence-in-noise recognition task than controls to achieve the same criterion performance level. Poorer speech-in-noise recognition, a hallmark of impaired central auditory processing, was related to efferent inhibition, and could not be attributed to the middle ear or cochlear mechanics.SIGNIFICANCE STATEMENT Otitis media is the second most common reason children go to the doctor. Previously, degraded auditory experience because of otitis media has been associated with reorganized ascending neural pathways, even after middle ear pathology resolved. Here, we show that altered afferent auditory input because of otitis media during childhood is also associated with long-lasting reduced descending neural pathway function and poorer speech-in-noise recognition. These novel, efferent findings may be important for the detection and treatment of childhood otitis media.

Engineering olivocochlear inhibition to reduce acoustic trauma

Efferent brain-stem neurons release acetylcholine to desensitize cochlear hair cells and can protect the inner ear from acoustic trauma. That protection is absent from knockout mice lacking efferent inhibition and is stronger in mice with a gain-of-function point mutation of the hair cell-specific nicotinic acetylcholine receptor. The present work uses viral transduction of gain-of-function receptors to restore acoustic prophylaxis to the knockout mice. Widespread postsynaptic expression of the transgene was visualized in excised tissue with a fluorophore-conjugated peptide toxin that binds selectively to hair cell acetylcholine receptors. Viral transduction into efferent knockout mice reduced the temporary hearing loss measured 1day post acoustic trauma. The acoustic evoked-response waveform (auditory brain-stem response) recovered more rapidly in treated mice than in control mice. Thus, both cochlear amplification by outer hair cells (threshold shift) and afferent signaling (evoked-response amplitude) in knockout mice were protected by viral transduction of hair cell acetylcholine receptors. Gene therapy to strengthen efferent cochlear feedback could be complementary to existing and future therapies to prevent hearing loss, including ear coverings, hearing aids, single-gene repair, or small-molecule therapies.

Estimation of efferent inhibition and speech in noise perception on vocal musicians and music sleepers: A comparative study

Estimation of efferent inhibition and speech in noise perception on vocal musicians and music sleepers: A comparative study

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 provides a negative feedback to hair cells to regulate hearing sensitivity and protect hearing from noise. The medial olivocochlear (MOC) efferent nerves project to outer hair cells (OHCs) to regulate OHC electromotility, which is an active cochlear amplifier and can increase hearing sensitivity. Here, we report that the MOC efferent nerves also could innervate supporting cells (SCs) in the vicinity of OHCs to regulate hearing sensitivity. MOC nerve fibers are cholinergic, and acetylcholine (ACh) is a primary neurotransmitter. Immunofluorescent staining showed that MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChTs), and postsynaptic ACh receptors were visible at SCs and in the SC area. Application of ACh in SCs could evoke a typical inward current and reduce gap junctions (GJs) between them, which consequently enhanced the direct effect of ACh on OHCs to shift but not eliminate OHC electromotility. This indirect, GJ-mediated inhibition had a long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway decreased the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion product 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 SC GJ-mediated efferent pathway may play a critical role in long-term efferent inhibition and is required for protection of hearing from noise trauma.NEW & NOTEWORTHY The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

Sexual Dimorphism in the Functional Development of the Cochlear Amplifier in Humans.

Otoacoustic emissions, a byproduct of active cochlear mechanisms, exhibit a higher magnitude in females than in males. The relatively higher levels of androgen exposure in the male fetus are thought to cause this difference. Postnatally, the onset of puberty is also associated with the androgen surge in males. In this study, we investigated sexual dimorphism in age-related changes in stimulus-frequency otoacoustic emissions for children. In a retrospective design, stimulus-frequency otoacoustic emissions were analyzed from a cross-sectional sample of 170 normal-hearing children (4 to 12 years) and 67 young adults. Wideband acoustic immittance and efferent inhibition measures were analyzed to determine the extent to which middle ear transmission and efferent inhibition can account for potential sex differences in stimulus-frequency otoacoustic emissions. Male children showed a significant reduction in otoacoustic emission magnitudes with age, whereas female children did not show any such changes. Females showed higher stimulus-frequency otoacoustic emission magnitudes compared with males. However, the effect size of sex differences in young adults was larger compared with children. Unlike the otoacoustic emission magnitude, the noise floor did not show sexual dimorphism; however, it decreased with age. Neither the wideband absorbance nor efferent inhibition could account for the sex differences in stimulus-frequency otoacoustic emissions. The cochlear-amplifier function remains robust in female children but diminishes in male children between 4 and 12 years of age. We carefully eliminated lifestyle, middle ear, and efferent factors to conclude that the androgen surge associated with puberty likely caused the observed masculinization of stimulus-frequency otoacoustic emissions in male children. These findings have significant theoretical consequences. The cochlea is considered mature at birth; however, the present findings highlight that functional cochlear maturation, as revealed by otoacoustic emissions, can be postnatally influenced by endogenous hormonal factors, at least in male children. Overall, work reported here demonstrates sexual dimorphism in the functional cochlear maturational processes during childhood.

The role of efferents in human auditory development: efferent inhibition predicts frequency discrimination in noise for children.

The descending corticofugal fibers originate from the auditory cortex and exert control on the periphery via the olivocochlear efferents. Medial efferents are thought to enhance the discriminability of transient sounds in background noise. In addition, the observation of deleterious long-term effects of efferent sectioning on the response properties of auditory nerve fibers in neonatal cats supports an efferent-mediated control of normal development. However, the role of the efferent system in human hearing remains unclear. The objective of the present study was to test the hypothesis that the medial efferents are involved in the development of frequency discrimination in noise. The hypothesis was examined with a combined behavioral and physiological approach. Frequency discrimination in noise and efferent inhibition were measured in 5- to 12-yr-old children (n = 127) and young adults (n = 37). Medial efferent strength was noninvasively assayed with a rigorous otoacoustic emission protocol. Results revealed an age-mediated relationship between efferent inhibition and frequency discrimination in noise. Efferent inhibition strongly predicted frequency discrimination in noise for younger children (5-9 yr). However, for older children (>9 yr) and adults, efferent inhibition was not related to frequency discrimination in noise. These findings support the role of efferents in the development of hearing-in-noise in humans; specifically, younger children compared with older children and adults are relatively more dependent on efferent inhibition for extracting relevant cues in noise. Additionally, the present findings caution against postulating an oversimplified relationship between efferent inhibition and measures of auditory perception in humans.NEW & NOTEWORTHY Despite several decades of research, the functional role of medial olivocochlear efferents in humans remains controversial and is thought to be insignificant. Here it is shown that medial efferent inhibition strongly predicts frequency discrimination in noise for younger children but not for older children and adults. Young children are relatively more dependent on the efferent system for listening-in-noise. This study highlights the role of the efferent system in hearing-in-noise during childhood development.

The Influence of Efferent Inhibition on Speech Perception in Noise: A Revisit Through Its Level-Dependent Function.

Purpose The study aimed to assess the relationship between the level-dependent function of efferent inhibition and speech perception in noise across different intensities of suppressor and across different signal-to-noise ratios (SNRs) of speech. Method Twenty-six young normal-hearing adults participated in the study. Contralateral suppression of transient evoked otoacoustic emissions (TEOAEs) was measured for 3 levels of suppressor (40, 50, and 60 dB SPL). Speech identification score (SIS) was measured at 5 ipsilateral SNR conditions (quiet, 0, -5, -10, and -15 dB), with and without contralateral broadband noise at 3 levels (40, 50, and 60 dB SPL). Furthermore, SNR-50 was measured with and without the same 3 levels of contralateral broadband noise. Results The results showed that the suppression magnitude of TEOAE increased with an increase in suppressor level. However, neither SIS nor SNR-50 was influenced by the contralateral noise. In addition, SIS and SNR-50 did not show significant correlation with contralateral suppression of TEOAEs. This was true at all the SNRs and contralateral noise levels used in the study. Conclusions The findings suggest that the intensity of noise directly influences medial olivocochlear bundle-mediated efferent inhibition. However, the role of the medial olivocochlear bundle in regulating speech perception in noise needs to be revisited. Supplemental Material https://doi.org/10.23641/asha.9336353.

Cochlea-Specific Deletion of Cav1.3 Calcium Channels Arrests Inner Hair Cell Differentiation and Unravels Pitfalls of Conditional Mouse Models.

Inner hair cell (IHC) Cav1.3 Ca2+ channels are multifunctional channels mediating Ca2+ influx for exocytosis at ribbon synapses, the generation of Ca2+ action potentials in pre-hearing IHCs and gene expression. IHCs of deaf systemic Cav1.3-deficient (Cav1.3-/-) mice stay immature because they fail to up-regulate voltage- and Ca2+-activated K+ (BK) channels but persistently express small conductance Ca2+-activated K+ (SK2) channels. In pre-hearing wildtype mice, cholinergic neurons from the superior olivary complex (SOC) exert efferent inhibition onto spontaneously active immature IHCs by activating their SK2 channels. Because Cav1.3 plays an important role for survival, health and function of SOC neurons, SK2 channel persistence and lack of BK channels in systemic Cav1.3-/- IHCs may result from malfunctioning neurons of the SOC. Here we analyze cochlea-specific Cav1.3 knockout mice with green fluorescent protein (GFP) switch reporter function, Pax2::cre;Cacna1d-eGFPflex/flex and Pax2::cre;Cacna1d-eGFPflex/-. Profound hearing loss, lack of BK channels and persistence of SK2 channels in Pax2::cre;Cacna1d-eGFPflex/- mice recapitulated the phenotype of systemic Cav1.3-/- mice, indicating that in wildtype mice, regulation of SK2 and BK channel expression is independent of Cav1.3 expression in SOC neurons. In addition, we noticed dose-dependent GFP toxicity leading to death of basal coil IHCs of Pax2::cre;Cacna1d-eGFPflex/flex mice, likely because of high GFP concentration and small repair capacity. This and the slower time course of Pax2-driven Cre recombinase in switching two rather than one Cacna1d-eGFPflex allele lead us to study Pax2::cre;Cacna1d-eGFPflex/- mice. Notably, control Cacna1d-eGFPflex/- IHCs showed a significant reduction in Cav1.3 channel cluster sizes and currents, suggesting that the intronic construct interfered with gene translation or splicing. These pitfalls are likely to be a frequent problem of many genetically modified mice with complex or multiple gene-targeting constructs or fluorescent proteins. Great caution and appropriate controls are therefore required.

Auditory Attention Reduced Ear-Canal Noise in Humans by Reducing Subject Motion, Not by Medial Olivocochlear Efferent Inhibition: Implications for Measuring Otoacoustic Emissions During a Behavioral Task.

Otoacoustic emissions (OAEs) are often measured to non-invasively determine activation of medial olivocochlear (MOC) efferents in humans. Usually these experiments assume that ear-canal noise remains constant. However, changes in ear-canal noise have been reported in some behavioral experiments. We studied the variability of ear-canal noise in eight subjects who performed a two-interval-forced-choice (2IFC) sound-level-discrimination task on monaural tone pips in masker noise. Ear-canal noise was recorded directly from the unstimulated ear opposite the task ear. Recordings were also made with similar sounds presented, but no task done. In task trials, ear-canal noise was reduced at the time the subject did the discrimination, relative to the ear-canal noise level earlier in the trial. In two subjects, there was a decrease in ear-canal noise, primarily at 1–2 kHz, with a time course similar to that expected from inhibition by MOC activity elicited by the task-ear masker noise. These were the only subjects with spontaneous OAEs (SOAEs). We hypothesize that the SOAEs were inhibited by MOC activity elicited by the task-ear masker. Based on the standard rationale in OAE experiments that large bursts of ear-canal noise are artifacts due to subject movement, ear-canal noise bursts above a sound-level criterion were removed. As the criterion was lowered and more high- and moderate-level ear-canal noise bursts were removed, the reduction in ear-canal noise level at the time of the 2IFC discrimination decreased to almost zero, for the six subjects without SOAEs. This pattern is opposite that expected from MOC-induced inhibition (which is greater on lower-level sounds), but can be explained by the hypothesis that subjects move less and create fewer bursts of ear-canal noise when they concentrate on doing the task. In no-task trials for these six subjects, the ear-canal noise level was little changed throughout the trial. Our results show that measurements of MOC effects on OAEs must measure and account for changes in ear-canal noise, especially in behavioral experiments. The results also provide a novel way of showing the time course of the buildup of attention via the time course of the reduction in ear-canal noise.

Efferent Inhibition of the Cochlea.

Cholinergic efferent neurons originating in the brainstem innervate the acoustico-lateralis organs (inner ear, lateral line) of vertebrates. These release acetylcholine (ACh) to inhibit hair cells through activation of calcium-dependent potassium channels. In the mammalian cochlea, ACh shunts and suppresses outer hair cell (OHC) electromotility, reducing the essential amplification of basilar membrane motion. Consequently, medial olivocochlear neurons that inhibit OHCs reduce the sensitivity and frequency selectivity of afferent neurons driven by cochlear vibration of inner hair cells (IHCs). The cholinergic synapse on hair cells involves an unusual ionotropic ACh receptor, and a near-membrane postsynaptic cistern. Lateral olivocochlear (LOC) neurons modulate type I afferents by still-to-be-defined synaptic mechanisms. Olivocochlear neurons can be activated by a reflex arc that includes the auditory nerve and projections from the cochlear nucleus. They are also subject to modulation by higher-order central auditory interneurons. Through its actions on cochlear hair cells, afferent neurons, and higher centers, the olivocochlear system protects against age-related and noise-induced hearing loss, improves signal coding in noise under certain conditions, modulates selective attention to sensory stimuli, and influences sound localization.

Voltage-Gated Calcium Influx Modifies Cholinergic Inhibition of Inner Hair Cells in the Immature Rat Cochlea.

Until postnatal day (P) 12, inner hair cells of the rat cochlea are invested with both afferent and efferent synaptic connections. With the onset of hearing at P12, the efferent synapses disappear, and afferent (ribbon) synapses operate with greater efficiency. This change coincides with increased expression of voltage-gated potassium channels, the loss of calcium-dependent electrogenesis, and the onset of graded receptor potentials driven by sound. The transient efferent synapses include near-membrane postsynaptic cisterns thought to regulate calcium influx through the hair cell's α9-containing and α10-containing nicotinic acetylcholine receptors. This influx activates small-conductance Ca2+-activated K+ (SK) channels. Serial-section electron microscopy of inner hair cells from two 9-d-old (male) rat pups revealed many postsynaptic efferent cisterns and presynaptic afferent ribbons whose average minimal separation in five cells ranged from 1.1 to 1.7 μm. Efferent synaptic function was studied in rat pups (age, 7-9 d) of either sex. The duration of these SK channel-mediated IPSCs was increased by enhanced calcium influx through L-type voltage-gated channels, combined with ryanodine-sensitive release from internal stores-presumably the near-membrane postsynaptic cistern. These data support the possibility that inner hair cell calcium electrogenesis modulates the efficacy of efferent inhibition during the maturation of inner hair cell synapses.SIGNIFICANCE STATEMENT Strict calcium buffering is essential for cellular function. This problem is especially acute for compact hair cells where increasing cytoplasmic calcium promotes the opposing functions of closely adjoining afferent and efferent synapses. The near-membrane postsynaptic cistern at efferent synapses segregates synaptic calcium signals by acting as a dynamic calcium store. The hair cell serves as an informative model for synapses with postsynaptic cisterns (C synapses) found in central neurons.

Efferent-induced alterations in distortion and reflection otoacoustic emissions in children.

The medial olivocochlear efferent fibers control outer hair cell responses and inhibit the cochlear-amplifier gain. Measuring efferent function is both theoretically and clinically relevant. In humans, medial efferent inhibition can be assayed via otoacoustic emissions (OAEs). OAEs arise by two fundamentally different mechanisms-nonlinear distortion and coherent reflection. Distortion and reflection emissions are typically applied in isolation for studying the efferent inhibition. Such an approach inadvertently assumes that efferent-induced shifts in distortion and reflection emissions provide redundant information. In this study, efferent-induced shifts in distortion and reflection emissions (click-evoked and stimulus frequency OAEs) were measured in the same subjects-5- to 10-yr-old children. Consistent with the OAE generation theory, efferent-induced shifts in distortion and reflection emissions did not correlate, whereas the two reflection emission shifts correlated. This suggests that using either OAE types provides fragmented information on efferent inhibition and highlights the need to use both distortion and reflection emissions for describing efferent effects.

Efferent modulation of pre-neural and neural distortion products

Distortion product otoacoustic emissions (DPOAEs) and distortion product frequency following responses (DPFFRs) are respectively pre-neural and neural measurements associated with cochlear nonlinearity. Because cochlear nonlinearity is putatively linked to outer hair cell electromotility, DPOAEs and DPFFRs may provide complementary measurements of the human medial olivocochlear (MOC) reflex, which directly modulates outer hair cell function. In this study, we first quantified MOC reflex-induced DPOAE inhibition at spectral fine structure peaks in 22 young human adults with normal hearing. The f1 and f2 tone pairs producing the largest DPOAE fine structure peak for each subject were then used to evoke DPFFRs with and without MOC reflex activation to provide a related neural measure of efferent inhibition. We observed significant positive relationships between DPOAE fine structure peak inhibition and inhibition of DPFFR components representing neural phase locking to f2 and 2f1-f2, but not f1. These findings may support previous observations that the MOC reflex inhibits DPOAE sources differentially. That these effects are maintained and represented in the auditory brainstem suggests that the MOC reflex may exert a potent influence on subsequent subcortical neural representation of sound.

Efferent inhibition strength is a physiological correlate of hyperacusis in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a developmental disability that is poorly understood. ASD can influence communication, social interaction, and behavior. Children with ASD often have sensory hypersensitivities, including auditory hypersensitivity (hyperacusis). In adults with hyperacusis who are otherwise neurotypical, the medial olivocochlear (MOC) efferent reflex is stronger than usual. In children with ASD, the MOC reflex has been measured, but without also assessing hyperacusis. We assessed the MOC reflex in children with ASD by measuring the strength of MOC-induced inhibition of transient-evoked otoacoustic emissions (TEOAEs), a noninvasive physiological measure that reflects cochlear amplification. MOC activity was evoked by contralateral noise. Hyperacusis was assessed subjectively on the basis of the children's symptoms. We found a significant correlation between hyperacusis scores and MOC strength in children with ASD. When children were divided into ASD-with-severe-hyperacusis (ASDs), ASD-with-not-severe-hyperacusis (ASDns), and neurotypical (NT) groups, the last two groups had similar hyperacusis and MOC reflexes, whereas the ASDs group, on average, had hyperacusis and MOC reflexes that were approximately twice as strong. The MOC inhibition of TEOAEs averaged larger at all frequencies in the ASDs compared with ASDns and NT groups. The results suggest that the MOC reflex can be used to estimate hyperacusis in children with ASD and might be used to validate future questionnaires to assess hyperacusis. Our results also provide evidence that strong MOC reflexes in children with ASD are associated with hyperacusis and that hyperacusis is a comorbid condition and is not a necessary, integral part of the abnormal neural processing associated with ASD.NEW & NOTEWORTHY Children with autism spectrum disorder (ASD) are a heterogeneous group, some with hyperacusis and some without. Our research shows that hyperacusis can be estimated in children with ASD by using medial olivocochlear (MOC) reflex measurements. By establishing that an objective measure correlates with attributes of hyperacusis, our results enable future work to enable subtyping of children with ASD to provide improved individualized treatments to at-risk children and those without adequate language to describe their hyperacusis symptoms.

MGluR1 enhances efferent inhibition of inner hair cells in the developing rat cochlea.

Spontaneous activity of the sensory inner hair cells shapes maturation of the developing ascending (afferent) auditory system before hearing begins. Just before the onset of hearing, descending (efferent) input from cholinergic neurons originating in the brainstem inhibit inner hair cell spontaneous activity and may further refine maturation. We show that agonist activation of the group I metabotropic glutamate receptor mGluR1 increases the strength of this efferent inhibition by enhancing the presynaptic release of acetylcholine. We further show that the endogenous release of glutamate from the inner hair cells may increase the strength of efferent inhibition via the activation of group I metabotropic glutamate receptors. Thus, before the onset of hearing, metabotropic glutamate signalling establishes a local negative feedback loop that is positioned to regulate inner hair cell excitability and refine maturation of the auditory system. Just before the onset of hearing, the inner hair cells (IHCs) receive inhibitory efferent input from cholinergic medial olivocochlear (MOC) neurons originating in the brainstem. This input may serve a role in the maturation of the ascending (afferent) auditory system by inhibiting spontaneous activity of the IHCs. To investigate the molecular mechanisms regulating these IHC efferent synapses, we combined electrical stimulation of the efferent fibres with patch clamp recordings from the IHCs to measure efferent synaptic strength. By examining evoked responses, we show that activation of metabotropic glutamate receptors (mGluRs) by general and groupI-specific mGluR agonists enhances IHC efferent inhibition. This enhancement is blocked by application of a groupI mGluR1-specific antagonist, indicating that enhancement of IHC efferent inhibition is mediated by groupI mGluRs and specifically by mGluR1s. By comparing spontaneous and evoked responses, we show that groupI mGluR agonists act presynaptically to increase neurotransmitter release without affecting postsynaptic responsiveness. Moreover, endogenous glutamate released from the IHCs also enhances IHC efferent inhibition via the activation of groupI mGluRs. Finally, immunofluorescence analysis indicates that the efferent terminals are sufficiently close to IHC glutamate release sites to allow activation of mGluRs on the efferent terminals by glutamate spillover. Together, these results suggest that glutamate released from the IHCs activates group I mGluRs (mGluR1s), probably present on the efferent terminals, which, in turn, enhances release of acetylcholine and inhibition of the IHCs. Thus, mGluRs establish a local negative feedback loop positioned to regulate IHC activity and maturation of the ascending auditory system in the developing cochlea.

Deficit in acoustic signal-in-noise detection in glycine receptor α3 subunit knockout mice.

Hearing is an essential sense for communication in animals and humans. Normal function of the cochlea of higher vertebrates relies on a fine-tuned interplay of afferent and efferent innervation of both inner and outer hair cells. Efferent inhibition is controlled via olivocochlear feedback loops, mediated mainly by acetylcholine, γ-aminobutyric acid (GABA) and glycine, and is one of the first sites affected by synapto- and neuropathy in the development of hearing loss. While the functions of acetylcholine, GABA and other inhibitory transmitters within these feedback loops are at least partially understood, especially the function of glycine still remains elusive. To address this question, we investigated hearing in glycine receptor (GlyR) α3 knockout (KO) and wildtype (WT) mice. We found no differences in pure tone hearing thresholds at 11.3 and 16kHz between the two groups as assessed by auditory brainstem response (ABR) measurements. Detailed analysis of the ABR waves at 11.3kHz, however, revealed a latency decrease of wave III and an amplitude increase of wave IV in KO compared to WT animals. GlyRα3 KO animals showed significantly impaired prepulse inhibition of the auditory startle response in a noisy environment, indicating that GlyRα3-mediated glycinergic inhibition is important for signal-in-noise detection.

The potential role of unregulated autonomous bladder micromotions in urinary storage and voiding dysfunction; overactive bladder and detrusor underactivity

The isolated bladder shows autonomous micromotions, which increase with bladder distension, generate sensory nerve activity, and are altered in models of urinary dysfunction. Intravesical pressure resulting from autonomous activity putatively reflects three key variables; the extent of micromotion initiation, distances over which micromotions propagate, and overall bladder tone. In vivo, these variables are subordinate to the efferent drive of the central nervous system. In the micturition cycle storage phase, efferent inhibition keeps autonomous activity generally at a low level, where it may signal 'state of fullness', whilst maintaining compliance. In the voiding phase, mass efferent excitation elicits generalised contraction (global motility initiation). In lower urinary tract dysfunction, efferent control of the bladder can be impaired, for example due to peripheral 'patchy' denervation. In this case, loss of efferent inhibition may enable unregulated micromotility, and afferent stimulation, predisposing to urinary urgency. If denervation is relatively slight, the detrimental impact on voiding may be low, as the adjacent innervated areas may be able to initiate micromotility synchronous with the efferent nerve drive, so that even denervated areas can contribute to the voiding contraction. This would become increasingly inefficient the more severe the denervation, such that ability of triggered micromotility to propagate sufficiently to engage the denervated areas in voiding declines, so the voiding contraction increasingly develops the characteristics of underactivity. In summary, reduced peripheral coverage by the dual efferent innervation (inhibitory and excitatory) impairs regulation of micromotility initiation and propagation, potentially allowing emergence of overactive bladder and, with progression, detrusor underactivity.