Auditory Neurophysiology publications

Sound-evoked vestibular myogenic potentials recorded from the sternocleidomastoid muscles (the cervical vestibular-evoked myogenic potential or cVEMP) and the extraocular muscles (the ocular VEMP or oVEMP) have proven useful in clinical assessment of vestibular function. VEMPs are commonly interpreted as a test of saccular function, based on neurophysiological evidence showing activation of saccular afferents by intense acoustic click stimuli. However, recent neurophysiological studies suggest that the clicks used in clinical VEMP tests activate vestibular end organs other than the saccule. To provide the neural basis for interpreting clinical VEMP testing results, the present study examined the extent to which air-conducted clicks differentially activate the various vestibular end organs at several intensities and durations in Sprague-Dawley rats. Single unit recordings were made from 562 vestibular afferents that innervated the otoliths [inferior branch otolith (IO) and superior branch otolith (SO)], the anterior canal (AC), the horizontal canal (HC), and the posterior canal (PC). Clicks higher than 60 dB SL (re-auditory brainstem response threshold) activated both semicircular canal and otolith organ afferents. Clicks at or below 60 dB SL, however, activated only otolith organ afferents. Longer duration clicks evoked larger responses in AC, HC, and SO afferents, but not in IO afferents. Intra-axonal recording and labeling confirmed that sound sensitive vestibular afferents innervated the horizontal and anterior canal cristae as well as the saccular and utricular maculae. Interestingly, all sound sensitive afferents are calyx-bearing fibers. These results demonstrate stimulus-dependent acoustic activation of both semicircular canals and otolith organs, and suggest that sound activation of vestibular end organs other than the saccule should not be ruled out when designing and interpreting clinical VEMP tests.

Ongoing clinical studies on patients recently implanted with the auditory midbrain implant (AMI) into the inferior colliculus (IC) for hearing restoration have shown that these patients do not achieve performance levels comparable to cochlear implant patients. The AMI consists of a single-shank array (20 electrodes) for stimulation along the tonotopic axis of the IC. Recent findings suggest that one major limitation in AMI performance is the inability to sufficiently activate neurons across the three-dimensional (3-D) IC. Unfortunately, there are no currently available 3-D array technologies that can be used for clinical applications. More recently, there has been a new initiative by the European Commission to fund and develop 3-D chronic electrode arrays for science and clinical applications through the NeuroProbes project that can overcome the bulkiness and limited 3-D configurations of currently available array technologies. As part of the NeuroProbes initiative, we investigated whether their new array technology could be potentially used for future AMI patients. Since the NeuroProbes technology had not yet been tested for electrical stimulation in an in vivo animal preparation, we performed experiments in ketamine-anesthetized guinea pigs in which we inserted and stimulated a NeuroProbes array within the IC and recorded the corresponding neural activation within the auditory cortex. We used 2-D arrays for this initial feasibility study since they were already available and were sufficient to access the IC and also demonstrate effective activation of the central auditory system. Based on these encouraging results and the ability to develop customized 3-D arrays with the NeuroProbes technology, we can further investigate different stimulation patterns across the ICC to improve AMI performance.

Background: Noise induced injury of the cochlea causes shifts in activation thresholds and changes of frequency response in the inferior colliculus (IC). Noise overexposure also induces pathological changes in the cochlea, and is highly correlated to hearing loss. However, the underlying mechanism has not been fully elucidated. In this study, we hypothesized that overexposure to noise induces substantial electrophysiological changes in the IC of guinea pigs. Results: During the noise exposure experiment, the animals were undergoing a bilateral exposure to noise. Additionally, various techniques were employed including confocal microscopy for the detection of cochlea hair cells and single neuron recording for spontaneous firing activity measurement. There were alterations among three types of frequency response area (FRA) from sound pressure levels, including V-, M-, and N-types. Our results indicate that overexposure to noise generates different patterns in the FRAs. Following a short recovery (one day after the noise treatment), the percentage of V-type FRAs considerably decreased, whereas the percentage of M-types increased. This was often caused by a notch in the frequency response that occurred at 4 kHz (noise frequency). Following a long recovery from noise exposure (11-21 days), the percentage of V-types resumed to a normal level, but the portion of M-types remained high. Interestingly, the spontaneous firing in the IC was enhanced in both short and long recovery groups. Conclusion: Our data suggest that noise overexposure changes the pattern of the FRAs and stimulates spontaneous firing in the IC in a unique way, which may likely relate to the mechanism of tinnitus.

Brief sounds produce a period of suppressed responsiveness in the auditory cortex (ACx). This forward suppression can last for hundreds of milliseconds and might contribute to mechanisms of temporal separation of sounds and stimulus-specific adaptation. However, the mechanisms of forward suppression remain unknown. We used in vivo recordings of sound-evoked responses in the mouse ACx and whole-cell recordings, two-photon calcium imaging in presynaptic terminals, and two-photon glutamate uncaging in dendritic spines performed in brain slices to show that synaptic depression at thalamocortical (TC) projections contributes to forward suppression in the ACx. Paired-pulse synaptic depression at TC projections lasts for hundreds of milliseconds and is attributable to a switch between firing modes in thalamic neurons. Thalamic neurons respond to a brief depolarizing pulse with a burst of action potentials; however, within hundreds of milliseconds, the same pulse repeated again produces only a single action potential. This switch between firing modes depends on Ca v 3.1 T-type calcium channels enriched in thalamic relay neurons. Pharmacologic inhibition or knockdown of Ca v 3.1 T-type calcium channels in the auditory thalamus substantially reduces synaptic depression at TC projections and forward suppression in the ACx. These data suggest that Ca v 3.1-dependent synaptic depression at TC projections contributes to mechanisms of forward suppression in the ACx.

Mutations in GJB2, which codes for the gap junction (GJ) protein connexin26 (Cx26), are the most common causes of human nonsyndromic hereditary deafness. We inoculated modified adeno-associated viral (AAV) vectors into the scala media of early postnatal conditional Gjb2 knockout mice to drive exogenous Cx26 expression. We found extensive virally expressed Cx26 in cells lining the scala media, and intercellular GJ network was re-established in the organ of Corti of mutant mouse cochlea. Widespread ectopic Cx26 expression neither formed ectopic GJs nor affected normal hearing thresholds in wild-type (WT) mice, suggesting that autonomous cellular mechanisms regulate proper membrane trafficking of exogenously expressed Cx26 and govern the functional manifestation of them. Functional recovery of GJ-mediated coupling among the supporting cells was observed. We found that both cell death in the organ of Corti and degeneration of spiral ganglion neurons in the cochlea of mutant mice were substantially reduced, although auditory brainstem responses did not show significant hearing improvement. This is the first report demonstrating that virally mediated gene therapy restored extensive GJ intercellular network among cochlear non-sensory cells in vivo. Such a treatment performed at early postnatal stages resulted in a partial rescue of disease phenotypes in the cochlea of the mutant mice.

Neurons in the primary auditory cortex (A1) can show rapid changes in receptive fields when animals are engaged in sound detection and discrimination tasks. The source of a signal to A1 that triggers these changes is suspected to be in frontal cortical areas. How or whether activity in frontal areas can influence activity and sensory processing in A1 and the detailed changes occurring in A1 on the level of single neurons and in neuronal populations remain uncertain. Using electrophysiological techniques in mice, we found that pairing orbitofrontal cortex (OFC) stimulation with sound stimuli caused rapid changes in the sound-driven activity within A1 that are largely mediated by noncholinergic mechanisms. By integrating in vivo two-photon Ca 2+ imaging of A1 with OFC stimulation, we found that pairing OFC activity with sounds caused dynamic and selective changes in sensory responses of neural populations in A1. Further, analysis of changes in signal and noise correlation after OFC pairing revealed improvement in neural population-based discrimination performance within A1. This improvement was frequency specific and dependent on correlation changes. These OFC-induced influences on auditory responses resemble behavior-induced influences on auditory responses and demonstrate that OFC activity could underlie the coordination of rapid, dynamic changes in A1 to dynamic sensory environments.

Sound localization is important for orienting and focusing attention and for segregating sounds from different sources in the environment. In humans, horizontal sound localization mainly relies on interaural differences in sound arrival time and sound level. Despite their perceptual importance, the neural processing of interaural time and level differences (ITDs and ILDs) remains poorly understood. Animal studies suggest that, in the brainstem, ITDs and ILDs are processed independently by different specialized circuits. The aim of the current study was to investigate whether, at higher processing levels, they remain independent or are integrated into a common code of sound laterality. For that, we measured late auditory cortical potentials in response to changes in sound lateralization elicited by perceptually matched changes in ITD and/or ILD. The responses to the ITD and ILD changes exhibited significant morphological differences. At the same time, however, they originated from overlapping areas of the cortex and showed clear evidence for functional coupling. These results suggest that the auditory cortex contains an integrated code of sound laterality, but also retains independent information about ITD and ILD cues. This cue-related information might be used to assess how consistent the cues are, and thus, how likely they would have arisen from the same source.

The mammalian neocortex is a highly interconnected network of different types of neurons organized into both layers and columns. Overlaid on this structural organization is a pattern of functional connectivity that can be rapidly and flexibly altered during behavior. Parvalbumin-positive (PV+) inhibitory neurons, which are implicated in cortical oscillations and can change neuronal selectivity, may play a pivotal role in these dynamic changes. We found that optogenetic activation of PV+ neurons in the auditory cortex enhanced feedforward functional connectivity in the putative thalamorecipient circuit and in cortical columnar circuits. In contrast, stimulation of PV+ neurons induced no change in connectivity between sites in the same layers. The activity of PV+ neurons may thus serve as a gating mechanism to enhance feedforward, but not lateral or feedback, information flow in cortical circuits. Functionally, it may preferentially enhance the contribution of bottom-up sensory inputs to perception.

The rat is a widely used species for study of the auditory system. Psychophysical results from rats have shown an inability to discriminate sound source locations within a lateral hemifield, despite showing fairly sharp near-midline acuity. We tested the hypothesis that those characteristics of the rat's sound localization psychophysics are evident in the characteristics of spatial sensitivity of its cortical neurons. In addition, we sought quantitative descriptions of in vivo spatial sensitivity of cortical neurons that would support development of an in vitro experimental model to study cortical mechanisms of spatial hearing. We assessed the spatial sensitivity of single- and multiple-neuron responses in the primary auditory cortex (A1) of urethane-anesthetized rats. Free-field noise bursts were varied throughout 360° of azimuth in the horizontal plane at sound levels from 10 to 40 dB above neural thresholds. All neurons encountered in A1 displayed contralateral-hemifield spatial tuning in that they responded strongly to contralateral sound source locations, their responses cut off sharply for locations near the frontal midline, and they showed weak or no responses to ipsilateral sources. Spatial tuning was quite stable across a 30-dB range of sound levels. Consistent with rat psychophysical results, a linear discriminator analysis of spike counts exhibited high spatial acuity for near-midline sounds and poor discrimination for off-midline locations. Hemifield spatial tuning is the most common pattern across all mammals tested previously. The homogeneous population of neurons in rat area A1 will make an excellent system for study of the mechanisms underlying that pattern.

Successful categorization of phonemes in speech requires that the brain analyze the acoustic signal along both spectral and temporal dimensions. Neural encoding of the stimulus amplitude envelope is critical for parsing the speech stream into syllabic units. Encoding of voice onset time (VOT) and place of articulation (POA), cues necessary for determining phonemic identity, occurs within shorter time frames. An unresolved question is whether the neural representation of speech is based on processing mechanisms that are unique to humans and shaped by learning and experience, or is based on rules governing general auditory processing that are also present in non-human animals. This question was examined by comparing the neural activity elicited by speech and other complex vocalizations in primary auditory cortex of macaques, who are limited vocal learners, with that in Heschl's gyrus, the putative location of primary auditory cortex in humans. Entrainment to the amplitude envelope is neither specific to humans nor to human speech. VOT is represented by responses time-locked to consonant release and voicing onset in both humans and monkeys. Temporal representation of VOT is observed both for isolated syllables and for syllables embedded in the more naturalistic context of running speech. The fundamental frequency of male speakers is represented by more rapid neural activity phase-locked to the glottal pulsation rate in both humans and monkeys. In both species, the differential representation of stop consonants varying in their POA can be predicted by the relationship between the frequency selectivity of neurons and the onset spectra of the speech sounds. These findings indicate that the neurophysiology of primary auditory cortex is similar in monkeys and humans despite their vastly different experience with human speech, and that Heschl's gyrus is engaged in general auditory, and not language-specific, processing. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives".

Interaural time differences (ITDs) are a major cue for localizing low-frequency (<1.5 kHz) sounds. Sensitivity to this cue first occurs in the medial superior olive (MSO), which is thought to perform a coincidence analysis on its monaural inputs. Extracellular single-neuron recordings in MSO are difficult to obtain because (1) MSO action potentials are small and (2) a large field potential locked to the stimulus waveform hampers spike isolation. Consequently, only a limited number of studies report MSO data, and even in these studies data are limited in the variety of stimuli used, in the number of neurons studied, and in spike isolation. More high-quality data are needed to better understand the mechanisms underlying neuronal ITD-sensitivity. We circumvented these difficulties by recording from the axons of MSO neurons in the lateral lemniscus (LL) of the chinchilla, a species with pronounced low-frequency sensitivity. Employing sharp glass electrodes we successfully recorded from neurons with ITD sensitivity: the location, response properties, latency, and spike shape were consistent with an MSO axonal origin. The main difficulty encountered was mechanical stability. We obtained responses to binaural beats and dichotic noise bursts to characterize the best delay versus characteristic frequency distribution, and compared the data to recordings we obtained in the inferior colliculus (IC). In contrast to most reports in other rodents, many best delays were close to zero ITD, both in MSO and IC, with a majority of the neurons recorded in the LL firing maximally within the presumed ethological ITD range.

Humans and animals readily generalize previously learned knowledge to new situations. Determining similarity is critical for assigning category membership to a novel stimulus. We tested the hypothesis that category membership is initially encoded by the similarity of the activity pattern evoked by a novel stimulus to the patterns from known categories. We provide behavioral and neurophysiological evidence that activity patterns in primary auditory cortex contain sufficient information to explain behavioral categorization of novel speech sounds by rats. Our results suggest that category membership might be encoded by the similarity of the activity pattern evoked by a novel speech sound to the patterns evoked by known sounds. Categorization based on featureless pattern matching may represent a general neural mechanism for ensuring accurate generalization across sensory and cognitive systems.

The principal inhibitory neurotransmitter in the mammalian cochlear nucleus (CN) is glycine. During age-related hearing loss (AHL), glycinergic inhibition becomes weaker in CN. However, it is unclear what aspects of glycinergic transmission are responsible for weaker inhibition with AHL. We examined glycinergic transmission onto bushy cells of the anteroventral CN in normal-hearing CBA/CaJ mice and in DBA/2J mice, a strain that exhibits an early onset AHL. Glycinergic synaptic transmission was examined in brain slices of mice at 10–15 postnatal days old, 20–35 days old, and at 6–7 mo old. Spontaneous inhibitory postsynaptic current (sIPSC) event frequency and amplitude were the same among all three ages in both strains of mice. However, the amplitudes of IPSCs evoked (eIPSC) from stimulating the dorsal CN were smaller, and the failure rate was higher, with increasing age due to decreased quantal content in both mouse strains, independent of hearing status. The coefficient of variation of the eIPSC amplitude also increased with age. The decay time constant (τ) of sIPSCs and eIPSCs were constant in CBA/CaJ mice at all ages, but were significantly slower in DBA/2J mice at postnatal days 20–35, following the onset of AHL, and not at earlier or later ages. Our results suggest that glycinergic inhibition at the synapses onto bushy cells becomes weaker and less reliable with age through changes in release. However, the hearing loss in DBA/2J mice is accompanied by a transiently enhanced inhibition, which could disrupt the balance of excitation and inhibition.

Novel stimulus detection by single neurons in the auditory system, known as stimulus-specific adaptation (SSA), appears to function as a real-time filtering/gating mechanism in processing acoustic information. Particular stimulus paradigms allowing for quantification of a neuron's ability to detect novel or deviant stimuli have been used to examine SSA in the inferior colliculus, medial geniculate body (MGB), and auditory cortex of anesthetized rodents. However, the study of SSA in awake animals is limited to auditory cortex. The present study used individually advanceable tetrodes to record single-unit responses from auditory thalamus (MGB) of awake young adult and aged Fischer Brown Norway (FBN) rats to 1) examine the presence of SSA in the MGB of awake rats and 2) determine whether SSA is altered by aging in MGB. MGB single units in awake FBN rats displayed SSA in response to two stimulus paradigms: the oddball paradigm and a random blocked/interleaved presentation of a set of frequencies. SSA levels were modestly, but nonsignificantly, increased in the nonlemniscal regions of the MGB and at lower stimulus intensities, where 27 of 57 (47%) young adult MGB units displayed SSA. The present findings provide the initial description of SSA in the MGB of awake rats and support SSA as being qualitatively independent of arousal level or anesthetized state. Finally, contrary to previous studies in auditory cortex of anesthetized rats, MGB units in aged rats showed SSA levels indistinguishable from SSA levels in young adult rats, suggesting that SSA in MGB was not impacted by aging in an awake preparation.

Echolocating bats use the time from biosonar pulse emission to the arrival of echo (defined as echo delay) to calculate the space depth of targets. In the dorsal auditory cortex of several species, neurons that encode increasing echo delays are organized rostrocaudally in a topographic arrangement defined as chronotopy. Precise chronotopy could be important for precise target-distance computations. Here we show that in the cortex of three echolocating bat species (Pteronotus quadridens, Pteronotus parnellii and Carollia perspicillata), chronotopy is not precise but blurry. In all three species, neurons throughout the chronotopic map are driven by short echo delays that indicate the presence of close targets and the robustness of map organization depends on the parameter of the receptive field used to characterize neuronal tuning. The timing of cortical responses (latency and duration) provides a binding code that could be important for assembling acoustic scenes using echo delay information from objects with different space depths.

Fragile X syndrome, the most common form of heritable mental retardation, is a developmental disorder with known effects within sensory systems. Altered developmental plasticity has been reported in the visual and somatosensory systems in Fmr1 knock-out (KO) mice. Behavioral studies have revealed maladaptive auditory responses in fragile X syndrome patients and Fmr1 KO mice, suggesting that adaptive plasticity may also be impaired in the auditory system. Here we show that, whereas tonotopic frequency representation develops normally in Fmr1 KO mice, developmental plasticity in primary auditory cortex is grossly impaired. This deficit can be rescued by pharmacological blockade of mGluR5 receptors. These results support the mGluR hypothesis of fragile X mental retardation and suggest that deficient developmental plasticity may contribute to maladaptive auditory processing in fragile X syndrome.

Background: Human magneto/electrophysiology studies suggest that the phantom sound of tinnitus arises from spontaneous oscillatory neural activity in auditory cortex; however, in animal models, behavioral techniques suitable for testing this hypothesis in combination with electrophysiology recordings have yet to be evaluated. While electrophysiological studies of tinnitus have been reported in passive, awake animals, these studies fail to control for attentional mechanisms likely to play a role in the perception of tinnitus. New method: A novel appetitive operant conditioning, two-alternative identification task was developed for detecting acute tinnitus in rats. The procedure optimizes conditions for simultaneously recording oscillatory neural activity while controlling for the attentional state of the animal. Results: Tinnitus was detected in six of seven rats following systemic injection with sodium salicylate (200mg/kg IP), a known inducer of tinnitus. Analysis of ongoing local field potentials recorded from chronically implanted electrodes in auditory cortex of a rat reporting tinnitus revealed changes in the spectrum of ongoing neural activity. Comparison with existing method(s): Existing tinnitus-detection methods were not explicitly designed for the simultaneous recording of neural activity. The behavioral method reported here is the first to provide the conditions necessary for obtaining these recordings in chronically implanted rats. Conclusions: The behavioral assay presented here will facilitate research into the neural mechanisms of tinnitus by allowing researchers to compare the electrophysiological data in animals with confirmed tinnitus.

Auditory brain stem circuits rely on fast, precise, and reliable neurotransmission to process auditory information. To determine the fundamental role of myelination in auditory brain stem function, we examined the evoked auditory brain stem response (ABR) from the Long Evans shaker ( LES) rat, which lacks myelin due to a genetic deletion of myelin basic protein. In control rats, the ABR evoked by a click consisted of five well-defined waves (denoted waves I–V). In LES rats, waves I, IV, and V were present, but waves II and III were undetectable, indicating disrupted function in the earliest stages of central nervous system auditory processing. In addition, the developmental shortening of the interval between waves I and IV that normally occurs in control rats was arrested and resulted in a significant increase in the central conduction time in LES rats. In brain stem slices, action potential transmission between the calyx of Held terminals and the medial nucleus of the trapezoid body (MNTB) neurons was delayed and less reliable in LES rats, although the resting potential, threshold, input resistance, and length of the axon initial segment of the postsynaptic MNTB neurons were normal. The amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) and the degree of synaptic depression during high-frequency stimulation were not different between LES rats and controls, but LES rats exhibited a marked slow component to the EPSC decay and a much higher rate of presynaptic failures. Together, these results indicate that loss of myelin disrupts brain stem auditory processing, increasing central conduction time and reducing the reliability of neurotransmission.

Early binaural experience can recalibrate central auditory circuits that support spatial hearing. However, it is not known how binaural integration matures shortly after hearing onset or whether various developmental stages are differentially impacted by disruptions of normal binaural experience. Here we induce a brief, reversible unilateral conductive hearing loss (CHL) at several experimentally determined milestones in mouse primary auditory cortex (A1) development and characterize its effects ~1 week after normal hearing is restored. We find that CHL shapes A1 binaural selectivity during two early critical periods. CHL before P16 disrupts the normal coregistration of interaural frequency tuning, whereas CHL on P16, but not before or after, disrupts interaural level difference sensitivity contained in long-latency spikes. These data highlight an evolving plasticity in the developing auditory cortex that may relate to the aetiology of amblyaudia, a binaural hearing impairment associated with bouts of otitis media during human infancy.

The medial nucleus of the trapezoid body (MNTB) in the superior olivary complex (SOC) is an inhibitory hub considered critical for binaural sound localization. We show that genetic ablation of MNTB neurons in mice only subtly affects this ability by prolonging the minimum time required to detect shifts in sound location. Furthermore, glycinergic innervation of the SOC is maintained without an MNTB, consistent with the existence of parallel inhibitory inputs. These findings redefine the role of MNTB in sound localization and suggest that the inhibitory network is more complex than previously thought.