Auditory Research publications

Enhanced detection and discrimination, along with faster reaction times, are the most typical behavioural manifestations of the brain's capacity to integrate multisensory signals arising from the same object. In this study, we examined whether multisensory behavioural gains are observable across different components of the localization response that are potentially under the command of distinct brain regions. We measured the ability of ferrets to localize unisensory (auditory or visual) and spatiotemporally coincident auditory–visual stimuli of different durations that were presented from one of seven locations spanning the frontal hemifield. During the localization task, we recorded the head movements made following stimulus presentation, as a metric for assessing the initial orienting response of the ferrets, as well as the subsequent choice of which target location to approach to receive a reward. Head‐orienting responses to auditory–visual stimuli were more accurate and faster than those made to visual but not auditory targets, suggesting that these movements were guided principally by sound alone. In contrast, approach‐to‐target localization responses were more accurate and faster to spatially congruent auditory–visual stimuli throughout the frontal hemifield than to either visual or auditory stimuli alone. Race model inequality analysis of head‐orienting reaction times and approach‐to‐target response times indicates that different processes, probability summation and neural integration, respectively, are likely to be responsible for the effects of multisensory stimulation on these two measures of localization behaviour.

With their essential role in inner ear function, stereocilia of sensory hair cells demonstrate the importance of cellular actin protrusions. Actin packing in stereocilia is mediated by cross-linkers of the plastin, fascin, and espin families. Although mice lacking espin (ESPN) have no vestibular or auditory function, we found that mice that either lacked plastin 1 (PLS1) or had nonfunctional fascin 2 (FSCN2) had reduced inner ear function, with double-mutant mice most strongly affected. Targeted mass spectrometry indicated that PLS1 was the most abundant cross-linker in vestibular stereocilia and the second most abundant protein overall; ESPN only accounted for ∼15% of the total cross-linkers in bundles. Mouse utricle stereocilia lacking PLS1 were shorter and thinner than wild-type stereocilia. Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing. Although all three cross-linkers are required for stereocilia structure and function, PLS1 biases actin toward liquid packing, which allows stereocilia to grow to a greater diameter.

Regular physical exercise reduces the risk for obesity, cardiovascular diseases, and disability and is associated with longer lifespan expectancy (Taylor et al., 2004; Pahor et al., 2014; Anton et al., 2015; Arem et al., 2015). In contrast, decreased physical function is associated with hearing loss among older adults (Li et al., 2013; Chen et al., 2015). Here, we investigated the effects of long-term voluntary wheel running (WR) on age-related hearing loss (AHL) in CBA/CaJ mice, a well established model of AHL (Zheng et al., 1999). WR activity peaked at 6 months of age (12,280 m/d) and gradually decreased over time. At 24 months of age, the average WR distance was 3987 m/d. Twenty-four-month-old runners had less cochlear hair cell and spiral ganglion neuron loss and better auditory brainstem response thresholds at the low and middle frequencies compared with age-matched, non-WR controls. Gene ontology (GO) enrichment analysis of inner ear tissues from 6-month-old controls and runners revealed that WR resulted in a marked enrichment for GO gene sets associated with immune response, inflammatory response, vascular function, and apoptosis. In agreement with these results, there was reduced stria vascularis (SV) atrophy and reduced loss of capillaries in the SV of old runners versus old controls. Given that SV holds numerous capillaries that are essential for transporting oxygen and nutrients into the cochlea, our findings suggest that long-term exercise delays the progression of AHL by reducing age-related loss of strial capillaries associated with inflammation. SIGNIFICANCE STATEMENT Nearly two-thirds of adults aged 70 years or older develop significant age-related hearing loss (AHL), a condition that can lead to social isolation and major communication difficulties. AHL is also associated with decreased physical function among older adults. In the current study, we show that regular exercise slowed AHL and cochlear degeneration significantly in a well established murine model. Our data suggest that regular exercise delays the progression of AHL by reducing age-related loss of strial capillaries associated with inflammation.

Mice are frequently used as animal models for human hearing research, yet their auditory capabilities have not been fully explored. Previous studies have established auditory threshold sensitivities for pure tone stimuli in CBA/CaJ mice using ABR and behavioral methodologies. Little is known about how they perceive their own ultrasonic vocalizations (USVs), and nothing is known about how aging influences this perception. The aim of the present study was to establish auditory threshold sensitivity for several USV types, as well as to track these thresholds across the mouse's lifespan. In order to determine how well mice detect these complex communication stimuli, several CBA/CaJ mice were trained and tested at various ages on a detection task using operant conditioning procedures. Results showed that mice were able to detect USVs into old age. Not surprisingly, thresholds differed for the different USV types. Male mice suffered greater hearing loss than females for all calls but not for 42 kHz tones. In conclusion, the results highlight the importance of studying complex signals across the lifespan.

The common marmoset (Callithrix jacchus) is a highly vocal New World primate species that has emerged in recent years as a promising model system for studies of auditory and vocal processing. Our recent studies have examined perceptual mechanisms related to the pitch of harmonic complex tones in this species. However, no previous psychoacoustic work has measured marmosets' frequency discrimination abilities for pure tones across a broad frequency range. Here we systematically examined frequency difference limens (FDLs), which measure the minimum discriminable frequency difference between two pure tones, in marmosets across most of their hearing range. Results show that marmosets' FDLs are comparable to other New World primates, with lowest values in the frequency range of ∼3.5-14 kHz. This region of lowest FDLs corresponds with the region of lowest hearing thresholds in this species measured in our previous study and also with the greatest concentration of spectral energy in the major types of marmoset vocalizations. These data suggest that frequency discrimination in the common marmoset may have evolved to match the hearing sensitivity and spectral characteristics of this species' vocalizations.

Background: The characteristic voice quality of a speaker conveys important linguistic, paralinguistic, and vocal health-related information. Pitch strength refers to the salience of pitch sensation in a sound and was recently reported to be strongly correlated with the magnitude of perceived breathiness based on a small number of voice stimuli. Objective: The current study examined the relationship between perceptual judgments of breathiness and computational estimates of pitch strength based on the Aud-SWIPE (P-NP) algorithm for a large number of voice stimuli (330 synthetic and 57 natural). Methods and results: Similar to the earlier study, the current results confirm a strong relationship between estimated pitch strength and listener judgments of breathiness such that low pitch-strength values are associated with voices that have high perceived breathiness. Based on this result, a model was developed for the perception of breathy voice quality using a pitch-strength estimator. Regression functions derived between the pitch-strength estimates and perceptual judgments of breathiness obtained from matching task revealed a linear relationship for a subset of the natural stimuli. We then used this function to obtain predicted breathiness values for the synthetic and the remaining natural stimuli. Conclusions: Predicted breathiness values from our model were highly correlated with the perceptual data for both types of stimuli. Systematic differences between the breathiness of natural and synthetic stimuli are discussed.

Tonotopic map plasticity in the adult auditory cortex (AC) is a well established and oft-cited measure of auditory associative learning in classical conditioning paradigms. However, its necessity as an enduring memory trace has been debated, especially given a recent finding that the areal expansion of core AC tuned to a newly relevant frequency range may arise only transiently to support auditory learning. This has been reinforced by an ethological paradigm showing that map expansion is not observed for ultrasonic vocalizations (USVs) or for ultrasound frequencies in postweaning dams for whom USVs emitted by pups acquire behavioral relevance. However, whether transient expansion occurs during maternal experience is not known, and could help to reveal the generality of cortical map expansion as a correlate for auditory learning. We thus mapped the auditory cortices of maternal mice at postnatal time points surrounding the peak in pup USV emission, but found no evidence of frequency map expansion for the behaviorally relevant high ultrasound range in AC. Instead, regions tuned to low frequencies outside of the ultrasound range show progressively greater suppression of activity in response to the playback of ultrasounds or pup USVs for maternally experienced animals assessed at their pups’ postnatal day 9 (P9) to P10, or postweaning. This provides new evidence for a lateral-band suppression mechanism elicited by behaviorally meaningful USVs, likely enhancing their population-level signal-to-noise ratio. These results demonstrate that tonotopic map enlargement has limits as a construct for conceptualizing how experience leaves neural memory traces within sensory cortex in the context of ethological auditory learning.

The study measured listener sensitivity to increments in the duration of one or two target silent intervals embedded within unaccented tone sequences and sequences that featured a single accented component. The baseline unaccented sequences consisted of six 1000-Hz 40-ms tone bursts that were separated equally by silent intervals to establish a slower tone sequence rate, with tonal inter-onset intervals (IOIs) set to 200 ms, or a faster rate with tonal IOIs set to 100 ms. Stimulus accent was created by doubling the baseline duration of a single sequence component, either the second tone burst (tonal accent), or the second tonal IOI (interval accent). Duration difference limens for increments of the target interval(s) were measured adaptively by varying a single inter-tone silent interval or co-varying two successive inter-tone silent intervals; target intervals occurred at the third, or third and fourth, sequence locations. Listeners included younger normal-hearing adults and groups of older listeners with and without hearing loss. Discrimination for the two older groups was equivalent and poorer than that of the younger listeners, especially for the faster accented sequences. Discrimination was best for stimuli with two successive target intervals, indicating that target repetition within accented sequences acts to improve listener temporal sensitivity.

Zebrafish are increasingly used in auditory studies, in part due to the development of several transgenic lines that express hair cell-specific fluorescent proteins. However, it is largely unknown how transgene expression influences auditory phenotype. We previously observed reduced auditory sensitivity in adult Brn3c:mGFP transgenic zebrafish, which express membrane-bound green fluorescent protein (GFP) in sensory hair cells. Here, we examine the auditory sensitivity of zebrafish from multiple transgenic and background strains. We recorded auditory evoked potentials in adult animals and observed significantly higher auditory thresholds in three lines that express hair cell-specific GFP. There was no obvious correlation between hair cell density and auditory thresholds, suggesting that reduced sensitivity was not due to a reduction in hair cell density. FM1-43 uptake was reduced in Brn3c:mGFP fish but not in other lines, suggesting that a mechanotransduction defect may be responsible for the auditory phenotype in Brn3c animals, but that alternate mechanisms underlie the increased AEP thresholds in other lines. We found reduced prepulse inhibition (a measure of auditory-evoked behavior) in larval Brn3c animals, suggesting that auditory defects develop early in this line. We also found significant differences in auditory sensitivity between adults of different background strains, akin to strain differences observed in mouse models of auditory function. Our results suggest that researchers should exercise caution when selecting an appropriate zebrafish transgenic or background strain for auditory studies.

Physical features of sensory stimuli are fixed, but sensory perception is context dependent. The precise mechanisms that govern contextual modulation remain unknown. Here, we trained mice to switch between two contexts: passively listening to pure tones and performing a recognition task for the same stimuli. Two-photon imaging showed that many excitatory neurons in auditory cortex were suppressed during behavior, while some cells became more active. Whole-cell recordings showed that excitatory inputs were affected only modestly by context, but inhibition was more sensitive, with PV+, SOM+, and VIP+ interneurons balancing inhibition and disinhibition within the network. Cholinergic modulation was involved in context switching, with cholinergic axons increasing activity during behavior and directly depolarizing inhibitory cells. Network modeling captured these findings, but only when modulation coincidently drove all three interneuron subtypes, ruling out either inhibition or disinhibition alone as sole mechanism for active engagement. Parallel processing of cholinergic modulation by cortical interneurons therefore enables context-dependent behavior.

The hearing sensitivity of 18 free-ranging and 10 captive harbour seals (Phoca vitulina) to aerial sounds was measured in the presence of typical environmental noise through auditory brainstem response measurements. A focus was put on the comparative hearing sensitivity at low frequencies. Low- and mid-frequency thresholds appeared to be elevated in both captive and free-ranging seals, but this is likely due to masking effects and limitations of the methodology used. The data also showed individual variability in hearing sensitivity with probable age-related hearing loss found in two old harbour seals. These results suggest that the acoustic sensitivity of free-ranging animals was not negatively affected by the soundscape they experienced in the wild.

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity. SIGNIFICANCE STATEMENT The detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds.

Listeners with normal hearing thresholds (NHTs) differ in their ability to steer attention to whatever sound source is important. This ability depends on top-down executive control, which modulates the sensory representation of sound in the cortex. Yet, this sensory representation also depends on the coding fidelity of the peripheral auditory system. Both of these factors may thus contribute to the individual differences in performance. We designed a selective auditory attention paradigm in which we could simultaneously measure envelope following responses (EFRs, reflecting peripheral coding), onset event-related potentials (ERPs) from the scalp (reflecting cortical responses to sound) and behavioral scores. We performed two experiments that varied stimulus conditions to alter the degree to which performance might be limited due to fine stimulus details vs. due to control of attentional focus. Consistent with past work, in both experiments we find that attention strongly modulates cortical ERPs. Importantly, in Experiment I, where coding fidelity limits the task, individual behavioral performance correlates with subcortical coding strength (derived by computing how the EFR is degraded for fully masked tones compared to partially masked tones); however, in this experiment, the effects of attention on cortical ERPs were unrelated to individual subject performance. In contrast, in Experiment II, where sensory cues for segregation are robust (and thus less of a limiting factor on task performance), inter-subject behavioral differences correlate with subcortical coding strength. In addition, after factoring out the influence of subcortical coding strength, behavioral differences are also correlated with the strength of attentional modulation of ERPs. These results support the hypothesis that behavioral abilities amongst listeners with NHTs can arise due to both subcortical coding differences and differences in attentional control, depending on stimulus characteristics and task demands.

Sea turtles spend much of their life in aquatic environments, but critical portions of their life cycle, such as nesting and hatching, occur in terrestrial environments, suggesting that it may be important for them to detect sounds in both air and water. In this study we compared underwater and aerial hearing sensitivities in five juvenile green sea turtles (Chelonia mydas) by measuring auditory evoked potential responses to tone pip stimuli. Green sea turtles detected acoustic stimuli in both media, responding to underwater stimuli between 50 and 1600 Hz and aerial stimuli between 50 and 800 Hz, with maximum sensitivity between 200 and 400 Hz underwater and 300 and 400 Hz in air. When underwater and aerial hearing sensitivities were compared in terms of pressure, green sea turtle aerial sound pressure thresholds were lower than underwater thresholds, however they detected a wider range of frequencies underwater. When thresholds were compared in terms of sound intensity, green sea turtle sound intensity level thresholds were 2-39 dB lower underwater particularly at frequencies below 400 Hz. Acoustic stimuli may provide important environmental cues for sea turtles. Further research is needed to determine how sea turtles behaviorally and physiologically respond to sounds in their environment.

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ 35 S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca 2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1 neo−/− mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.

Human aging studies suggest that an increased use of top-down knowledge-based resources would compensate for degraded upstream acoustic information to accurately identify important temporally rich signals. Sinusoidal amplitude-modulated (SAM) stimuli have been used to mimic the fast-changing temporal features in speech and species-specific vocalizations. Single units were recorded from auditory thalamus [medial geniculate body (MGB)] of young awake, aged awake, young anesthetized, and aged anesthetized rats. SAM stimuli were modulated between 2 and 1024 Hz with the modulation frequency ( f m) changed randomly (RAN) across trials or sequentially (SEQ) after several repeated trials. Units were found to be RAN-preferring, SEQ-preferring, or nonselective based on total firing rate. Significant anesthesia and age effects were found. The majority (86%) of young anesthetized units preferred RAN SAM stimuli; significantly fewer young awake units (51%, p < 0.0001) preferred RAN SAM signals with 16% preferring SEQ SAM. Compared with young awake units, there was a significant increase of aged awake units preferring SEQ SAM (30%, p < 0.05). We examined RAN versus SEQ differences across f ms by measuring selective f m areas under the rate modulation transfer function curve. The largest age-related differences from awake animals were found for mid-to-high f ms in MGB units, with young units preferring RAN SAM while aged units showed a greater preference for SEQ-presented SAM. Together, these findings suggest that aged MGB units/animals employ increased top-down mediated stimulus context to enhance processing of “expected” temporally rich stimuli, especially at more challenging higher f ms. SIGNIFICANCE STATEMENT Older individuals compensate for impaired ascending acoustic information by increasing use of cortical cognitive and attentional resources. The interplay between ascending and descending influences in the thalamus may serve to enhance the salience of speech signals that are degraded as they ascend to the cortex. The present findings demonstrate that medial geniculate body units from awake rats show an age-related preference for predictable modulated signals relative to randomly presented signals, especially at higher, more challenging modulation frequencies. Conversely, units from anesthetized animals, with little top-down influences, strongly preferred randomly presented modulated sequences. These results suggest a neuronal substrate for an age-related increase in experience/attentional-based influences in processing temporally complex auditory information in the auditory thalamus.

The multi-C2 domain protein otoferlin is required for hearing and mutated in human deafness. Some OTOF mutations cause a mild elevation of auditory thresholds but strong impairment of speech perception. At elevated body temperature, hearing is lost. Mice homozygous for one of these mutations, OtofI515T/I515T, exhibit a moderate hearing impairment involving enhanced adaptation to continuous or repetitive sound stimulation. In OtofI515T/I515T inner hair cells (IHCs), otoferlin levels are diminished by 65%, and synaptic vesicles are enlarged. Exocytosis during prolonged stimulation is strongly reduced. This indicates that otoferlin is critical for the reformation of properly sized and fusion-competent synaptic vesicles. Moreover, we found sustained exocytosis and sound encoding to scale with the amount of otoferlin at the plasma membrane. We identified a 20 amino acid motif including an RXR motif, presumably present in human but not in mouse otoferlin, which reduces the plasma membrane abundance of Ile515Thr-otoferlin. Together, this likely explains the auditory synaptopathy at normal temperature and the temperature-sensitive deafness in humans carrying the Ile515Thr mutation.

Bidirectional manipulations – activation and inactivation – are widely used to identify the functions supported by specific cortical interneuron types. Implicit in much of this work is the notion that tonic activation and inactivation will both produce valid, internally consistent insights into interneurons’ computational roles. Here, using single-unit recordings in auditory cortex of awake mice, we show that this may not generally hold true. Optogenetically manipulating somatostatin-positive (Sst+) or parvalbumin-positive (Pvalb+) interneurons while recording tone-responses showed that Sst+ inactivation increased response gain, while Pvalb+ inactivation weakened tuning and decreased information transfer, implying that these neurons support delineable computational functions. But activating Sst+ and Pvalb+ interneurons revealed no such differences. We used a simple network model to understand this asymmetry, and showed how relatively small changes in key parameters, such as spontaneous activity or strength of the light manipulation, determined whether activation and inactivation would produce consistent or paradoxical conclusions regarding interneurons’ computational functions.

Integration of multiple sensory cues can improve performance in detection and estimation tasks. There is an open theoretical question of the conditions under which linear or nonlinear cue combination is Bayes-optimal. We demonstrate that a neural population decoded by a population vector requires nonlinear cue combination to approximate Bayesian inference. Specifically, if cues are conditionally independent, multiplicative cue combination is optimal for the population vector. The model was tested on neural and behavioral responses in the barn owl's sound localization system where space-specific neurons owe their selectivity to multiplicative tuning to sound localization cues interaural phase (IPD) and level (ILD) differences. We found that IPD and ILD cues are approximately conditionally independent. As a result, the multiplicative combination selectivity to IPD and ILD of midbrain space-specific neurons permits a population vector to perform Bayesian cue combination. We further show that this model describes the owl's localization behavior in azimuth and elevation. This work provides theoretical justification and experimental evidence supporting the optimality of nonlinear cue combination.

Contrary to cats and primates, cortical contribution to hindlimb locomotor movements is not critical in rats. However, the importance of the motor cortex to regain locomotion after neurological disorders in rats suggests that cortical engagement in hindlimb motor control may depend on the behavioral context. To investigate this possibility, we recorded whole-body kinematics, muscle synergies, and hindlimb motor cortex modulation in freely moving rats performing a range of natural locomotor procedures. We found that the activation of hindlimb motor cortex preceded gait initiation. During overground locomotion, the motor cortex exhibited consistent neuronal population responses that were synchronized with the spatiotemporal activation of hindlimb motoneurons. Behaviors requiring enhanced muscle activity or skilled paw placement correlated with substantial adjustment in neuronal population responses. In contrast, all rats exhibited a reduction of cortical activity during more automated behavior, such as stepping on a treadmill. Despite the facultative role of the motor cortex in the production of locomotion in rats, these results show that the encoding of hindlimb features in motor cortex dynamics is comparable in rats and cats. However, the extent of motor cortex modulations appears linked to the degree of volitional engagement and complexity of the task, reemphasizing the importance of goal-directed behaviors for motor control studies, rehabilitation, and neuroprosthetics. SIGNIFICANCE STATEMENT We mapped the neuronal population responses in the hindlimb motor cortex to hindlimb kinematics and hindlimb muscle synergies across a spectrum of natural locomotion behaviors. Robust task-specific neuronal population responses revealed that the rat motor cortex displays similar modulation as other mammals during locomotion. However, the reduced motor cortex activity during more automated behaviors suggests a relationship between the degree of engagement and task complexity. This relationship emphasizes the importance of the behavioral procedure to engage the motor cortex during motor control studies, gait rehabilitation, and locomotor neuroprosthetic developments in rats.