Efferent Feedback Research Articles

Spike Firing Pattern of Output Neurons of the Limulus Circadian Clock

The lateral eyes of the horseshoe crab (Limulus polyphemus) show a daily rhythm in visual sensitivity that is mediated by efferent nerve signals from a circadian clock in the crab's brain. How these signals communicate circadian messages is not known for this or other animals. Here the authors describe in quantitative detail the spike firing pattern of clock output neurons in living horseshoe crabs and discuss its possible significance to clock organization and function. Efferent fiber spike trains were recorded extracellularly for several hours to days, and in some cases, the electroretinogram was simultaneously acquired to monitor eye sensitivity. Statistical features of single- and multifiber recordings were characterized via interval distribution, serial correlation, and power spectral analysis. The authors report that efferent feedback to the eyes has several scales of temporal structure, consisting of multicellular bursts of spikes that group into clusters and packets of clusters that repeat throughout the night and disappear during the day. Except near dusk and dawn, the bursts occur every 1 to 2 sec in clusters of 10 to 30 bursts separated by a minute or two of silence. Within a burst, each output neuron typically fires a single spike with a preferred order, and intervals between bursts and clusters are positively correlated in length. The authors also report that efferent activity is strongly modulated by light at night and that just a brief flash has lasting impact on clock output. The multilayered firing pattern is likely important for driving circadian rhythms in the eye and other target organs.

Evaluating the effects of efferent feedback, temporal integration, and off-frequency listening on perceptual estimates of frequency selectivity.

A computational model was used to predict detection thresholds in two forward masking tasks used to estimate frequency selectivity. Tasks simulated involved obtaining psychophysical tuning curves and notch-noise tuning characteristics. These simulations were obtained for a series of signal levels ranging from 20–90 dB SPL and for three masking conditions. Short (20 ms) and long (120 ms) maskers were used in the first and second masking conditions, respectively. The third masking condition was identical to the first, except an additional sinusoid (called a “precursor”) preceded the masker. The precursor and long masker were assumed to reduce cochlear gain during the time window in which the signal was detected. Conversely, the short masker was assumed to have no effect on cochlear gain during the presentation of the signal. Several variables related to frequency selectivity were evaluated to determine their influence on estimated filter sharpness, filter high-side/low-side slopes, and filter best frequency. These variables included (1) gain reduction via the medial olivocochlear reflex, (2) temporal integration, and (3) off-frequency listening. Model predictions are compared to psychophysical data, and the influence of the aforementioned variables is discussed.

Evaluating Adaptation and Olivocochlear Efferent Feedback as Potential Explanations of Psychophysical Overshoot

Masked detection threshold for a short tone in noise improves as the tone's onset is delayed from the masker's onset. This improvement, known as "overshoot," is maximal at mid-masker levels and is reduced by temporary and permanent cochlear hearing loss. Computational modeling was used in the present study to evaluate proposed physiological mechanisms of overshoot, including classic firing rate adaptation and medial olivocochlear (MOC) feedback, for both normal hearing and cochlear hearing loss conditions. These theories were tested using an established model of the auditory periphery and signal detection theory techniques. The influence of several analysis variables on predicted tone-pip detection in broadband noise was evaluated, including: auditory nerve fiber spontaneous-rate (SR) pooling, range of characteristic frequencies, number of synapses per characteristic frequency, analysis window duration, and detection rule. The results revealed that overshoot similar to perceptual data in terms of both magnitude and level dependence could be predicted when the effects of MOC efferent feedback were included in the auditory nerve model. Conversely, simulations without MOC feedback effects never produced overshoot despite the model's ability to account for classic firing rate adaptation and dynamic range adaptation in auditory nerve responses. Cochlear hearing loss was predicted to reduce the size of overshoot only for model versions that included the effects of MOC efferent feedback. These findings suggest that overshoot in normal and hearing-impaired listeners is mediated by some form of dynamic range adaptation other than what is observed in the auditory nerve of anesthetized animals. Mechanisms for this adaptation may occur at several levels along the auditory pathway. Among these mechanisms, the MOC reflex may play a leading role.

Recovery from on- and off-frequency forward masking in listeners with normal and impaired hearing

The aim of this study was to investigate the possible mechanisms underlying an effect reported earlier [Wojtczak, M., and Oxenham, A. J. (2009). J. Acoust. Soc. Am. 125, 270-281] in normal-hearing listeners, whereby recovery from forward masking can be slower for off-frequency tonal maskers than for on-frequency tonal maskers that produce the same amount of masking at a 0-ms masker-signal delay. To rule out potential effects of confusion between the tonal signal and tonal masker, one condition used a noise-band forward masker. To test whether the effect involved temporal build-up, another condition used a short-duration (30-ms) forward masker. To test whether the effect is dependent on normal cochlear function, conditions were tested in five listeners with sensorineural hearing loss. For the 150-ms noise maskers, the data from normal-hearing listeners replicated the findings from the previous study that used tonal maskers. In contrast, no significant difference in recovery from on- and off-frequency masking was observed for the 30-ms tonal maskers in normal-hearing listeners, or for the 150-ms tonal maskers in hearing-impaired listeners. Overall, the results are consistent with a mechanism based on efferent feedback that affects the recovery from forward masking in the normal auditory system.

Muscarinic Signaling in the Cochlea: Presynaptic and Postsynaptic Effects on Efferent Feedback and Afferent Excitability

Acetylcholine is the major neurotransmitter of the olivocochlear efferent system, which provides feedback to cochlear hair cells and sensory neurons. To study the role of cochlear muscarinic receptors, we studied receptor localization with immunohistochemistry and reverse transcription-PCR and measured olivocochlear function, cochlear responses, and histopathology in mice with targeted deletion of each of the five receptor subtypes. M2, M4, and M5 were detected in microdissected immature (postnatal days 10-13) inner hair cells and spiral ganglion cells but not outer hair cells. In the adult (6 weeks), the same transcripts were found in microdissected organ of Corti and spiral ganglion samples. M2 protein was found, by immunohistochemistry, in olivocochlear fibers in both outer and inner hair cell areas. M3 mRNA was amplified only from whole cochleas, and M1 message was never seen in wild-type ears. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were unaffected by loss of Gq-coupled receptors (M1, M3, or M5), as were shock-evoked olivocochlear effects and vulnerability to acoustic injury. In contrast, loss of Gi-coupled receptors (M2 and/or M4) decreased neural responses without affecting DPOAEs (at low frequencies). This phenotype and the expression pattern are consistent with excitatory muscarinic signaling in cochlear sensory neurons. At high frequencies, both ABRs and DPOAEs were attenuated by loss of M2 and/or M4, and the vulnerability to acoustic injury was dramatically decreased. This aspect of the phenotype and the expression pattern are consistent with a presynaptic role for muscarinic autoreceptors in decreasing ACh release from olivocochlear terminals during high-level acoustic stimulation and suggest that muscarinic antagonists could enhance the resistance of the inner ear to noise-induced hearing loss.

Behavioral consequences of weakened medial olivocochlear efferent noise‐control mechanisms in mice.

The mammalian medial olivocochlear (MOC) efferent feedback system protects the ear from intense noise exposure, aids in cochlear gain control, and improves responses to signals in noise. Unequivocal behavioral effects of eliminating MOC feedback have been difficult to demonstrate. We used an acoustic startle reflex (ASR) modification paradigm to reveal behavioral effects of eliminating MOC feedback in mice. Mice lacking the alpha9 nicotinic acetylcholine receptor subunit showed increased facilitation of the ASR reflex in the presence of background noise, abnormal responses to brief fluctuations in background noise, and abnormal inhibition of the ASR by changes in the location of noise in azimuth and elevation. Abnormal behavioral responses occurred in the absence of cochlear hearing loss. The behavioral effects of weakened MOC feedback may reflect both direct and indirect effects of abnormal cochlear gain control in the presence of noise. The results provide further evidence for a role of MOC efferent feedback in hearing in noise and demonstrate that noise‐related hearing deficits can occur when hearing thresholds are normal.

Sensitization to masked tones following notched-noise correlates with estimates of cochlear function using distortion product otoacoustic emissions

Neuronal gain adaptation has been proposed as the underlying mechanism leading to the perception of phantom sounds such as Zwicker tones and tinnitus. In this gain-adaptation theory, cochlear compression plays a significant role with weaker compression leading to stronger phantom percepts. The specific aim of this study was to find a link between the strength of neuronal gain adaptation and cochlear compression. Compression was assessed using distortion product otoacoustic emissions (DPOAEs). Gain adaptation is hypothesized to manifest itself in the sensitization observed for the detection of masked tones when preceded by notched noise. Perceptual thresholds for pure tones in notched noise were measured at multiple frequencies following various priming signals. The observed sensitization was larger than expected from the combined effect of the various maskers. However, there was no link between sensitization and compression. Instead, across subjects, stronger sensitization correlated with stronger DPOAEs evoked by low-level primaries. In addition, growth of DPOAEs correlated reliably with perceptual thresholds across frequencies within subjects. Together, the data suggest that short-term dynamic adaptation leading to perceptual sensitization is the result of an active process mediated by the outer hair cells, which are thought to modulate the gain of the cochlear amplifier via efferent feedback.

F1 (CBA×C57) mice show superior hearing in old age relative to their parental strains: Hybrid vigor or a new animal model for “Golden Ears”?

Age-related hearing loss - presbycusis - is the most common communication problem and third most prevalent chronic medical disorder of the aged. The CBA and C57BL/6 mouse strains are useful for studying features of presbycusis. The CBA loses its hearing slowly, like most humans. Because the C57 develops a rapid, high frequency hearing loss by middle age, it has an "old" ear but a relatively young brain, a model that helps separate peripheral (cochlear) from central (brain) etiologies. This field of sensory neuroscience lacks a good mouse model for the 5-10% of aged humans with normal cochlear sensitivity, but who have trouble perceiving speech in background noise. We hypothesized that F1 (CBA×C57) hybrids would have better hearing than either parental strain. Measurements of peripheral auditory sensitivity supported this hypothesis, however, a rapid decline in the auditory efferent feedback system, did not. Therefore, F1s might be an optimal model for studying cases where the peripheral hearing is quite good in old age; thereby allowing isolation of central auditory changes due to brain neurodegeneration.

Efferent innervation to the auditory basilar papilla of scincid lizards

Hair cells of the inner ear of vertebrates are innervated by afferent neurons that transmit sensory information to the brain as well as efferent neurons that receive feedback from the brainstem. The function of the efferent feedback system is poorly understood and may have changed during evolution when different tetrapod groups acquired sensitivity to airborne sound and extended their hearing ranges to higher frequencies. Lizards show a unique subdivision of their basilar papilla (homologous to the mammalian organ of Corti) into a low-frequency (<1 kHz) and a high-frequency (approximately 1-5 kHz) region. The high-frequency region was reported to have lost its efferent innervation, suggesting it was insignificant or even functionally detrimental at higher frequencies. We re-examined the innervation to the basilar papilla of five species of Australian scincid lizards, by using immunohistochemistry. Anti-choline acetyltransferase (ChAT) was used as an efferent marker. Co-localization with anti-synaptic vesicle protein 2 confirmed the synaptic identity of label. Cholinergic terminals were observed along the whole length of the basilar papilla, including the regions that had previously been described as devoid of efferent innervation. However, there was a clear decrease in terminal density from apical, low-frequency to basal, high-frequency locations. Our findings suggest that efferent innervation is a general feature of the hair cells in the basilar papilla of lizards, irrespective of tonotopic location. This re-enforces the notion that efferent feedback control of hair cells is a fundamental and important property of all vertebrate hearing organs.

Noise‐induced increase in human auditory evoked neuromagnetic fields

Noise is usually detrimental to auditory perception. However, recent psychophysical studies have shown that low levels of broadband noise may improve signal detection. Here, we measured auditory evoked fields (AEFs) while participants listened passively to low-pitched and high-pitched tones (Experiment 1) or complex sounds that included a tuned or a mistuned component that yielded the perception of concurrent sound objects (Experiment 2). In both experiments, stimuli were embedded in low or intermediate levels of Gaussian noise or presented without background noise. For each participant, the AEFs were modeled with a pair of dipoles in the superior temporal plane, and the effects of noise were examined on the resulting source waveforms. In both experiments, the N1m was larger when the stimuli were embedded in low background noise than in the no-noise control condition. Complex sounds with a mistuned component generated an object-related negativity that was larger in the low-noise condition. The results show that low-level background noise facilitates AEFs associated with sound onset and can be beneficial for sorting out concurrent sound objects. We suggest that noise-induced increases in transient evoked responses may be mediated via efferent feedback connections between the auditory cortex and lower auditory centers.

アブミ骨筋の生理と機能

The stapedius muscle constitutes one of the efferent feedback pathways to the auditory periphery, which can be elicited by sound in either ear. Contraction of the stapedius muscle causes attenuation of the low frequency component of the input signal by increasing the stiffness of the ossicular chain. The effects of the acoustic reflex have been investigated for many years and a number of hypotheses have been proposed. Two of these hypotheses are: (1) that this reflex helps to protect the ear from acoustic injuries and (2) that it aids in the control of masking. However, there is still significant controversy as to its functional significance. In the present paper, possible functional roles of the stapedius muscle are discussed based on the physiological properties of the acoustic reflex of this muscle.

A Point Mutation in the Hair Cell Nicotinic Cholinergic Receptor Prolongs Cochlear Inhibition and Enhances Noise Protection

The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9′T line of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9′T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9′T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.

Reflex control of the human inner ear: a half-octave offset in medial efferent feedback that is consistent with an efferent role in the control of masking.

The high sensitivity and frequency selectivity of the mammalian cochlea is due to amplification produced by outer hair cells (OHCs) and controlled by medial olivocochlear (MOC) efferents. Data from animals led to the view that MOC fibers provide frequency-specific inhibitory feedback; however, these studies did not measure intact MOC reflexes. To test whether MOC inhibition is primarily at the frequency that elicits the MOC activity, acoustically elicited MOC effects were quantified in humans by the change in otoacoustic emissions produced by 60-dB SPL tone and half-octave-band noise elicitors at different frequencies relative to a 40-dB SPL, 1-kHz probe tone. On average, all elicitors produced MOC effects that were skewed (elicitor frequencies -1 octave below the probe produced larger effects than those -1 octave above). The largest MOC effects were from elicitors below the probe frequency for contra- and bilateral elicitors but were from elicitors centered at the probe frequency for ipsilateral elicitors. Typically, ipsilateral elicitors produced larger effects than contralateral elicitors and bilateral elicitors produced effects near the ipsi+contra sum. Elicitors at levels down to 30-dB SPL produced similar patterns. Tuning curves (TCs) interpolated from these data were V-shaped with Q10s approximately 2. These are sharper than MOC-fiber TCs found near 1 kHz in cats and guinea pigs. Because cochlear amplification is skewed (more below the best frequency of a cochlear region), these data are consistent with an anti-masking role of MOC efferents that reduces masking by reducing the cochlear amplification seen at 1 kHz.

SK2 channels are required for function and long-term survival of efferent synapses on mammalian outer hair cells

Cochlear hair cells use SK2 currents to shape responses to cholinergic efferent feedback from the brain. Using SK2 −/− mice, we demonstrate that, in addition to their previously defined role in modulating hair cell membrane potentials, SK2 channels are necessary for long-term survival of olivocochlear fibers and synapses. Loss of the SK2 gene also results in loss of electrically driven olivocochlear effects in vivo, and down regulation of ryanodine receptors involved in calcium-induced calcium release, the main inducer of nAChR evoked SK2 activity. Generation of double-null mice lacking both the α10 nAChR gene, loss of which results in hypertrophied olivocochlear terminals, and the SK2 gene, recapitulates the SK2 −/− synaptic phenotype and gene expression, and also leads to down regulation of α9 nAChR gene expression. The data suggest a hierarchy of activity necessary to maintain early olivocochlear synapses at their targets, with SK2 serving an epistatic, upstream, role to the nAChRs.

Perisaccadic Mislocalization of Visual Targets by Head-Free Gaze Shifts: Visual or Motor?

Such perisaccadic mislocalization is maximal in the direction of the saccade and varies systematically with the target-saccade onset delay. We have recently shown that under head-fixed conditions perisaccadic errors do not follow the quantitative predictions of current visuomotor models that explain these mislocalizations in terms of spatial updating. These models all assume sluggish eye-movement feedback and therefore predict that errors should vary systematically with the amplitude and kinematics of the intervening saccade. Instead, we reported that errors depend only weakly on the saccade amplitude. An alternative explanation for the data is that around the saccade the perceived target location undergoes a uniform transient shift in the saccade direction, but that the oculomotor feedback is, on average, accurate. This "visual shift" hypothesis predicts that errors will also remain insensitive to kinematic variability within much larger head-free gaze shifts. Here we test this prediction by presenting a brief visual probe near the onset of gaze saccades between 40 and 70 degrees amplitude. According to models with inaccurate gaze-motor feedback, the expected perisaccadic errors for such gaze shifts should be as large as 30 degrees and depend heavily on the kinematics of the gaze shift. In contrast, we found that the actual peak errors were similar to those reported for much smaller saccadic eye movements, i.e., on average about 10 degrees, and that neither gaze-shift amplitude nor kinematics plays a systematic role. Our data further corroborate the visual origin of perisaccadic mislocalization under open-loop conditions and strengthen the idea that efferent feedback signals in the gaze-control system are fast and accurate.

Expression of glycine receptors and gephyrin in the rat cochlea

The cochlear efferent feedback system exerts direct impact on cochlear nerve activity and balances interaural sensitivity. So far, acetylcholine, GABA and dopamine are known to be transmitters of the inhibitory efferent system. Despite the wealth of information about glycinergic neurotransmission in the central auditory system, the inhibitory glycine receptor (GlyR) has not yet been regarded as a target molecule of efferent transmission in the cochlea. Using RT-PCR, in situ hybridization and immunohistochemistry, we show that GlyRalpha3, GlyRbeta and gephyrin are expressed in the organ of Corti and spiral ganglion neurons. Furthermore, two alternative splice variants of GlyRalpha3, corresponding to the long (alpha3_L) and short (alpha3_K) human isoforms, could be distinguished. The localization of glycine receptors below inner hair cells and in outer hair cells of the adult cochlea suggests that these inhibitory receptors may serve as target molecules of the efferent olivocochlear bundle.

Auditory efferent feedback system deficits precede age‐related hearing loss: Contralateral suppression of otoacoustic emissions in mice

The C57BL/6J mouse has been a useful model of presbycusis, as it displays an accelerated age-related peripheral hearing loss. The medial olivocochlear efferent feedback (MOC) system plays a role in suppressing cochlear outer hair cell (OHC) responses, particularly for background noise. Neurons of the MOC system are located in the superior olivary complex, particularly in the dorsomedial periolivary nucleus (DMPO) and in the ventral nucleus of the trapezoid body (VNTB). We previously discovered that the function of the MOC system declines with age prior to OHC degeneration, as measured by contralateral suppression (CS) of distortion product otoacoustic emissions (DPOAEs) in humans and CBA mice. The present study aimed to determine the time course of age changes in MOC function in C57s. DPOAE amplitudes and CS of DPOAEs were collected for C57s from 6 to 40 weeks of age. MOC responses were observed at 6 weeks but were gone at middle (15-30 kHz) and high (30-45 kHz) frequencies by 8 weeks. Quantitative stereological analyses of Nissl sections revealed smaller neurons in the DMPO and VNTB of young adult C57s compared with CBAs. These findings suggest that reduced neuron size may underlie part of the noteworthy rapid decline of the C57 efferent system. In conclusion, the C57 mouse has MOC function at 6 weeks, but it declines quickly, preceding the progression of peripheral age-related sensitivity deficits and hearing loss in this mouse strain.

Arterial Chemoreceptors and Sympathetic Nerve Activity

Chronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension1 and contributes to the progression of chronic heart failure (CHF).2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF2 and depressed or reset in hypertension.3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes.4,5 It is also clear that sympathoexcitatory cardiac,6 somatic,7 and central/peripheral chemoreceptor reflexes8 are enhanced in CHF and hypertension. Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function.9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. Arterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and …

Selective Removal of Lateral Olivocochlear Efferents Increases Vulnerability to Acute Acoustic Injury

Cochlear sensory cells and neurons receive efferent feedback from the olivocochlear (OC) system. The myelinated medial component of the OC system and its effects on outer hair cells (OHCs) have been implicated in protection from acoustic injury. The unmyelinated lateral (L)OC fibers target ipsilateral cochlear nerve dendrites and pharmacological studies suggest the LOC's dopaminergic component may protect these dendrites from excitotoxic effects of acoustic overexposure. Here, we explore LOC function in vivo by selective stereotaxic destruction of LOC cell bodies in mouse. Lesion success in removing the LOC, and sparing the medial (M)OC, was assessed by histological analysis of brain stem sections and cochlear whole mounts. Auditory brain stem responses (ABRs), a neural-based metric, and distortion product otoacoustic emissions (DPOAEs), an OHC-based metric, were measured in control and surgical mice. In cases where the LOC was at least partially destroyed, there were increases in suprathreshold neural responses that were frequency- and level-independent and not attributable to OHC-based effects. These interaural response asymmetries were not found in controls or in cases where the lesion missed the LOC. In LOC-lesion cases, after exposure to a traumatic stimulus, temporary threshold shifts were greater in the ipsilateral ear, but only when measured in the neural response; OHC-based measurements were always bilaterally symmetric, suggesting OHC vulnerability was unaffected. Interaural asymmetries in threshold shift were not found in either unlesioned controls or in cases that missed the LOC. These findings suggest that the LOC modulates cochlear nerve excitability and protects the cochlea from neural damage in acute acoustic injury.

Functional Role of GABAergic Innervation of the Cochlea: Phenotypic Analysis of Mice Lacking GABAAReceptor Subunits α1, α2, α5, α6, β2, β3, or δ

The olivocochlear efferent system is both cholinergic and GABAergic and innervates sensory cells and sensory neurons of the inner ear. Cholinergic effects on cochlear sensory cells are well characterized, bothin vivoandin vitro; however, the robust GABAergic innervation is poorly understood. To explore the functional roles of GABA in the inner ear, we characterized the cochlear phenotype of seven mouse lines with targeted deletion of a GABAAreceptor subunit (α1, α2, α5, α6, β2, β3, or δ). Four of the lines (α1, α2, α6, and δ) were normal: there was no cochlear histopathology, and cochlear responses suggested normal function of hair cells, afferent fibers, and efferent feedback. The other three lines (α5, β2, and β3) showed threshold elevations indicative of outer hair cell dysfunction. α5 and β2 lines also showed decreased effects of efferent bundle activation, associated with decreased density of efferent terminals on outer hair cells: although the onset of this degeneration was later in α5 (&gt;6 weeks) than β2 (&lt;6 weeks), both lines shows normal efferent development (up to 3 weeks). Two lines (β2 and β3) showed signs of neuropathy, either decreased density of afferent innervation (β3) or decreased neural responses without concomitant attenuation of hair cell responses (β2). One of the lines (β2) showed a clear sexual dimorphism in cochlear phenotype. Results suggest that the GABAergic component of the olivocochlear system contributes to the long-term maintenance of hair cells and neurons in the inner ear.