Auditory Research publications

Overexposure to loud noise is known to lead to deficits in auditory sensitivity and perception. We studied the effects of noise exposure on sensorimotor behaviors of larval (5-7 days post-fertilization) zebrafish (Danio rerio), particularly the auditory-evoked startle response and hearing sensitivity to acoustic startle stimuli. We observed a temporary 10-15 dB decrease in startle response threshold after 18 h of flat-spectrum noise exposure at 20 dB re·1 ms-2. Larval zebrafish also exhibited decreased habituation to startle-inducing stimuli following noise exposure. The noise-induced sensitization was not due to changes in absolute hearing thresholds, but was specific to the auditory-evoked escape responses. The observed noise-induced sensitization was disrupted by AMPA receptor blockade using DNQX, but not NMDA receptor blockade. Together, these experiments suggest a complex effect of noise exposure on the neural circuits mediating auditory-evoked behaviors in larval zebrafish.

Serine/threonine kinase 33 ( STK 33), a member of the calcium/calmodulin‐dependent kinase ( CAMK ), plays vital roles in a wide spectrum of cell processes. The present study was designed to investigate whether STK 33 expressed in the mammalian cochlea and, if so, what effect STK 33 exerted on aminoglycoside‐induced ototoxicity in House Ear Institute‐Organ of Corti 1 ( HEI ‐ OC 1) cells. Immunofluorescence staining and western blotting were performed to investigate STK 33 expression in cochlear hair cells ( HC s) and HEI ‐ OC 1 cells with or without gentamicin treatment. CCK 8, flow cytometry, immunofluorescence staining and western blotting were employed to detect the effects of STK 33 knockdown, and/or U0126, and/or N‐acetyl‐L‐cysteine ( NAC ) on the sensitivity to gentamicin‐induced ototoxicity in HEI ‐ OC 1 cells. We found that STK 33 was expressed in both mice cochlear HC s and HEI ‐ OC 1 cells, and the expression of STK 33 was significantly decreased in cochlear HC s and HEI ‐ OC 1 cells after gentamicin exposure. STK 33 knockdown resulted in an increase in the cleaved caspase‐3 and Bax expressions as well as cell apoptosis after gentamicin damage in HEI ‐ OC 1 cells. Mechanistic studies revealed that knockdown of STK 33 led to activated mitochondrial apoptosis pathway as well as augmented reactive oxygen species ( ROS ) accumulation after gentamicin damage. Moreover, STK 33 was involved in extracellular signal‐regulated kinase 1/2 pathway in primary culture of HC s and HEI ‐ OC 1 cells in response to gentamicin insult. The findings from this work indicate that STK 33 decreases the sensitivity to the apoptosis dependent on mitochondrial apoptotic pathway by regulating ROS generation after gentamicin treatment, which provides a new potential target for protection from the aminoglycoside‐induced ototoxicity.

Noise is the most common occupational and environmental hazard, and noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit. Although therapeutics that target the free-radical pathway have shown promise, none of these compounds is currently approved against NIHL by the United States Food and Drug Administration. The present study has demonstrated that tetrandrine (TET), a traditional Chinese medicinal alkaloid and the main chemical isolate of the Stephania tetrandra S. Moore herb, significantly attenuated NIHL in CBA/CaJ mice. TET is known to exert antihypertensive and antiarrhythmic effects through the blocking of calcium channels. Whole-cell patch-clamp recording from adult spiral ganglion neurons showed that TET blocked the transient Ca2+ current in a dose-dependent manner and the half-blocking concentration was 0.6 + 0.1 μM. Consistent with previous findings that modulations of calcium-based signaling pathways have both prophylactic and therapeutic effects against neural trauma, NIHL was significantly diminished by TET administration. Importantly, TET has a long-lasting protective effect after noise exposure (48 weeks) in comparison to 2 weeks after noise exposure. The otoprotective effects of TET were achieved mainly by preventing outer hair cell damage and synapse loss between inner hair cells and spiral ganglion neurons. Thus, our data indicate that TET has great potential in the prevention and treatment of NIHL.

The use of cisplatin (CDDP), the most common chemotherapy drug for head and neck cancer, is limited by its undesirable side effects, especially nephrotoxicity. We investigated ultrasound microbubbles (USMB) as a tool to increase the local intra-tumoral CDDP level while decreasing systemic CDDP cytotoxicity. We allowed CDDP to interact with human serum albumin and then sonicated the resulting CDDP‒albumin complex to generate CDDP-loaded MBs (CDDP-MBs). We then established a head-and-neck tumor-bearing mouse model by implanting FaDu-fLuc/GFP cells into severe combined immunodeficiency mice and used IVIS® bioluminescence imaging to determine the tumor xenograft formation and size. Twice weekly (until Day 33), we administered CDDP only, CDDP + MBs + US, CDDP-MBs, or CDDP-MBs + US intravenously by tail-vein injection. The US treatment was administered at the tumor site immediately after injection. The in vivo systemic distribution of CDDP indicated that the kidney was the most vulnerable organ, followed by the liver, and then the inner ear. However, CDDP uptake into the kidney and liver was significantly decreased in both the CDDP-MBs and CDDP-MBs + US groups, suggesting that MB binding significantly reduced the systemic toxicity of CDDP. The CDDP-MBs + US treatment reduced the tumor size as effectively as conventional CDDP-only chemotherapy. Therefore, the combination of CDDP-MBs with ultrasound is effective and significantly attenuates CDDP-associated nephrotoxicity, indicating a promising clinical potential for this approach.

Auditory sensory outer hair cells are thought to amplify sound-induced basilar membrane vibration through a feedback mechanism to enhance hearing sensitivity. For optimal amplification, the outer hair cell-generated force must act on the basilar membrane at an appropriate time at every cycle. However, the temporal relationship between the outer hair cell-driven reticular lamina vibration and the basilar membrane vibration remains unclear. By measuring sub-nanometer vibrations directly from outer hair cells using a custom-built heterodyne low-coherence interferometer, we demonstrate in living gerbil cochleae that the reticular lamina vibration occurs after, not before, the basilar membrane vibration. Both tone- and click-induced responses indicate that the reticular lamina and basilar membrane vibrate in opposite directions at the cochlear base and they oscillate in phase near the best-frequency location. Our results suggest that outer hair cells enhance hearing sensitivity through a global hydromechanical mechanism, rather than through a local mechanical feedback as commonly supposed.

The perceived pitch of iterated rippled noise (IRN) with negative gain (IRNn) is an octave lower than that of IRN with positive gain (IRNp). IRNp and IRNn have identical waveform envelopes (ENV), but differing stimulus waveform fine structure (TFS), which likely accounts for this perceived pitch difference. Here, we examine whether differences in the temporal pattern of phase-locked activity reflected in the human brainstem Frequency Following Response (FFR) elicited by IRNp and IRNn can account for the differences in perceived pitch for the two stimuli. FFRs using a single onset polarity were measured in 13 normal-hearing, adult listeners in response to IRNp and IRNn stimuli with 2 ms, and 4 ms delay. Autocorrelation functions (ACFs) and Fast Fourier Transforms (FFTs) were used to evaluate the dominant periodicity and spectral pattern (harmonic spacing) in the phase-locked FFR neural activity. For both delays, the harmonic spacing in the spectra corresponded more strongly with the perceived lowering of pitch from IRNp to IRNn, compared to the ACFs. These results suggest that the FFR elicited by a single polarity stimulus reflects phase-locking to both stimulus ENV and TFS. A post-hoc experiment evaluating the FFR phase-locked activity to ENV (FFRENV), and TFS (FFRTFS) elicited by IRNp and IRNn confirmed that only the phase-locked activity to the TFS, reflected in FFRTFS, showed differences in both spectra and ACF that closely matched the pitch difference between the two stimuli. The results of the post-hoc experiment suggests that pitch-relevant information is preserved in the temporal pattern of phase-locked activity and suggests that the differences in stimulus ENV and TFS driving the pitch percept of IRNp and IRNn are preserved in the brainstem neural response. The scalp recorded FFR may provide for a noninvasive analytic tool to evaluate the relative contributions of envelope and temporal fine-structure in the neural representation of complex sounds in humans.

Background: Current concepts suggest that impaired representation of information in cortical networks contributes to loss of consciousness under anaesthesia. We tested this idea in rat auditory cortex using information theory analysis of multiunit responses recorded under three anaesthetic agents with different molecular targets: isoflurane, propofol, and dexmedetomidine. We reasoned that if changes in the representation of sensory stimuli are causal for loss of consciousness, they should occur regardless of the specific anaesthetic agent. Methods: Spiking responses were recorded with chronically implanted microwire arrays in response to acoustic stimuli incorporating varied temporal and spectral dynamics. Experiments consisted of four drug conditions: awake (pre-drug), sedation (i.e. intact righting reflex), loss of consciousness (a dose just sufficient to cause loss of righting reflex), and recovery. Measures of firing rate, spike timing, and mutual information were analysed as a function of drug condition. Results: All three drugs decreased spontaneous and evoked spiking activity and modulated spike timing. However, changes in mutual information were inconsistent with altered stimulus representation being causal for loss of consciousness. First, direction of change in mutual information was agent-specific, increasing under dexmedetomidine and decreasing under isoflurane and propofol. Second, mutual information did not decrease at the transition between sedation and LOC for any agent. Changes in mutual information under anaesthesia correlated strongly with changes in precision and reliability of spike timing, consistent with the importance of temporal stimulus features in driving auditory cortical activity. Conclusions: The primary sensory cortex is not the locus for changes in representation of information causal for loss of consciousness under anaesthesia.

To characterize the patterns of ABR waves in tree shrews, we must understand the hearing sensitivity and auditory function of healthy adult tree shrews. Fifteen tree shrews (30 ears) were stimulated with clicks and tone-pips at 11 different frequencies from 1 to 60 kHz. The ABR waves were recorded and analyzed. The ABR consisted of five to seven positive waves in the first 10 ms after a click stimulus, and the average hearing threshold of component III was 27.86 ± 3.78 dB SPL. Wave III was the largest and most clear. The ABR threshold was related to the tone-pip sitmulus by a "U" shaped curve. The sensitive frequency was approximately 8 kHz in tree shrews. The latencies systematically decreased with increasing stimulus frequencies. The ABR amplitudes of wave III increased as the sound pressure level increased. All of these results provide an empirical basis for future studies of hearing diseases in tree shrews.

Everyday speech perception is challenged by external acoustic interferences that hinder verbal communication. Here, we directly compared how different levels of the auditory system (brainstem vs. cortex) code speech and how their neural representations are affected by two acoustic stressors: noise and reverberation. We recorded multichannel (64 ch) brainstem frequency-following responses (FFRs) and cortical event-related potentials (ERPs) simultaneously in normal hearing individuals to speech sounds presented in mild and moderate levels of noise and reverb. We matched signal-to-noise and direct-to-reverberant ratios to equate the severity between classes of interference. Electrode recordings were parsed into source waveforms to assess the relative contribution of region-specific brain areas [i.e., brainstem (BS), primary auditory cortex (A1), inferior frontal gyrus (IFG)]. Results showed that reverberation was less detrimental to (and in some cases facilitated) the neural encoding of speech compared to additive noise. Inter-regional correlations revealed associations between BS and A1 responses, suggesting subcortical speech representations influence higher auditory-cortical areas. Functional connectivity analyses further showed that directed signaling toward A1 in both feedforward cortico-collicular (BS→A1) and feedback cortico-cortical (IFG→A1) pathways were strong predictors of degraded speech perception and differentiated "good" vs. "poor" perceivers. Our findings demonstrate a functional interplay within the brain's speech network that depends on the form and severity of acoustic interference. We infer that in addition to the quality of neural representations within individual brain regions, listeners' success at the "cocktail party" is modulated based on how information is transferred among subcortical and cortical hubs of the auditory-linguistic network.

When a wideband harmonic tone complex (wHTC) is passed through a noise vocoder, the resulting sounds can have spectra with large peak-to-valley ratios, but little or no periodicity strength in the autocorrelation functions. We measured judgments of pitch strength for normal-hearing listeners for noise-vocoded wideband harmonic tone complexes (NV-wHTCs) relative to standard and anchor stimuli. The standard was a 1-channel NV-wHTC and the anchor was either the unprocessed wHTC or an infinitely-iterated rippled noise (IIRN). Although there is variability among individuals, the magnitude judgment functions obtained with the IIRN anchor suggest different listening strategies among individuals. In order to gain some insight into possible listening strategies, test stimuli were analyzed at the output of an auditory filterbank model based on gammatone filters. The weak periodicity strengths of NV-wHTCs observed in the stimulus autocorrelation functions are augmented at the output of the gammatone filterbank model. Six analytical models of pitch strength were evaluated based on summary correlograms obtained from the gammatone tone filterbank. The results of the filterbank analysis suggest that, contrary to the weak or absent periodicity strengths in the stimulus domain, temporal cues contribute to pitch strength perception of noise-vocoded harmonic stimuli such that listeners' judgments of pitch strength reflect a nonlinear, weighted average of the temporal information between the fine structure and the envelope.

Sounds can arise from the environment and also predictably from many of our own movements, such as vocalizing, walking, or playing music. The capacity to anticipate these movement-related (reafferent) sounds and distinguish them from environmental sounds is essential for normal hearing1,2, but the neural circuits that learn to anticipate the often arbitrary and changeable sounds that result from our movements remain largely unknown. Here we developed an acoustic virtual reality (aVR) system in which a mouse learned to associate a novel sound with its locomotor movements, allowing us to identify the neural circuit mechanisms that learn to suppress reafferent sounds and to probe the behavioural consequences of this predictable sensorimotor experience. We found that aVR experience gradually and selectively suppressed auditory cortical responses to the reafferent frequency, in part by strengthening motor cortical activation of auditory cortical inhibitory neurons that respond to the reafferent tone. This plasticity is behaviourally adaptive, as aVR-experienced mice showed an enhanced ability to detect non-reafferent tones during movement. Together, these findings describe a dynamic sensory filter that involves motor cortical inputs to the auditory cortex that can be shaped by experience to selectively suppress the predictable acoustic consequences of movement.

Plasticity of thalamocortical (TC) synapses is robust during early development and becomes limited in the adult brain. We previously reported that a short duration of deafening strengthens TC synapses in the primary visual cortex (V1) of adult mice. Here, we demonstrate that deafening restores NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of TC synapses onto principal neurons in V1 layer 4 (L4), which is accompanied by an increase in NMDAR function. In contrast, deafening did not recover long-term depression (LTD) at TC synapses. Potentiation of TC synapses by deafening is absent in parvalbumin-positive (PV+) interneurons, resulting in an increase in feedforward excitation to inhibition (E/I) ratio. Furthermore, we found that a brief duration of deafening adult mice recovers rapid ocular dominance plasticity (ODP) mainly by accelerating potentiation of the open-eye responses. Our results suggest that cross-modal sensory deprivation promotes adult cortical plasticity by specifically recovering TC-LTP and increasing the E/I ratio.

The ability to intentionally control attention based on task goals and stimulus properties is critical to communication in many environments. However, when a person has a damaged auditory system, such as with hearing loss, perceptual organization may also be impaired, making it more difficult to direct attention to different auditory objects in the environment. Here we examined the behavioral cost associated with maintaining and switching attention in people with hearing loss compared to the normal hearing population, and found a cost associated with attending to a target stream in a multi-talker environment that cannot solely be attributed to audibility issues.

Objectives: The purpose of this study was to evaluate the extent to which infants, school-age children, and adults benefit from a target/masker sex mismatch in the context of speech detection or recognition in a background of 2 competing talkers. It was hypothesized that the ability to benefit from a target/masker sex mismatch develops between infancy and the early school-age years, as children gain listening experience in multi-talker environments. Design: Listeners were infants (7 to 13 months), children (5 to 10 years), and adults (18 to 33 years) with normal hearing. A series of five experiments compared speech detection or recognition in continuous two-talker speech across target/masker conditions that were sex matched or sex mismatched. In experiments 1 and 2, an observer-based, single-interval procedure was used to estimate speech detection thresholds for a spondaic word in a two-talker speech masker. In experiments 3 and 4, speech recognition thresholds were estimated in continuous two-talker speech using a four-alternative, forced-choice procedure. In experiment 5, speech reception thresholds (SRTs) were estimated for adults using the forced-choice recognition procedure after ideal time-frequency segregation processing was applied to the stimuli. Results: Speech detection thresholds for adults tested in experiments 1 and 2 were significantly higher when the target word and speech masker were matched in sex than when they were mismatched, but thresholds for infants were similar across sex-matched and sex-mismatched conditions. Results for experiments 3 and 4 showed that school-age children and adults benefit from a target/masker sex mismatch for a forced-choice word recognition task. Children, however, obtained greater benefit than adults in 1 condition, perhaps due to greater susceptibility to masking overall. In experiment 5, adults had substantial threshold reductions and more uniform performance across the 4 conditions evaluated in experiments 3 and 4 after the application of ideal time-frequency segregation to the stimuli. Conclusions: The pattern of results observed across experiments suggests that the ability to take advantage of differences in vocal characteristics typically found between speech produced by male and female talkers develops between infancy and the school-age years. Considerable child–adult differences in susceptibility to speech-in-speech masking were observed for school-age children as old as 11 years of age in both sex-matched and sex-mismatched conditions.

Objective: The binaural-hearing system interaurally compares inputs, which underlies the ability to localize sound sources and to better understand speech in complex acoustic environments. Cochlear implants (CIs) are provided in both ears to increase binaural-hearing benefits; however, bilateral CI users continue to struggle with understanding speech in the presence of interfering sounds and do not achieve the same level of spatial release from masking (SRM) as normal-hearing listeners. One reason for diminished SRM in CI users could be that the electrode arrays are inserted at different depths in each ear, which would cause an interaural frequency mismatch. Because interaural frequency mismatch diminishes the salience of interaural differences for relatively simple stimuli, it may also diminish binaural benefits for spectral-temporally complex stimuli like speech. This study evaluated the effect of simulated frequency-to-place mismatch on speech understanding and SRM. Design: Eleven normal-hearing listeners were tested on a speech understanding task. There was a female target talker who spoke five-word sentences from a closed set of words. There were two interfering male talkers who spoke unrelated sentences. Nonindividualized head-related transfer functions were used to simulate a virtual auditory space. The target was presented from the front (0°), and the interfering speech was either presented from the front (colocated) or from 90° to the right (spatially separated). Stimuli were then processed by an eight-channel vocoder with tonal carriers to simulate aspects of listening through a CI. Frequency-to-place mismatch (“shift”) was introduced by increasing the center frequency of the synthesis filters compared with the corresponding analysis filters. Speech understanding was measured for different shifts (0, 3, 4.5, and 6 mm) and target-to-masker ratios (TMRs: +10 to −10 dB). SRM was calculated as the difference in the percentage of correct words for the colocated and separated conditions. Two types of shifts were tested: (1) bilateral shifts that had the same frequency-to-place mismatch in both ears, but no interaural frequency mismatch, and (2) unilateral shifts that produced an interaural frequency mismatch. Results: For the bilateral shift conditions, speech understanding decreased with increasing shift and with decreasing TMR, for both colocated and separate conditions. There was, however, no interaction between shift and spatial configuration; in other words, SRM was not affected by shift. For the unilateral shift conditions, speech understanding decreased with increasing interaural mismatch and with decreasing TMR for both the colocated and spatially separated conditions. Critically, there was a significant interaction between the amount of shift and spatial configuration; in other words, SRM decreased for increasing interaural mismatch. Conclusions: A frequency-to-place mismatch in one or both ears resulted in decreased speech understanding. SRM, however, was only affected in conditions with unilateral shifts and interaural frequency mismatch. Therefore, matching frequency information between the ears provides listeners with larger binaural-hearing benefits, for example, improved speech understanding in the presence of interfering talkers. A clinical procedure to reduce interaural frequency mismatch when programming bilateral CIs may improve benefits in speech segregation that are due to binaural-hearing abilities.

Auditory nerve single-unit recordings were obtained from two groups of young barn owls (age, between posthatching days 11 and 86) in terminal experiments under two different anesthetic regimes: ketamine (6-11 mg/kg) plus xylazine (∼2 mg/kg); or isoflurane (1-1.5%) in oxygen, delivered via artificial respiration. In a second series of minimally invasive experiments, auditory brainstem responses (ABRs) were recorded in the same four adult barn owls (Tyto alba; age, between 5 and 32 months) under three different anesthetic protocols: ketamine (10 mg/kg) plus xylazine (3 mg/kg), isoflurane (1-1.5%), and sevoflurane (2-3%) in carbogen. Finally, the ABR measurements on adult owls were repeated in terminal experiments including more invasive procedures such as artificial respiration and higher isoflurane dosage. The main finding was a significant deterioration of auditory sensitivity in barn owls under gas anesthesia, at the level of the auditory nerve (i.e., a very peripheral level of the auditory system). The effect was drastic in the young animals that experienced threshold elevations in auditory nerve single-unit responses of ≥20 dB. ABR thresholds assessed repeatedly in experiments on adult owls were also significantly higher under isoflurane and sevoflurane, on average by 7 and 15 dB, compared with ketamine/xylazine. This difference already occurred with minimal dosages and was reversibly enlarged with increased isoflurane concentration. Finally, there was evidence for confounding detrimental effects associated with artificial respiration over many hours, which suggested oxygen toxicity.

Pairing vagus nerve stimulation (VNS) with movements or sounds can direct robust plasticity in motor or auditory cortex, respectively. The degree of map plasticity is influenced by the intensity and pulse width of VNS, number of VNS-event pairings, and the interval between each pairing. It is likely that these parameters interact, influencing optimal implementation of VNS pairing protocols. We varied VNS intensity, number of stimulations, and inter-stimulation interval (ISI) to test for interactions among these parameters. Rats were implanted with a vagus nerve stimulating cuff and randomly assigned to one of three treatment groups to receive 20 days of VNS paired with a 9-kHz tone: (1) Fast VNS: 50 daily pairings of 400-µA VNS with a 30-s ISI; (2) Dispersed VNS: 50 daily pairings of 400-µA VNS with a 180-s ISI; and (3) Standard VNS: 300 daily pairings of 800-µA VNS with a 30-s ISI. Following 20 days of VNS-tone pairing, multi-unit recordings were conducted in primary auditory cortex (A1) and receptive field properties were analyzed. Increasing ISI (Dispersed VNS) did not lead to an enhancement of cortical plasticity. Reducing the current intensity and number of stimulations (Fast VNS) resulted in robust cortical plasticity, using 6 times fewer VNS pairings than the Standard protocol. These findings reveal an interaction between current intensity, stimulation number, and ISI and identify a novel VNS paradigm that is substantially more efficient than the previous standard paradigm.

Hearing and balance depend upon the precise morphogenesis and mechanosensory function of stereocilia, the specialized structures on the apical surface of sensory hair cells in the inner ear. Previous studies of Grxcr1 mutant mice indicated a critical role for this gene in control of stereocilia dimensions during development. In this study, we analyzed expression of the paralog Grxcr2 in the mouse and evaluated auditory and vestibular function of strains carrying targeted mutations of the gene. Peak expression of Grxcr2 occurs during early postnatal development of the inner ear and GRXCR2 is localized to stereocilia in both the cochlea and in vestibular organs. Homozygous Grxcr2 deletion mutants exhibit significant hearing loss by 3 weeks of age that is associated with developmental defects in stereocilia bundle orientation and organization. Despite these bundle defects, the mechanotransduction apparatus assembles in relatively normal fashion as determined by whole cell electrophysiological evaluation and FM1-43 uptake. Although Grxcr2 mutants do not exhibit overt vestibular dysfunction, evaluation of vestibular evoked potentials revealed subtle defects of the mutants in response to linear accelerations. In addition, reduced Grxcr2 expression in a hypomorphic mutant strain is associated with progressive hearing loss and bundle defects. The stereocilia localization of GRXCR2, together with the bundle pathologies observed in the mutants, indicate that GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity.

Nocturnal insects have evolved ultrasound-sensitive hearing in response to predation pressures from echolocating insectivorous bats. Flying tympanate moths take various evasive actions when they detect bat cries, including turning away, performing a steering/zigzagging flight and ceasing flight. In general, infrequent ultrasonic pulses with low sound intensities that are emitted by distant bats evoke slight turns, whereas frequent and loud ultrasonic pulses of nearby bats evoke erratic or rapid unpredictable changes in the flight path of a moth. Flight cessation, which is a freezing response that causes the moth to passively dive (drop) to the ground, is considered the ultimate last-ditch evasive behaviour against approaching bats where there is a high predation threat. Here, we found that the crambid moth Nomophila nearctica never performed passive dives in response to frequent and loud ultrasonic pulses of >60 dB sound pressure level (SPL) that simulated the attacking echolocation call sequence of the predominant sympatric insectivorous bat Eptesicus fuscus, but rather turned away or flew erratically, regardless of the temporal structure of the stimulus. Consequently, N. nearctica is likely to survive predation by bats by taking early evasive action even when it detects the echolocation calls of sympatric bats hunting other insects at a distance. Since aerially hawking bats can track and catch erratically flying moths after targeting their prey, this early escape strategy may be common among night-flying tympanate insects.

Sensory processing, and auditory processing in particular, is altered in individuals with neurodevelopmental disorders such as autism spectrum disorders (ASDs). The typical maturation of the auditory system is perturbed in these individuals during early development, which may underlie altered auditory reactivity that persists in later life. Of the many genes that regulate the auditory system development, loss-of-function mutations in the CNTNAP2 gene are strongly associated with language processing deficits and ASD. Therefore, using a novel Cntnap2 knock-out rat model, we tested the impact of Cntnap2 loss on auditory processing, filtering, and reactivity throughout development and young adulthood in male and female animals. Although hearing thresholds were not altered in Cntnap2 knock-out animals, we found a reduction in response amplitudes and a delay in response latency of the auditory brainstem response (ABR) in juvenile Cntnap2 knock-out rats compared with age-matched controls. Amplitudes and latency of the ABR largely normalized by adulthood, indicating a delayed maturation of auditory processing pathways in Cntnap2 knock-out rats. Despite the reduced ABR amplitudes, adolescent Cntnap2 knock-out animals displayed increased startle reactivity accompanied by disruptions in sensory filtering and sensorimotor gating across various conditions, most of which persisted in adulthood. All of these observations show striking parallels to disruptions reported in ASD. Our results also imply that developmental disruptions of sensory signal processing are associated with persistent changes in neural circuitries responsible for implicit auditory evoked behavior, emphasizing the need for interventions that target sensory processing disruptions early during development in ASD. SIGNIFICANCE STATEMENT This is the first study of brainstem auditory processing in a novel knock-out rat model with very high construct and face validity for autism spectrum disorders. Electrophysiological and behavioral measures of implicit auditory-evoked responses were systematically taken across developmental stages. Auditory processing, filtering, and reactivity disruptions show striking similarities to observations in autism. We also show for the first time that, whereas auditory brainstem responses normalize by adulthood, disruptions in brainstem-mediated auditory-evoked behavior persist. This indicates that early developmental perturbations in sensory processing can cause permanent maladaptive changes in circuitries responsible for auditory reactivity, underlining the importance for interventions early during development aiming at normalizing sensory processing.