Olivocochlear Efferent Neurons Research Articles

Efferent-induced change in human cochlear compression and its influence on masking of tones

Several lines of evidence suggest that medial olivocochlear (MOC) efferent neurons modify cochlear output to improve signal detection in noise. In animal models, stimulation of MOC efferents reduces the amount of compression in basilar membrane (BM) growth functions. Linearization of BM growth functions may assist in extending the neural response to the signal above that of noise, leading to a decrease in masking. In order to test this hypothesis, effects of MOC efferent neurons on BM compression were studied indirectly in humans by examining the effects of contralateral noise on distortion-product otoacoustic emission (DPOAE) input–output functions at 1.0 and 2.0 kHz. Compression threshold estimates from a three-segment linear regression model applied to the DPOAE functions were derived in order to determine correlations with psychophysical measurements of masking of tones at 1.0 and 2.0 kHz. Contralateral noise shifted the DPOAE compression threshold to a significantly higher level at 1.0 kHz, but not at 2.0 kHz. A significant negative correlation between the change in DPOAE compression threshold and the amount of masking at 1.0 kHz was observed, but no correlation between these variables was detected at 2.0 kHz. The results of this experiment at the lower test frequency indicated that contralateral noise linearized DPOAE input–output functions, and individuals with larger DPOAE compression threshold shifts tended to exhibit less masking. Under certain conditions, decreases in cochlear compression induced by MOC efferent neurons may lead to unmasking of tones presented in noise.

Bi-phasic intensity-dependent opioid-mediated neural amplitude changes in the chinchilla cochlea: Partial blockade by an N-Methyl- d-Aspartate (NMDA)-receptor antagonist

Dynorphins, glutamate, and glutamate-sensitive N-Methyl- d-Aspartate (NMDA) receptors exist in the mammalian cochlea. Dynorphins produce neural excitation and excitotoxic effects in the spinal cord through a κ-opioid facilitation of NMDA receptor-sensitivity to glutamate. The κ-opioid receptor drug agonists N-dimethylallyl-normetazocine [(−)-pentazocine (50 mmol)] and trans-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide [U-50488H (100 mmol)] were administered across the cochlear round window membrane in the chinchilla. Each drug produced significant post-baseline amplitude changes in the click-evoked auditory nerve compound action potential. Amplitude changes at threshold amounted to increases in sensitivity that ranged from 4–8 decibels, measured in sound pressure level (dB SPL). The large neural amplitude increases at threshold were accompanied by progressively smaller amplitude changes at 5 and 10 dB above threshold (dB SL). However, at stimulus intensities ≥ 20 dB SL, post-baseline neural amplitudes were suppressed to levels below baseline and control values. These bi-phasic intensity-dependent neural amplitude changes have never before been observed following i.v. administered (−)-pentazocine in this species. Finally, the bi-phasic neural amplitude changes in U-50488H-treated (100 mmol) animals were partially blocked (except at 20 dB SL), following a round window pre-treatment with the NMDA receptor drug antagonist, dizocilpine hydrogen maleate [(+)-MK-801 (8 mmol)]. Our data suggests that endogenous dynorphins within lateral efferent olivocochlear neurons differentially modulate auditory neural excitation, possibly through cochlear NMDA receptors and glutamate. The role played by lateral efferent opioid neuromodulation at cochlear NMDA receptors, is discussed.

Reelin signaling is necessary for a specific step in the migration of hindbrain efferent neurons

The cytoarchitecture of the hindbrain results from precise and co-ordinated sequences of neuronal migrations. Here, we show that reelin, an extracellular matrix protein involved in neuronal migration during CNS development, is necessary for an early, specific step in the migration of several hindbrain nuclei. We identified two cell populations not previously known to be affected in reeler mutants that show a common migratory defect: the olivocochlear efferent neurons and the facial visceral motor nucleus. In control embryos, these cells migrate first toward a lateral position within the neural tube, and then parallel to the glial cell processes, to a ventral position where they settle close to the pial surface. In reeler mutants, the first migration is not affected, but the neurons are unable to reach the pial surface and remain in an ectopic position. Indeed, this is the first evidence that the migration of specific hindbrain nuclei can be divided into two parts: a reelin-independent and a reelin-dependent migration. We also show that reelin is expressed at high levels at the final destination of the migratory process, while the reelin intracellular effector Dab1 was expressed by cell groups that included the two populations affected. Mice mutant at the Dab1 locus, called scrambler, exhibit the same phenotype, a failure of final migration. However, examination of mice lacking both reelin receptors, ApoER2 and VLDLR, did not reveal the same phenotype, suggesting involvement of an additional reelin-binding receptor. In the hindbrain, reelin signaling might alter the adhesive properties of efferent neurons and their ability to respond to directional cues, as has been suggested for the migration of olfactory bulb precursors.

Medial olivocochlear efferent activity in awake guinea pigs.

Cochlear outer hair cells receive numerous connections from the medial olivocochlear efferent neurons. Medial olivocochlear efferent activity is highly dependent on the level of anesthesia. The present study was thus designed to investigate the efficiency of contralateral white noise stimulation on the distortion product otoacoustic emissions (DPOAEs) in a large number of awake guinea pigs, and to compare in the same animals the effect of urethane- and pentobarbitone-anesthesia. The monitoring of DPOAEs during contralateral white noise stimulation in awake animals requires the development of a soft restraining box, together with a conditioning technique for the animals to accept the contralateral sound and DPOAEs monitoring device. This technique allows us to demonstrate that contralateral sound suppression is much stronger in awake than in anesthetized animals. In all the cases, the contralateral sound suppression was abolished 3 h after i.m. injection of gentamicin, an aminoglycoside antibiotic which blocks the medial olivocochlear efferents. These results suggest that future studies have to explore the function of medial olivocochlear efferents in awake animals.

A subpopulation of dorsal raphe nucleus neurons retrogradely labeled with cholera toxin-B injected into the inner ear.

Previous studies have shown that: (1) raphe neurons respond to acoustic and vestibular stimuli, some with a latency of 10-15 ms; (2) alterations of the raphe nuclei alter the acoustic startle reflex; (3) the dorsal raphe nucleus (DRN) is the major source of serotonergic neurons; and (4) approximately 57% of the DRN neurons are nonserotonergic. In the present study, cholera toxin subunit-B (CTB) was injected into cat cochleas, and the brain tissue was examined after a survival period of 5-7 days. Aside from neurons which were known to project to the inner ear, i.e., olivocochlear and vestibular efferent neurons, a surprising new finding was made that somata of a subpopulation of DRN neurons were intensely labeled with CTB. These CTB-labeled neurons were densely distributed in a dorsomedian part of the DRN with some in a surrounding area outside the DRN. The present results suggest that a novel raphe-labyrinthine projection may exist. A future study of anterograde labeling with injections of a tracer in the DRN will be needed to establish the existence of a raphe-labyrinthine projection more thoroughly. A raphe-labyrinthine descending input, together with an ascending input from the inner ear to the DRN through intervening neurons, such as the juxta-acousticofloccular raphe neurons (JAFRNs) described by Ye and Kim, may mediate a brain stem reflex whereby a salient multisensory (including auditory and vestibular) stimulus may alter the sensitivity of the inner ear. As a mammal responds to a biologically important auditory-vestibular multisensory event, the raphe projections to the inner ear and other auditory and vestibular structures may enhance the mammal's ability to localize and recognize the sound and respond properly. The raphe-labyrinthine projection may also modulate the inner ear's sensitivity as a function of the sleep-wake arousal state of an organism on a slower time course.

Patterns of GABA-like immunoreactivity in efferent fibers of the human cochlea

Olivocochlear efferent neurons originate in the superior olivary complex of the brainstem and terminate within sensory cell regions of the organ of Corti. Components of this complex include the lateral olivocochlear bundle whose unmyelinated axons synapse with radial afferent dendrites below inner hair cells and the medial olivocochlear bundle, from which myelinated axons form a direct synaptic contact with outer hair cells. γ-Aminobutyric acid (GABA), a major neurotransmitter of the central nervous system believed to be responsible for most fast-inhibitory transmissions, has been demonstrated with interspecies variation between mammal and primate auditory efferents. In the present study, we evaluate the immunocytochemical presence of GABA in 10 human cochleae using light and electron microscopy. GABA-like immunostaining could be observed in inner spiral fibers, tunnel spiral fibers, tunnel-crossing fibers, and at efferent endings synapsing with outer hair cells. To approximate medial efferent fiber quantifications, we counted labeled terminals at the base of each outer hair cell and then compared this sum with the number of tunnel crossing fibers. We found a ‘branching ratio’ of 1:2 implicating a doubling in quantifiable efferent fibers at the level of the outer hair cell. In human, the distribution of GABA-like immunoreactivity showed a consistent presence throughout all turns of the cochlea. A new method for application of immunoelectron microscopy on human cochleae using a pre-embedding technique is also presented and discussed.

Dopamine modulates sodium currents in cochlear spiral ganglion neurons.

Lateral olivocochlear (LOC) efferent neurons, putatively dopaminergic, synapse on afferent dendrites of type I spiral ganglion neurons (SGNs) in the cochlea and depress their activity. To investigate the underlying mechanisms, whole-cell patch clamp recordings were obtained from mouse SGNs. Dopamine (DA), and D1-like (D1, D5) and D2-like (D2, D3 and D4) receptor agonists, reduced AP amplitude and induced a slow transient depolarization. Under voltage clamp, D1-like and D2-like agonists induced a dose-dependent inward current that was reversibly blocked by their receptor antagonists. The inward current was blocked by tetrodotoxin (TTX), implicating Na+ channels. The reduction of AP amplitude and voltage-gated Na+ current by DA and DA agonists provides a mechanism for suppressing spike activity in type I afferent neurons.

Afferent innervation of outer and inner hair cells is normal in neonatally de-efferented cats

It has been hypothesized that normal pruning of exuberant branching of afferent neurons in the developing cochlea is caused by the arrival of the olivocochlear efferent neurons and the resulting competition for synaptic sites on hair cells. This hypothesis was supported by a report that afferent innervation density on mature outer hair cells (OHCs) is elevated in animals deefferented at birth, before the olivocochlear system reaches the outer hair cell area (Pujol and Carlier [1982] Dev. Brain Res. 3:151-154). In the current study, this claim was evaluated quantitatively at the electron microscopic level in four cats that were de-efferented at birth and allowed to survive for 6-11 months. A semiserial section analysis of 156 OHCs from de-efferented and normal ears showed that, although de-efferentation essentially was complete in all four cases, the number and distribution of afferent terminals on OHCs was indistinguishable from normal, and the morphology of afferent synapses was normal in both the inner hair cell area and the OHC area. Thus, the postnatal presence of an efferent system is not required for the normal development of cochlear afferent innervation, and the synaptic competition hypothesis is not supported.

Firing properties of chopper and delay neurons in the lateral superior olive of the rat.

Neurons in the lateral superior olivary nucleus (LSO) respond to acoustic stimuli with the "chopper response", a regular repetitive firing pattern with a short and precise latency. In the past, this pattern has been attributed to dendritic integration of synaptic inputs. We investigated a possible contribution of intrinsic membrane properties using intracellular recording techniques in a tissue slice preparation. We found two electrophysiological classes of neurons in the LSO. Chopper neurons responded to depolarizing current pulses with a single onset spike at short, precise latency close to threshold and with repetitive, regular, but accommodating discharges at greater current intensities. An emphasis of response onset and subsequent rate accommodation resulted from the activation of a voltage- and time-dependent sustained outward rectification in a range depolarized from rest. Responses to hyperpolarizing pulses were characterized by an inward rectification, which caused a depolarizing voltage sag in a range negative to -65 mV. Peristimulus time histograms were multimodal, and discharge regularity was evident in narrow unimodal interspike interval time histograms and low coefficients of variation. The accommodation time course was usually fit best by two exponentials with time constants of tau1=3-8 ms and tau2=32-97 ms. Delay neurons responded with a regular repetitive firing to depolarization by current pulses. However, repetitive spike discharge occurred with a prolonged, variable delay of 25-180 ms. High current intensities evoked an additional onset spike with short, precise latency. Activation of a transient outward conductance in the depolarized voltage range caused an early repolarization, which terminated as a depolarizing ramp, reaching spike threshold after the delay. Flat peristimulus time histograms characterized the repetitive discharge in spite of narrow unimodal interspike interval time histograms and low coefficients of variation. Intracellular neurobiotin injections revealed morphological differences between these classes. Chopper neurons were large and fusiform, with a bipolar dendritic distribution oriented perpendicular to the curvature of the LSO. Delay neurons were small and spherical, with highly branched tortuous dendritic arbours of bipolar origin and variable orientation. Chopper and delay neurons are probably LSO principal cells and lateral olivocochlear efferent neurons, respectively. Our findings suggest that the pattern of firing activity of LSO neurons to sound, in vivo, is determined to a large extent by intrinsic membrane properties. Somato-dendritic integration of synaptic inputs are fundamental to the encoding of interaural sound differences, but membrane non-linearities play an important role in determining postsynaptic response patterns.

Choline acetyltransferase expression during a putative developmental waiting period

The relationship between the cholinergic expression, morphological development, and target cell innervation of olivocochlear (OC) efferent neurons was investigated in the postnatal hamster. Similar to what was found in previous studies, tracer injections into the contralateral cochlea labeled cells bodies retrogradely in periolivary regions and labeled cell bodies only rarely in the lateral superior olive (LSO). Few morphological differences were found among cell bodies labeled between postnatal day 1 (P1) and P30. Tracer injections into the crossed OC bundles within the brainstem anterogradely labeled terminals below the inner hair cells of the cochlea prior to P5 and labeled terminals below outer hair cells after P5, consistent with a period of transient innervation, as hypothesized previously. Within the superior olive, choline acetyltransferase (ChAT) was expressed differentially. In periolivary regions, ChAT was expressed as early as P0. ChAT-immunoreactive cell bodies in periolivary regions were similar morphologically to retrogradely labeled OC neurons. In contrast, within the LSO, ChAT was not expressed until after P2. Consistent with a medical OC projection to the cochlea at early postnatal ages, ChAT immunoreactivity was detected below inner hair cells as early as P2 but was not detected below outer hair cells until after P6. Our results suggest that medial OC neurons not only provide transient connections to inner hair cells but also may express ChAT when they are below inner hair cells. Furthermore, these results raise the possibility that OC neurons may be capable of acetylcholine synthesis and release prior to or simultaneous with their innervation of the cochlea.

Single olivocochlear neurons in the guinea pig. II. Response plasticity due to noise conditioning.

Previous studies have shown that daily, moderate-level sound exposure, or conditioning, can reduce injury from a subsequent high-level noise exposure. We tested the hypothesis that this conditioning produces an increased activity in the olivocochlear efferent reflex, a reflex known to provide protection to the cochlea. Guinea pigs were conditioned by a 10-day intermittent exposure to 2-4 kHz noise at 85 dB sound pressure level. This conditioning is known to reduce damage from a subsequent high-level exposure to the same noise band. Responses to monaural and binaural sound were recorded from single medial olivocochlear (MOC) efferent neurons, and data from conditioned animals were compared with those obtained from unexposed controls. MOC neurons were classified by their response to noise bursts in the ipsilateral or contralateral ears as ipsi units, contra units, or either-ear units. There were no significant differences in the distributions of these unit types between control and conditioned animals. There were also no differences in other responses to monaural stimuli, including the distribution of characteristic frequencies (CFs), the sharpness of tuning, or thresholds at the CF. For binaural sound at high levels, particularly relevant to sound-evoked activation of the MOC reflex during acoustic overstimulation, the firing rates of MOC neurons with CFs just above the conditioning band showed slight (but statistically significant) elevations relative to control animals. Frequency regions just above the conditioning band also demonstrated maximum conditioning-related protection; thus protection could be due, in part, to long-term changes in MOC discharge rates. For binaural sound at low levels, MOC firing rates in conditioned animals also were increased significantly relative to controls. Again, increases were largest for neurons with CFs just above the conditioning band. For equivalent monaural sound, rates were not significantly increased; thus, conditioning appears to increase binaural facilitation by opposite-ear sound. These data indicate that MOC neurons show long-term plasticity in acoustic responsiveness that is dependent on their acoustic history.

Improvement in Auditory Function Following Pentazocine Suggests a Role for Dynorphins in Auditory Sensitivity

The pharmacologic specificity of potentially beneficial drug effects on the auditory system were investigated. Changes in auditory sensitivity were evaluated in chinchillas following the infusion of an opioid narcotic. This drug (pentazocine) mimics endogenous opioid peptides (dynorphins), postulated to be chemical neurotransmitters (or neuromodulators) within the mammalian cochlea. In this study, two pentazocine enantiomers were investigated over a range of stimulus intensities. Significant baseline-relative changes in compound action potential (CAP) amplitudes were observed following intravenous administration of the kappa-opioid agonist (-)pentazocine (8 mg/kg). The sigma-receptor drug agonist (+)pentazocine (8 mg/kg) produced no measurable auditory effects. The magnitude of the (-)pentazocine effects were inversely related to stimulus intensity, up to 10 dB above threshold (i.e., 10 dB SL). Consistent with the observed amplitude doubling, auditory sensitivity was also improved an average 5-7 dB sound pressure level (SPL) following the administration of (-)pentazocine, while CAP response latencies and cochlear microphonic (CM) amplitudes remained unchanged. Results indicate stereospecific kappa-receptor mediated actions of pentazocine at the auditory nerve, and suggest an auditory role for neuroactive dynorphin peptides contained within the lateral efferent olivocochlear neurons.

Contralateral sound suppresses distortion product otoacoustic emissions through cholinergic mechanisms

Presentation of an acoustic signal to one ear can suppress sound-evoked activity recorded at the opposite ear. The suppression appears to be mediated by medial olivocochlear (MOC) efferent neurons synapsing with outer hair cells (OHCs) and acting through the MOC neurotransmitter, acetylcholine (ACh). The purpose of the present investigation was to study the suppression of distortion product otoacoustic emissions (DPOAEs) by contralateral sound and to examine whether the suppression could be blocked by known antagonists of olivocochlear (OC) efferent activity. Urethane-anesthetized guinea pigs were used. Perilymph spaces of ipsilateral cochleae were alternately perfused with artificial perilymph and drugs at 2.5 μl/min for 10 min. After each period of perfusion, DPOAEs were measured before, during and after contralateral wideband noise (WBN) stimulation. Pre-perfusion, contralateral WBN attenuated the ipsilateral DPOAEs between 1–3 dB. This suppression was blocked reversibly by strychnine (10 μM), curare (10 μM) and atropine (20 μM), known antagonists of OC efferent activity. These results confirm the findings of Puel and Rebillard (1990) that contralateral WBN can suppress DPOAEs in anesthetized guinea pigs. Furthermore, results suggest that this efferent control of the cochlear mechanical response can either be mediated by both nicotinic and muscarinic cholinergic receptors, or that a single receptor with as yet undescribed structure and pharmacology mediates effects seen.

Effects of electrical stimulation of efferent olivocochlear neurons on cat auditory-nerve fibers. III. Tuning curves and thresholds at CF

In order to study the effects of efferent activity, olivocochlear efferents were stimulated with an electrode in the fourth ventricle at the decussation of the crossed olivocochlear bundle (midline-OCB stimulation) or with an electrode at the brainstem origin of medial efferents (MOC stimulation). Tuning curves, or similar measures of threshold, were obtained from auditory-nerve fibers in the presence or absence of efferent stimulation. Efferent stimulation raised the thresholds of fibers for tones at the characteristic frequency (CF) by an amount which varied with the spontaneous rate (SR) of the auditory-nerve fiber. On the average. high-SR fibers had the smallest threshold shifts, and low-SR fibers had the largest threshold shifts. The distribution of threshold shifts as a function of CF peaked at CFs of 3–8 kHz for high-SR and medium-SR fibers but appeared to peak at higher CFs for low-SR fibers. Within the high-SR or medium-SR groups, the fibers with the lowest thresholds had the largest threshold shifts. Efferent stimulation decreased the Q 20 of the tuning curves from most fibers (i.e. it made the tuning curves wider), but increased the Q 20 from some fibers with CFs below 2 kHz. For fibers with CFs above 4 kHz, efferent stimulation shifted the tuning-curve tails to higher sound levels by about l dB on the average. The qualitative patterns of the effects due to midline-OCB stimulation or to MOC stimulation were similar. The distribution of high-SR threshold shifts vs. CF appears to be displaced apically in the cochlea compared to the distribution of MOC endings on outer hair cells. This can be understood in terms of efferent activity depressing basilar membrane motion and affecting regions at, and apical to, the activated efferent synapses. To explain the low-SR threshold shifts, an additional way in which efferent activity inhibits responses appears to be required. The data are consistent with one function of the medial efferents being to raise the thresholds of auditory-nerve fibers and thereby adjust the effective range of the auditory system.

Response properties of cochlear efferent neurons: monaural vs. binaural stimulation and the effects of noise

1. Discharge properties of olivocochlear efferent neurons were measured in anesthetized cats. Previous studies of these neurons concentrated on monaural stimulation with tones and found sound-evoked discharge rates rarely exceeded 60 spikes/s (16, 20). In the present study, rates as high as 140 spikes/s were achieved by binaural stimulation and/or the addition of noise. Based on studies on the known effects of electrically stimulating the efferents such high rates of sound-evoked efferent activity probably have significant feedback effects on the auditory periphery. 2. Spontaneous discharge rate (SR) was weakly correlated with threshold among efferent neurons: those with SRs greater than 1 spikes/s were generally more sensitive than spontaneously inactive fibers. The discharge rate measured in the absence of acoustic stimulation was shown to be dependent on stimulation history: some units with zero SR became spontaneously active after several minutes of continuous noise stimulation. 3. For stimulation with monaural tones, efferent excitability varied with characteristic frequency (CF): units with CF less than 10 kHz tended to have lower thresholds, higher discharge rates, and shorter latencies than higher CF units. These differences could be minimized by the addition of broadband noise (see below). 4. When tones were presented to one ear at a time, most efferent units appeared monaural (91%), with roughly two-thirds excited by ipsilateral stimuli and one-third by contralateral stimuli. However, the effects of simultaneous stimulation of the two ears suggested that the great majority of efferent units have binaural inputs: the addition of opposite-ear noise or tones, which presented alone were not excitatory, typically enhanced the response to main-ear stimulation. This type of binaural facilitation was strongest among low-CF efferents when the opposite-ear stimuli were tones, and strongest among high-CF units when the opposite-ear stimulus was broadband noise. 5. The binaural facilitation seen using opposite-ear noise both lowered the threshold (by as much as 40 dB) and increased the discharge rate (by as much as 80%) to tones presented in the main ear. Significant facilitation was seen with noise levels as low as 25 dB SPL or tone levels as low as 30 dB SPL. In general, the weaker the response to monaural stimuli, the stronger the binaural facilitation. 6. The facilitatory effects of stimulation with continuous noise could outlast the stimulus. Persistent increases in efferent sensitivity were documented following 10-min exposures to broadband noise at 85-115 dB SPL.

Retrograde transport of [ 3H]-GABA by lateral olivocochlear neurons in the rat

Injection of [ 3H]-gamma aminobutyric acid (GABA) into the perilymphatic space of the rat's inner ear resulted in retrograde labeling of a portion of the small efferent olivocochlear neurons within the lateral superior olivary nucleus (LSO). These cells were of similar size as LSO neurons stained immunohistochemically with antibodies to the GABA synthesizing enzyme glutamic acid decarboxylase (GAD). They were of fusiform shape, but smaller than principal LSO cells, which did not stain for GAD and did not accumulate [ 3H]-GABA. Other efferent cochlear and vestibular neurons were not labeled.