Auditory Research publications

Detecting patterns, and noticing unexpected pattern changes, in the environment is a vital aspect of sensory processing. Adaptation and prediction error responses are two components of neural processing related to these tasks, and previous studies in the auditory system in rodents show that these two components are partially dissociable in terms of the topography and latency of neural responses to sensory deviants. However, many previous studies have focused on repetitions of single stimuli, such as pure tones, which have limited ecological validity. In this study, we tested whether the auditory cortical activity shows adaptation to repetition of more complex sound patterns (bisyllabic pairs). Specifically, we compared neural responses to violations of sequences based on single stimulus probability only, against responses to more complex violations based on stimulus order. We employed an auditory oddball paradigm and monitored the auditory cortex (ACtx) activity of awake mice (N=8) using wide-field calcium imaging. We found that cortical responses were sensitive both to single stimulus probabilities and to more global stimulus patterns, as mismatch signals were elicited following both substitution deviants and transposition deviants. Notably, A2 area elicited larger mismatch signaling to those deviants than primary ACtx (A1), which suggests a hierarchical gradient of prediction error signaling in the auditory cortex. Such a hierarchical gradient was observed for late but not early peaks of calcium transients to deviants, suggesting that the late part of the deviant response may reflect prediction error signaling in response to more complex sensory pattern violations.

We examined the effect of neonatal deafening on frequency-specific pathways for processing of interaural time differences (ITDs) in cochlear-implant stimuli. Animal studies have demonstrated differences in neural ITD sensitivity in the inferior colliculus (IC) depending on the intracochlear location of intracochlear stimulating electrodes. We used neonatally deafened (ND) rats of both sexes and recorded the responses of single neurons in the IC to electrical stimuli with ITDs delivered to the apical or basal cochlea and compared them with acutely deafened (AD) rats of both sexes with normal hearing (NH) during development. We found that neonatal deafness significantly impacted the ITD sensitivity and the ITD tuning patterns restricted to apically driven IC neurons. In ND rats, the ITD sensitivity of apically driven neurons is reduced to values similar to basally driven neurons. The prevalence of ITD-sensitive apical neurons with a peak-shaped ITD tuning curve, which may reflect predominant input from the medial superior olivary (MSO) complex, in ND rats was diminished compared with that in AD rats (67%, AD vs 40%, ND). Conversely, monotonic-type responses rarely occurred in AD rats (14%) but were approximately equally as prevalent as peak-type tuning curves in ND rats (42%). Nevertheless, in ND rats, the ITD at the maximum slope of the ITD tuning curve was still more concentrated within the physiological ITD range in apically driven than in basally driven neurons. These results indicate that the development of high ITD sensitivity processed by low-frequency pathways depends on normal auditory experience and associated biases in ITD tuning strategies.

From myriads of ongoing stimuli, the brain creates a fused percept of the environment. This process, which culminates in perceptual binding, is presumed to occur through the operations of multisensory neurons that occur throughout the brain. However, because different brain areas receive different inputs and have different cytoarchitechtonics, it would be expected that local multisensory features would also vary across regions. The present study investigated that hypothesis using multiple single-unit recordings from anesthetized cats in response to controlled, electronically-generated separate and combined auditory, visual, and somatosensory stimulation. These results were used to compare the multisensory features of neurons in cat primary auditory cortex (A1) with those identified in the nearby higher-order auditory region, the Dorsal Zone (DZ). Both regions exhibited the same forms of multisensory neurons, albeit in different proportions. Multisensory neurons exhibiting excitatory or inhibitory properties occurred in similar proportions in both areas. Also, multisensory neurons in both areas expressed similar levels of multisensory integration. Because responses to auditory cues alone were so similar to those that included non-auditory stimuli, it is proposed that this effect represents a mechanism by which multisensory neurons subserve the process of perceptual binding.

The prevailing theory of cochlear function states that outer hair cells amplify sound-induced vibration to improve hearing sensitivity and frequency specificity. Recent micromechanical measurements in the basal turn of gerbil cochleae through the round window have demonstrated that the reticular lamina vibration lags the basilar membrane vibration, and it is physiologically vulnerable not only at the best frequency but also at the low frequencies. These results suggest that outer hair cells from a broad cochlear region enhance hearing sensitivity through a global hydromechanical mechanism. However, the time difference between the reticular lamina and basilar membrane vibration has been thought to result from a systematic measurement error caused by the optical axis non-perpendicular to the cochlear partition. To address this concern, we measured the reticular lamina and basilar membrane vibrations in the transverse direction through an opening in the cochlear lateral wall in this study. Present results show that the phase difference between the reticular lamina and basilar membrane vibration decreases with frequency by ~ 180 degrees from low frequencies to the best frequency, consistent with those measured through the round window. Together with the round-window measurement, the low-coherence interferometry through the cochlear lateral wall demonstrates that the time difference between the reticular lamina and basilar membrane vibration results from the cochlear active processing rather than a measurement error.

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-related transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.

Nocturnal moths evolved ultrasound-triggered escape maneuvers for avoiding predatory bats emitting ultrasonic echolocation calls. Using ultrasound for pest control is not a novel concept, but the technique has not been systemized because of the moths’ habituation to sounds and the narrow directionality of conventional ultrasound speakers. Here, we report the use of pulsed ultrasonic white noise, which contributes to achieving ecologically concordant plant protection. An ultrasonic pulse, which is temporal mimicry of the search-phase pulse in the echolocation calls of a sympatric bat, was identified using neuroethological screening of eared moth–repelling ultrasounds; these pulses elicit flight-stopping reactions in moths but have no or little auditory adaptation. Such repellent ultrasounds broadcast from the cylindrical omni-azimuth ultrasound emitters suppressed the intrusion of gravid females of pest moths into cultivation fields. Thus, egg numbers and plant damage by hatched larvae were drastically reduced, enabling farmers to substantially skip applications of chemical insecticides for controlling moth pests.

In the post-natal mouse cochlea, type II spiral ganglion neurons (SGNs) innervating the electromotile outer hair cells (OHCs) of the ‘cochlear amplifier' selectively express the type III intermediate filament peripherin gene ( Prph) . Immunolabeling showed that Prph knockout (KO) mice exhibited disruption of this (outer spiral bundle) afferent innervation, while the radial fiber (type I SGN) innervation of the inner hair cells (~95% of the SGN population) was retained. Functionality of the medial olivocochlear (MOC) efferent innervation of the OHCs was confirmed in the Prph KO, based on suppression of distortion product otoacoustic emissions (DPOAEs) via direct electrical stimulation. However, “contralateral suppression” of the MOC reflex neural circuit, evident as a rapid reduction in cubic DPOAE when noise is presented to the opposite ear in wildtype mice, was substantially disrupted in the Prph KO. Auditory brainstem response (ABR) measurements demonstrated that hearing sensitivity (thresholds and growth-functions) were indistinguishable between wildtype and Prph KO mice. Despite this comparability in sound transduction and strength of the afferent signal to the central auditory pathways, high-intensity, broadband noise exposure (108 dB SPL, 1 h) produced permanent high frequency hearing loss (24–32 kHz) in Prph KO mice but not the wildtype mice, consistent with the attenuated contralateral suppression of the Prph KO. These data support the postulate that auditory neurons expressing Prph contribute to the sensory arm of the otoprotective MOC feedback circuit.

Vertigo is a debilitating disease affecting 15–20% of adults worldwide. Vestibular peripheral vertigo is the most common cause of vertigo, often due to Meniere's disease and benign paroxysmal positional vertigo. Although some vertigo symptoms can be controlled by conservative treatment and/or vestibular rehabilitation therapy, these treatments do not work for some patients. Semicircular canal occlusion surgery has proven to be very effective for these patients with intractable vertigo. However, its application is limited due to concern that the procedure will disrupt normal hearing. In this study, we investigated if occlusion of two semicircular canals would jeopardize auditory function by comparing auditory function and hair cell morphology between the surgical and contralateral ears before and after the surgery in a mouse model. By measuring the auditory brainstem response and distortion product otoacoustic emission 4 weeks post-surgery, we show that auditory function does not significantly change between the surgical and contralateral ears. In addition, confocal imaging has shown no hair cell loss in the cochlear and vestibular sensory epithelia, and scanning electron microscopy also indicates normal stereocilia morphology in the surgical ear. More importantly, the endocochlear potential measured from the surgical ear is not significantly different than that seen in the contralateral ear. Our study suggests that occlusion of two semicircular canals does not disrupt normal hearing in the mouse model, providing a basis to extend the procedure to patients, even those with normal hearing, benefitting more patients with intractable vertigo attacks.

Kanamycin and cisplatin are ototoxic drugs. The mechanisms are incompletely known. With subcutaneous kanamycin (400 mg/kg, 15 days), auditory threshold shifts were detected at days 12–13 at 16 and 32 kHz, extending to 8 and 4 kHz at days 14–15. The outer hair cell (OHC) loss was concentrated past day 12. The maximum cochlear length showing apoptotic cells, tested with TUNEL, was at day 13. At day 15, 1/5 of the apical cochlea contained preserved OHCs. 3-nitrotyrosine (3-NT) immunolabeling, showing oxidative stress, was found in surviving OHCs and in basal and middle portions of the stria vascularis (SV). The antioxidant Gpx1 gene expression was decreased. The immunocytochemistry showed diminished Gpx1 in OHCs. With intraperitoneal cisplatin (16 mg/kg, single injection), no evoked auditory activity was recorded at the end of treatment, at 72 h. The basal third of the cochlea lacked OHCs. Apoptosis occupied the adjacent 1/3, and the apical third contained preserved OHCs. 3-NT immunolabeling was extensive in OHCs and the SV. Gpx1 and Sod1 gene expression was downregulated. Gpx1 immunostaining diminished in middle and basal SV. More OHCs survived cisplatin than kanamycin towards the apex, despite undetectable evoked activity. Differential regulation of antioxidant enzyme levels suggests differences in the antioxidant response for both drugs.

Foraging on nocturnally migrating birds is one of the most challenging foraging tasks in the animal kingdom. Only three bat species (e.g., Ia io) known to date can prey on migratory birds. However, how these bats have exploited this challenging dietary niche remains unknown. Here, we demonstrate that I. io hunts at the altitude of migrating birds during the bird migration season. The foraging I. io exhibited high flight altitudes (up to 4945 m above sea level) and high flight speeds (up to 143.7 km h-1). I. io in flight can actively prey on birds in the night sky via echolocation cues. Genes associated with DNA damage repair, hypoxia adaptation, biting and mastication, and digestion and metabolism have evolved to adapt to this species' avivorous habits. Our results suggest that the evolution of behavioral innovation and genomic novelty are associated with the exploitation of challenging dietary opportunities.

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K + currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

Sensory responses typically vary depending on the recent history of sensory experience. This is essential for processes, including adaptation, efficient coding, and change detection. In the auditory cortex (AC), the short-term history dependence of sound-evoked (onset) responses has been well characterized. Yet many AC neurons also respond to sound terminations, and little is known about the history dependence of these "offset" responses, whether the short-term dynamics of onset and offset responses are correlated, or how these properties are distributed among cell types. Here we presented awake male and female mice with repeating noise burst stimuli while recording single-unit activity from primary AC. We identified parvalbumin and somatostatin interneurons through optotagging, and also separated narrow-spiking from broad-spiking units. We found that offset responses are typically less depressive than onset responses, and this result was robust to a variety of stimulus parameters, controls, measurement types, and selection criteria. Whether a cell's onset response facilitates or depresses does not predict whether its offset response facilitates or depresses. Cell types differed in the dynamics of their onset responses, and in the prevalence, but not the dynamics, of their offset responses. Finally, we clustered cells according to spiking responses and found that response clusters were associated with cell type. Each cluster contained cells of several types, but even within a cluster, cells often showed cell type-specific response dynamics. We conclude that onset and offset responses are differentially influenced by recent sound history, and discuss the implications of this for the encoding of ongoing sound stimuli.SIGNIFICANCE STATEMENT Sensory neuron responses depend on stimulus history. This history dependence is crucial for sensory processing, is precisely controlled at individual synapses and circuits, and is adaptive to the specific requirements of different sensory systems. In the auditory cortex, neurons respond to sound cessation as well as to sound itself, but how history dependence is used along this separate, "offset" information stream is unknown. We show that offset responses are more facilitatory than sound responses, even in neurons where sound responses depress. In contrast to sound onset responses, offset responses are absent in many cells, are relatively homogeneous, and show no cell type-specific differences in history dependence. Offset responses thus show unique response dynamics, suggesting their unique functions.

In everyday behavior, sensory systems are in constant competition for attentional resources, but the cellular and circuit-level mechanisms of modality-selective attention remain largely uninvestigated. We conducted translaminar recordings in mouse auditory cortex (AC) during an audiovisual (AV) attention shifting task. Attending to sound elements in an AV stream reduced both pre-stimulus and stimulus-evoked spiking activity, primarily in deep-layer neurons and neurons without spectrotemporal tuning. Despite reduced spiking, stimulus decoder accuracy was preserved, suggesting improved sound encoding efficiency. Similarly, task-irrelevant mapping stimuli during inter-trial intervals evoked fewer spikes without impairing stimulus encoding, indicating that attentional modulation generalized beyond training stimuli. Importantly, spiking reductions predicted trial-to-trial behavioral accuracy during auditory attention, but not visual attention. Together, these findings suggest auditory attention facilitates sound discrimination by filtering sound-irrelevant background activity in AC, and that the deepest cortical layers serve as a hub for integrating extramodal contextual information.

The functional organization of sensory cortices is modulated by both extrinsic events and intrinsic states. The present study aimed to assess the mouse auditory cortex (AC) responses under varying conditions of stimulus complexity and brain state. Using wide-field calcium imaging, our results suggest a complete outline of topographic maps of frequency and FM rate as well as highly responsive regions to mouse ultrasonic vocalizations (USVs) in both awake and anesthetized states. Three new regions responsive to high-frequency tones and four new gradients responsive to frequency modulations (FMs) were identified. These maps are highly replicable across weeks and between animals. In awake versus anesthetized states, cortical responsiveness to pure tones was stronger, and regions that preferentially responded to slow rate FMs were smaller. In both states, fast FM regions showed the greatest contribution to the processing of USVs. Finally, our modeling of how best tone frequency or FM rate changes as a function of distance along a topographic gradient resulted in a sigmoid function. Together, our findings provide a better understanding of mouse AC functional organization and how this organization is modulated by changes in stimulus complexity and brain state. The function of newly identified regions in higher-order auditory/vocal processing and animal behavior should be considered in future research.

Objective: Molecular hydrogen (H 2 ) has shown therapeutic potential in several oxidative stress-related conditions in humans, is well-tolerated, and is easily administered via inhalation.The aim of this preclinical in vivo study was to investigate whether impulse noise trauma can be prevented by H 2 when inhaled immediately after impulse noise exposure. Methods: Guinea pigs (n = 26) were subjected to impulse noise (n = 400; 156 dB SPL; 0.33/s; n = 11; the Noise group), to impulse noise immediately followed by H 2 inhalation (2 mol%; 500 ml/min; 1 hour; n = 10; the Noise + H 2 group), or to H 2 inhalation (n = 5; the H 2 group). The acoustically evoked ABR threshold at 3.15, 6.30, 12.5, 20.0, and 30.0 kHz was assessed before and 4 days after impulse noise and/or H 2 exposure. The cochleae were harvested after the final ABR assessment for quantification of hair cells. Results: Noise exposure caused ABR threshold elevations at all frequencies (median 35, 35, 30, 35, and 35 dB SPL, the Noise group; 20, 25, 10, 13, and 20 dB SPL, the Noise + H 2 group; P < .05) but significantly less so in the Noise + H 2 group ( P < .05). Outer hair cell (OHC) loss was in the apical, mid, and basal regions 8.8%, 53%, and 14% in the Noise group and 3.5%, 22%, and 1.2% in the Noise + H 2 group. The corresponding inner hair cell (IHC) loss was 0.1%, 14%, and 3.5% in the Noise group and 0%, 2.8%, and 0% in the Noise + H 2 group. The difference between the groups was significant in the basal region for OHCs ( P = .003) and apical ( P = .033) and basal ( P = .048) regions for IHCs. Conclusions: Acute acoustic trauma can be reduced by H 2 when inhaled immediately after impulse noise exposure.

Understanding computational principles in hierarchically organized sensory systems requires functional parcellation of brain structures and their precise targeting for manipulations. Although brain atlases are widely used to infer area locations in the mouse neocortex, it has been unclear whether stereotaxic coordinates based on standardized brain morphology accurately represent functional domains in individual animals. Here, we used intrinsic signal imaging to evaluate the accuracy of area delineation in the atlas by mapping functionally-identified auditory cortices onto bregma-based stereotaxic coordinates. We found that auditory cortices in the brain atlas correlated poorly with the true complexity of functional area boundaries. Inter-animal variability in functional area locations predicted surprisingly high error rates in stereotaxic targeting with atlas coordinates. This variability was not simply attributed to brain sizes or suture irregularities but instead reflected differences in cortical geography across animals. Our data thus indicate that functional mapping in individual animals is essential for dissecting cortical area-specific roles with high precision.

We introduce two EEG techniques, one based on conventional monopolar electrodes and one based on a novel tripolar electrode, to record for the first time auditory brainstem responses (ABRs) from the scalp of unanesthetized, unrestrained big brown bats. Stimuli were frequency-modulated (FM) sweeps varying in sweep direction, sweep duration, and harmonic structure. As expected from previous invasive ABR recordings, upward-sweeping FM signals evoked larger amplitude responses (peak-to-trough amplitude in the latency range of 3–5 ms post-stimulus onset) than downward-sweeping FM signals. Scalp-recorded responses displayed amplitude-latency trading effects as expected from invasive recordings. These two findings validate the reliability of our noninvasive recording techniques. The feasibility of recording noninvasively in unanesthetized, unrestrained bats will energize future research uncovering electrophysiological signatures of perceptual and cognitive processing of biosonar signals in these animals, and allows for better comparison with ABR data from echolocating cetaceans, where invasive experiments are heavily restricted.

Urethane has little effect on nervous system and is often used in neuroscience studies. However, the effect of urethane in neurons is not thoroughly clear. In this study, we investigated changes in neuron responses to tones in inferior colliculus during urethane anesthesia. As urethane was metabolized, the best and characteristic frequencies did not obviously change, but the minimal threshold (MT) remained relatively stable or was elevated. The frequency tuning bandwidth at 60 dB SPL (BW 60dBSPL ) remained unchanged or decreased, and the average evoked spike of effective frequencies at 60 dB SPL (ES 60dBSPL ) gradually decreased. Although the average evoked spike of effective frequencies at a tone intensity of 20 dB SPL above MT (ES 20dBSPLaboveMT ) decreased, the frequency tuning bandwidth at a tone intensity of 20 dB SPL above MT (BW 20dBSPLaboveMT ) did not change. In addition, the changes in MT, ES 60dBSPL , BW 60dBSPL , and ES 20dBSPLaboveMT increased with the MT in pre-anesthesia awake state (MT pre−anesthesiaawake ). In some neurons, the MT was lower, BW 60dBSPL was broader, and ES 60dBSPL and ES 20dBSPLaboveMT were higher in urethane anesthesia state than in pre-anesthesia awake state. During anesthesia, the inhibitory effect of urethane reduced the ES 20dBSPLaboveMT , but did not change the MT, characteristic frequency, or BW 20dBSPLaboveMT . In the recording session with the strongest neuron response, the first spike latency did not decrease, and the spontaneous spike did not increase. Therefore, we conclude that urethane can reduce/not change the MT, increase the evoked spike, or broaden/not change the frequency tuning range, and eventually improve the response of auditory neurons to tone with or without “pushing down” the tonal receptive field in thresholding model. The improved effect increases with the MT pre−anesthesiaawake of neurons. The changes induced by the inhibitory and improved effects of urethane abide by similar regularities, but the change directions are contrary. The improvement mechanism may be likely due to the increase in the ratio of excitatory/inhibitory postsynaptic inputs to neurons.

Information flow in the sensory cortex has been described as a predominantly feedforward sequence with deep layers as the output structure. Although recurrent excitatory projections from layer 5 (L5) to superficial L2/3 have been identified by anatomical and physiological studies, their functional impact on sensory processing remains unclear. Here, we use layer-selective optogenetic manipulations in the primary auditory cortex to demonstrate that feedback inputs from L5 suppress the activity of superficial layers regardless of the arousal level, contrary to the prediction from their excitatory connectivity. This suppressive effect is predominantly mediated by translaminar circuitry through intratelencephalic neurons, with an additional contribution of subcortical projections by pyramidal tract neurons. Furthermore, L5 activation sharpened tone-evoked responses of superficial layers in both frequency and time domains, indicating its impact on cortical spectro-temporal integration. Together, our findings establish a translaminar inhibitory recurrence from deep layers that sharpens feature selectivity in superficial cortical layers.

Aging leads to degeneration of the peripheral and central auditory systems, hearing loss, and difficulty understanding sounds in noise. Aging is also associated with changes in susceptibility to or recovery from damaging noise exposures, although the effects of the interaction between acute noise exposure and age on the perception of sounds are not well studied. We tested these effects in the CBA/CaJ mouse model of age-related hearing loss using operant conditioning procedures before and after noise exposure and longitudinally measured changes in their sensitivity for detecting tones in quiet or noise backgrounds. Cochleae from a subset of the behaviorally tested mice were immunolabeled to examine organ of Corti damage relative to what is expected based on aging alone. Mice tested in both quiet and noise background conditions experienced worse behavioral sensitivity immediately after noise exposure, but mice exposed at older ages generally showed greater threshold shifts and reduced recovery over time. Surprisingly, day-to-day stability in thresholds was markedly higher for mice detecting signals in the presence of a noise masker compared with detection in quiet conditions. Cochlear analysis revealed decreases in the total number of outer hair cells (OHCs) and the number of ribbons per inner cell in high-frequency regions in aged, noise-exposed mice relative to aging alone. Our findings build on previous work showing interactions between age and noise exposure and add that background noise can increase the stability of behavioral hearing sensitivity after noise damage.