Auditory Neurophysiology publications

Time-varying pitch is a vital cue for human speech perception. Neural processing of time-varying pitch has been extensively assayed using scalp-recorded frequency-following responses (FFRs), an electrophysiological signal thought to reflect integrated phase-locked neural ensemble activity from subcortical auditory areas. Emerging evidence increasingly points to a putative contribution of auditory cortical ensembles to the scalp-recorded FFRs. However, the properties of cortical FFRs and precise characterization of laminar sources are still unclear. Here we used direct human intracortical recordings as well as extracranial and intracranial recordings from macaques and guinea pigs to characterize the properties of cortical sources of FFRs to time-varying pitch patterns. We found robust FFRs in the auditory cortex across all species. We leveraged representational similarity analysis as a translational bridge to characterize similarities between the human and animal models. Laminar recordings in animal models showed FFRs emerging primarily from the thalamorecipient layers of the auditory cortex. FFRs arising from these cortical sources significantly contributed to the scalp-recorded FFRs via volume conduction. Our research paves the way for a wide array of studies to investigate the role of cortical FFRs in auditory perception and plasticity.

The binaural interaction component (BIC) is a sound-evoked electrophysiological signature of binaural processing in the auditory brainstem that has received attention as a potential biomarker for spatial hearing deficits. Yet the number of trials necessary to evoke the BIC, or its measurability, seems to vary across species: while it is easily measured in small rodents, it has proven to be highly variable and less reliably measured in humans. This has hindered its potential use as a diagnostic tool. Further measurements of the BIC across a wide range of species could help us better understand its origin and the possible reasons for the variation in its measurability. Statistical analysis on the function relating BIC DN1 amplitude and the interaural time difference has been performed in only a few small rodent species, thus it remains to be shown how the results apply to more taxonomically diverse mammals, and those with larger heads. To fill this gap, we measured BICs in rhesus macaque. We show the overall behavior of the BIC is the same as in smaller rodents, suggesting that the brainstem circuit responsible for the BIC is conserved across a wider range of mammals. We suggest that differences in measurability are likely because of differences in head size.

Bilateral cochlear implants (BI-CIs) or a CI for single-sided deafness (SSD-CI; one normally functioning acoustic ear) can partially restore spatial-hearing abilities, including sound localization and speech understanding in noise. For these populations, however, interaural place-of-stimulation mismatch can occur and thus diminish binaural sensitivity that relies on interaurally frequency-matched neurons. This study examined whether plasticity—reorganization of central neural pathways over time—can compensate for peripheral interaural place mismatch. We hypothesized differential plasticity across two systems: none for binaural processing but adaptation for pitch perception toward frequencies delivered by the specific electrodes. Interaural place mismatch was evaluated in 19 BI-CI and 23 SSD-CI human subjects (both sexes) using binaural processing (interaural-time-difference discrimination with simultaneous bilateral stimulation), pitch perception (pitch ranking for single electrodes or acoustic tones with sequential bilateral stimulation), and physical electrode-location estimates from computed-tomography (CT) scans. On average, CT scans revealed relatively little BI-CI interaural place mismatch (26° insertion-angle mismatch) but a relatively large SSD-CI mismatch, particularly at low frequencies (166° for an electrode tuned to 300 Hz, decreasing to 14° at 7000 Hz). For BI-CI subjects, the three metrics were in agreement because there was little mismatch. For SSD-CI subjects, binaural and CT measurements were in agreement, suggesting little binaural-system plasticity induced by mismatch. The pitch measurements disagreed with binaural and CT measurements, suggesting place-pitch plasticity or a procedural bias. These results suggest that reducing interaural place mismatch and potentially improving binaural processing by reprogramming the CI frequency allocation would be better done using CT-scan than pitch information. SIGNIFICANCE STATEMENT Electrode-array placement for cochlear implants (bionic prostheses that partially restore hearing) does not explicitly align neural representations of frequency information. The resulting interaural place-of-stimulation mismatch can diminish spatial-hearing abilities. In this study, adults with two cochlear implants showed reasonable interaural alignment, whereas those with one cochlear implant but normal hearing in the other ear often showed mismatch. In cases of mismatch, binaural sensitivity was best when the same cochlear locations were stimulated in both ears, suggesting that binaural brainstem pathways do not experience plasticity to compensate for mismatch. In contrast, interaurally pitch-matched electrodes deviated from cochlear-location estimates and did not optimize binaural sensitivity. Clinical correction of interaural place mismatch using binaural or computed-tomography (but not pitch) information may improve spatial-hearing benefits.

We reconstructed the intrinsic axons of 32 neurons in the guinea pig inferior colliculus (IC) following juxtacellular labeling. Biocytin was injected into cells in vivo , after first analyzing physiological response properties. Based on axonal morphology there were two classes of neuron: (1) laminar cells (14/32, 44%) with an intrinsic axon and flattened dendrites confined to a single fibrodendritic lamina and (2) translaminar cells (18/32, 56%) with axons that terminated in two or more laminae in the central nucleus (ICc) or the surrounding cortex. There was also one small, low-frequency cell with bushy-like dendrites that was very sensitive to interaural timing differences. The translaminar cells were subdivided into three groups of cells with: (a) stellate dendrites that crossed at least two laminae (8/32, 25%); (b) flattened dendrites confined to one lamina and that had mainly en passant axonal swellings (7/32, 22%) and (c) short, flattened dendrites and axons with distinctive clusters of large terminal boutons in the ICc (3/32, 9%). These terminal clusters were similar to those of cortical basket cells. The 14 laminar cells all had sustained responses apart from one offset response. Almost half the non-basket type translaminar cells (7/15) had onset responses while the others had sustained responses. The basket cells were the only ones to have short-latency (7–9 ms), chopper responses and this distinctive temporal response should allow them to be studied in more detail in future. This is the first description of basket cells in the auditory brainstem, but more work is required to confirm their neurotransmitter and precise post-synaptic targets.

When multiple sound sources are present at the same time, auditory perception is often challenged with disentangling the resulting mixture and focusing attention on the target source. It has been repeatedly demonstrated that background (distractor) sound sources are easier to ignore when their spectrotemporal signature is predictable. Prior evidence suggests that this ability to exploit predictability for foreground-background segregation degrades with age. On a theoretical level, this has been related with an impairment in elderly adults’ capabilities to detect certain types of sensory deviance in unattended sound sequences. Yet the link between those two capacities, deviance detection and predictability-based sound source segregation, has not been empirically demonstrated. Here we report on a combined behavioral-EEG study investigating the ability of elderly listeners (60–75 years of age) to use predictability as a cue for sound source segregation, as well as their sensory deviance detection capacities. Listeners performed a detection task on a target stream that can only be solved when a concurrent distractor stream is successfully ignored. We contrast two conditions whose distractor streams differ in their predictability. The ability to benefit from predictability was operationalized as performance difference between the two conditions. Results show that elderly listeners can use predictability for sound source segregation at group level, yet with a high degree of inter-individual variation in this ability. In a further, passive-listening control condition, we measured correlates of deviance detection in the event-related brain potential (ERP) elicited by occasional deviations from the same spectrotemporal pattern as used for the predictable distractor sequence during the behavioral task. ERP results confirmed neural signatures of deviance detection in terms of mismatch negativity (MMN) at group level. Correlation analyses at single-subject level provide no evidence for the hypothesis that deviance detection ability (measured by MMN amplitude) is related to the ability to benefit from predictability for sound source segregation. These results are discussed in the frameworks of sensory deviance detection and predictive coding.

Spiral ganglion neurons (SGNs) can be injured by a wide variety of insults. However, there still is a lack of degeneration models to specifically damage the SGNs without disturbing other types of cells in the inner ear. This study aims to generate an SGN-specific damage model using the Cre-LoxP transgenic mouse strains. The Cre-inducible diphtheria toxin receptor ( iDTR +/+ ) knock-in mouse strain was crossed with a mouse strain with Cre activity specific to neurons ( Nefl CreER/CreER ). Expression of the Cre-recombinase activity was evaluated using the reporter mouse strain Ai9 at pre-hearing, hearing onset, and post-hearing stages. Accordingly, heterozygous Nefl CreER/ + ;iDTR +/– mice were treated with tamoxifen on postnatal days 1–5 (P1–5), followed by diphtheria toxin (DT) or vehicle injection on P7, P14, and P21 to evaluate the SGN loss. Robust tamoxifen-induced Cre-mediated Ai9 tdTomato fluorescence was observed in the SGN area of heterozygous Nefl CreER/ + ;Ai9 +/– mice treated with tamoxifen, whereas vehicle-treated heterozygote mice did not show tdTomato fluorescence. Compared to vehicle-treated Nefl CreER/ + ;iDTR +/– mice, DT-treated Nefl CreER/ + ;iDTR +/– mice showed significant auditory brainstem response (ABR) threshold shifts and SGN cell loss. Hair cell count and functional study did not show significant changes. These results demonstrate that the Nefl CreER/CreER mouse strain exhibits inducible SGN-specific Cre activity in the inner ear, which may serve as a valuable SGN damage model for regeneration research of the inner ear.

Several studies have shown that type IV fibrocytes, located in the spiral ligament, degenerate first after noise exposure. Interestingly, this is the region where Coch expression is most abundant. As it is suggested that cochlin plays a role in our innate immune system, our goal is to investigate hearing thresholds and inner ear inflammation after noise exposure in Coch knockout (Coch−/−) mice compared to Coch wildtype (Coch+/+) mice. Animals were randomly allocated to a noise exposure group and a control group. Vestibular and auditory testing was performed at 48 h and one week after noise exposure. Whole mount staining and cryosectioning of the cochlea was performed in order to investigate hair cells, spiral ganglion neurons, inner ear inflammation, Coch expression and fibrocyte degeneration. Hearing assessment revealed that Coch+/+ mice had significantly larger threshold shifts than Coch−/− mice after noise exposure. We were unable to identify any differences in hair cells, neurons, fibrocytes and influx of macrophages in the inner ear between both groups. Interestingly, Coch expression was significantly lower in the group exposed to noise. Our results indicate that the absence of Coch has a protective influence on hearing thresholds after noise exposure, but this is not related to reduced inner ear inflammation in the knockout.

A topographic map of auditory space is a feature found in the superior colliculus (SC) of many species, including CBA/CaJ mice. In this genetic background, high-frequency monaural spectral cues and interaural level differences are used to generate spatial receptive fields (RFs) that form a topographic map along the azimuth. Unfortunately, C57BL/6 mice, a strain widely used for transgenic manipulation, display age-related hearing loss (AHL) due to an inbred mutation in the Cadherin 23 gene ( Cdh23) that affects hair cell mechanotransduction. To overcome this problem, researchers have used young C57BL/6 mice in their studies, as they have been shown to have normal hearing thresholds. However, important details of the auditory response characteristics of the SC such as spectral responses and spatial localization, have not been characterized in young C57BL/6 mice. Here we show that 2-4-month C57BL/6 mice lack neurons with frontal auditory RFs and therefore lack a topographic representation of auditory space in the SC. Analysis of the spectrotemporal receptive fields (STRFs) of the SC auditory neurons shows that C57BL/6 mouse SC neurons lack the ability to detect the high-frequency (>40kHz) spectral cues that are needed to compute frontal RFs. We also show that crossing C57BL/6 mice with CBA/CaJ mice or introducing one copy of the wild-type Cdh23 to C57BL/6 mice rescues the high-frequency hearing deficit and improves the topographic map of auditory space. Taken together, these results demonstrate the importance of high-frequency hearing in computing a topographic map of auditory space. Significance Statement Despite the strain’s age-dependent hearing loss, C57BL/6 mice are widely used in auditory studies because of the development of transgenic reporter and Cre lines in this genetic background. Here we examined the topographic map of auditory space and spectrotemporal properties of neurons in the SC of C57BL/6 mice. We found an early-onset high-frequency hearing deficit that results in the loss of SC neurons with frontal RFs and, consequently, an absence of a topographic map of auditory space. These findings stress the importance of high-frequency hearing in generating spatially restricted receptive fields and serve as a caution to researchers that doing auditory-related research using the C57BL/6 genetic background may not be representative of true wild-type mice.

The auditory cortex (AC) sends long-range projections to virtually all subcortical auditory structures. One of the largest and most complex of these—the projection between AC and inferior colliculus (IC; the corticocollicular pathway)—originates from layer 5 and deep layer 6. Though previous work has shown that these two corticocollicular projection systems have different physiological properties and network connectivities, their functional organization is poorly understood. Here, using a combination of traditional and viral tracers combined with in vivo imaging in both sexes of the mouse, we observed that layer 5 and layer 6 corticocollicular neurons differ in their areas of origin and termination patterns. Layer 5 corticocollicular neurons are concentrated in primary AC, while layer 6 corticocollicular neurons emanate from broad auditory and limbic areas in the temporal cortex. In addition, layer 5 sends dense projections of both small and large (>1 µm 2 area) terminals to all regions of nonlemniscal IC, while layer 6 sends small terminals to the most superficial 50–100 µm of the IC. These findings suggest that layer 5 and 6 corticocollicular projections are optimized to play distinct roles in corticofugal modulation. Layer 5 neurons provide strong, rapid, and unimodal feedback to the nonlemniscal IC, while layer 6 neurons provide heteromodal and limbic modulation diffusely to the nonlemniscal IC. Such organizational diversity in the corticocollicular pathway may help to explain the heterogeneous effects of corticocollicular manipulations and, given similar diversity in corticothalamic pathways, may be a general principle in top-down modulation. SIGNIFICANCE STATEMENT We demonstrate that a major descending system in the brain is actually two systems. That is, the auditory corticocollicular projection, which exerts considerable influence over the midbrain, comprises two projections: one from layer 5 and the other from layer 6. The layer 6 projection is diffusely organized, receives multisensory inputs, and ends in small terminals; while the layer 5 projection is derived from a circumscribed auditory cortical area and ends in large terminals. These data suggest that the varied effects of cortical manipulations on the midbrain may be related to effects on two disparate systems. These findings have broader implications because other descending systems derive from two layers. Therefore, a duplex organization may be a common motif in descending control.

Age-related hidden hearing loss is often described as a cochlear synaptopathy that results from a progressive degeneration of the inner hair cell (IHC) ribbon synapses. The functional changes occurring at these synapses during aging are not fully understood. Here, we characterized this aging process in IHCs of C57BL/6J mice, a strain which is known to carry a cadherin-23 mutation and experiences early hearing loss with age. These mice, while displaying a large increase in auditory brainstem thresholds due to 50% loss of IHC synaptic ribbons at middle age (postnatal day 365), paradoxically showed enhanced acoustic startle reflex suggesting a hyperacusis-like response. The auditory defect was associated with a large shrinkage of the IHCs' cell body and a drastic enlargement of their remaining presynaptic ribbons which were facing enlarged postsynaptic AMPAR clusters. Presynaptic Ca 2+ microdomains and the capacity of IHCs to sustain high rates of exocytosis were largely increased, while on the contrary the expression of the fast-repolarizing BK channels, known to negatively control transmitter release, was decreased. This age-related synaptic plasticity in IHCs suggested a functional potentiation of synaptic transmission at the surviving synapses, a process that could partially compensate the decrease in synapse number and underlie hyperacusis.

Vestibular evoked myogenic potentials (VEMP) have been used to assess otolith function in clinics worldwide. However, there are accumulating evidence suggesting that the clinically used sound stimuli activate not only the otolith afferents, but also the canal afferents, indicating canal contributions to the VEMPs. To better understand the neural mechanisms underlying the VEMPs and develop discriminative VEMP protocols, we further examined sound-evoked responses of the vestibular nucleus neurons and the abducens neurons, which have the interneurons and motoneurons of the vestibulo-ocular reflex (VOR) pathways. Air-conducted clicks (50–80 dB SL re ABR threshold, 0.1 ms duration) or tone bursts (60–80 dB SL, 125–4,000 Hz, 8 ms plateau, 1 ms rise/fall) were delivered to the ears of Sprague-Dawley or Long-Evans rats. Among 425 vestibular nucleus neurons recorded in anesthetized rats and 18 abducens neurons recorded in awake rats, sound activated 35.9% of the vestibular neurons that increased discharge rates for ipsilateral head rotation (Type I neuron), 15.7% of the vestibular neurons that increased discharge rates for contralateral head rotation (Type II neuron), 57.2% of the vestibular neurons that did not change discharge rates during head rotation (non-canal neuron), and 38.9% of the abducens neurons. Sound sensitive vestibular nucleus neurons and abducens neurons exhibited characteristic tuning curves that reflected convergence of canal and otolith inputs in the VOR pathways. Tone bursts also evoked well-defined eye movements that increased with tone intensity and duration and exhibited peak frequency of ∼1,500 Hz. For the left eye, tone bursts evoked upward/rightward eye movements for ipsilateral stimulation, and downward/leftward eye movements for contralateral stimulation. These results demonstrate that sound stimulation results in activation of the canal and otolith VOR pathways that can be measured by eye tracking devices to develop discriminative tests of vestibular function in animal models and in humans.

Background Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out ( Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. Methods To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. Results Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. Conclusions Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs.

Serotonin transporter (SERT) modulates the level of 5-HT and significantly affects the activity of serotonergic neurons in the central nervous system. The manipulation of SERT has lasting neurobiological and behavioral consequences, including developmental dysfunction, depression, and anxiety. Auditory disorders have been widely reported as the adverse events of these mental diseases. It is unclear how SERT impacts neuronal connections/interactions and what mechanism(s) may elicit the disruption of normal neural network functions in auditory cortex. In the present study, we report on the neuronal morphology and function of auditory cortex in SERT knockout (KO) mice. We show that the dendritic length of the fourth layer (L-IV) pyramidal neurons and the second-to-third layer (L-II/III) interneurons were reduced in the auditory cortex of the SERT KO mice. The number and density of dendritic spines of these neurons were significantly less than those of wild-type neurons. Also, the frequency-tonotopic organization of primary auditory cortex was disrupted in SERT KO mice. The auditory neurons of SERT KO mice exhibited border frequency tuning with high-intensity thresholds. These findings indicate that SERT plays a key role in development and functional maintenance of auditory cortical neurons. Auditory function should be examined when SERT is selected as a target in the treatment for psychiatric disorders.

Hearing is one of the five sensory organs that allows us to interact with society and our environment. However, one in eight Americans suffers from sensorineural hearing loss that is great enough to adversely impact their daily life. There is an urgent need to identify what part/degree of the auditory pathway (sensory or neural) is compromised so that appropriate treatment/intervention can be implemented. Single- or two-tone evoked potentials, the electrocochleography (eCochG), were measured along the auditory pathway, i.e., at the round window and remotely at the vertex, with simultaneous recordings of ear canal distortion product otoacoustic emissions. Sensory (cochlear) and neural components in the (remote-) eCochG responses showed distinct level- and frequency-dependent features allowing to be differentiated from each other. Specifically, the distortion products in the (remote-)eCochGs can precisely localize the sensory damage showing that they are effective to determine the sensory or neural damage along the auditory pathway.

In everyday life, predictable sensory stimuli are generally not ecologically informative. By contrast, novel or unexpected stimuli signal ecologically salient changes in the environment. This idea forms the basis of the predictive coding hypothesis: efficient sensory encoding minimizes neural activity associated with predictable backgrounds and emphasizes detection of changes in the environment. In real life, the brain must resolve multiple unexpected sensory events occurring over different time scales. The local/global deviant experimental paradigm examines auditory predictive coding over multiple time scales. For short-term novelty [hundreds of milliseconds; local deviance (LD)], sequences of identical sounds (/xxxxx/) are interspersed with sequences that contain deviants (/xxxxy/). Long-term novelty [several seconds; global deviance (GD)] is created using either (a) frequent /xxxxx/ and infrequent /xxxxy/ sequences, or (b) frequent /xxxxy/ and infrequent /xxxxx/ sequences. In scenario (a), there is both an LD and a GD effect (LDGD, “double surprise”). In (b), the global deviant is a local standard, i.e., sequence of identical sounds (LSGD). Cortical responses reflecting LD and GD originate in different brain areas, have a different time course, and are differentially sensitive to general anesthesia. Neural processes underlying LD and GD have been shown to interact, reflecting overlapping networks subserving the detection of novel auditory stimuli. This study examined these interactions using intracranial electroencephalography in neurosurgical patients. Subjects performed a GD target detection task before and during induction of anesthesia with propofol. Recordings were made from the auditory cortex, surrounding auditory-related and prefrontal cortex in awake, sedated, and unresponsive states. High gamma activity was used to measure the neural basis of local-by-global novelty interactions. Positive interaction was defined as a greater response to the double surprise LDGD condition compared to LSGD. Negative interaction was defined as a weaker response to LDGD. Positive interaction was more frequent than negative interaction and was primarily found in auditory cortex. Negative interaction typically occurred in prefrontal cortex and was more sensitive to general anesthesia. Temporo-parietal auditory-related areas exhibited both types of interaction. These interactions may have relevance in a clinical setting as biomarkers of conscious perception in the assessment of depth of anesthesia and disorders of consciousness.

Neuronal activation is often accompanied by the regulation of cerebral hemodynamics via a process known as neurovascular coupling (NVC) which is essential for proper brain function and has been observed to be disrupted in a variety of neuropathologies. A comprehensive understanding of NVC requires imaging capabilities with high spatiotemporal resolution and a field-of-view that spans different orders of magnitude. Here, we present an approach for concurrent multi-contrast mesoscopic and two-photon microscopic imaging of neurovascular dynamics in the cortices of live mice. We investigated the spatiotemporal correlation between sensory-evoked neuronal and vascular responses in the auditory cortices of living mice using four imaging modalities. Our findings unravel drastic differences in the NVC at the regional and microvascular levels and the distinctive effects of different brain states on NVC. We further investigated the brain-state-dependent changes of NVC in large cortical networks and revealed that anesthesia and sedation caused spatiotemporal disruption of NVC.

Individuals typically exhibit better cross-sensory perception following unisensory loss, demonstrating improved perception of information available from the remaining senses and increased cross-sensory use of neural resources. Even individuals with no sensory loss will exhibit such changes in cross-sensory processing following temporary sensory deprivation, suggesting that the brain's capacity for recruiting cross-sensory sources to compensate for degraded unisensory input is a general characteristic of the perceptual process. Many studies have investigated how auditory and visual neural structures respond to within- and cross-sensory input. However, little attention has been given to how general auditory and visual neural processing relates to within and cross-sensory perception. The current investigation examines the extent to which individual differences in general auditory neural processing accounts for variability in auditory, visual, and audiovisual speech perception in a sample of young healthy adults. Auditory neural processing was assessed using a simple click stimulus. We found that individuals with a smaller P1 peak amplitude in their auditory-evoked potential (AEP) had more difficulty identifying speech sounds in difficult listening conditions, but were better lipreaders. The results suggest that individual differences in the auditory neural processing of healthy adults can account for variability in the perception of information available from the auditory and visual modalities, similar to the cross-sensory perceptual compensation observed in individuals with sensory loss.

Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15–16 were exposed to 1–12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔC m showed the typical bell-shaped curve that mirrors the voltage dependence of Ca 2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca 2+ influx, suggesting a modification in coupling between Ca 2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca 2+ -dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 ( Vglut3 ) knock-out (KO) mice. Unlike WT, IHCs from Vglut3 KO mice showed a noise-induced reduction in ΔC m and Ca 2+ influx with no change in the Ca 2+ -dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3 -dependent potentiation of exocytosis.

Recent investigation of memory-related functions in the auditory system have capitalized on the use of memory-modulating molecules to probe the relationship between memory and substrates of memory in auditory system coding. For example, epigenetic mechanisms, which regulate gene expression necessary for memory consolidation, are powerful modulators of learning-induced neuroplasticity and long-term memory (LTM) formation. Inhibition of the epigenetic regulator histone deacetylase 3 (HDAC3) promotes LTM, which is highly specific for spectral features of sound. The present work demonstrates for the first time that HDAC3 inhibition also enables memory for temporal features of sound. Adult male rats trained in an amplitude modulation (AM) rate discrimination task and treated with a selective inhibitor of HDAC3 formed memory that was highly specific to the AM rate paired with reward. Sound-specific memory revealed behaviorally was associated with a signal-specific enhancement in temporal coding in the auditory system; stronger phase locking that was specific to the rewarded AM rate was revealed in both the surface-recorded frequency following response and auditory cortical multiunit activity in rats treated with the HDAC3 inhibitor. Furthermore, HDAC3 inhibition increased trial-to-trial cortical response consistency (relative to naive and trained vehicle-treated rats), which generalized across different AM rates. Stronger signal-specific phase locking correlated with individual behavioral differences in memory specificity for the AM signal. These findings support that epigenetic mechanisms regulate activity-dependent processes that enhance discriminability of sensory cues encoded into LTM in both spectral and temporal domains, which may be important for remembering spectrotemporal features of sounds, for example, as in human voices and speech. SIGNIFICANCE STATEMENT Epigenetic mechanisms have recently been implicated in memory and information processing. Here, we use a pharmacological inhibitor of HDAC3 in a sensory model of learning to reveal the ability of HDAC3 to enable precise memory for amplitude-modulated sound cues. In so doing, we uncover neural substrates for memory's specificity for temporal sound cues. Memory specificity was supported by auditory cortical changes in temporal coding, including greater response consistency and stronger phase locking. HDAC3 appears to regulate effects across domains that determine specific cue saliency for behavior. Thus, epigenetic players may gate how sensory information is stored in long-term memory and can be leveraged to reveal the neural substrates of sensory details stored in memory.

Alzheimer’s disease (AD) is characterized by a progressive loss of memory and cognitive decline. However, the assessment of AD-associated functional and cognitive changes is still a big challenge. Auditory-evoked cortical potential (AECP) is an event-related potential reflecting not only neural activation in the auditory cortex (AC) but also cognitive activity in the brain. In this study, we used the subdermal needle electrodes with the same electrode setting as the auditory brainstem response (ABR) recording and recorded AECP in normal aging CBA/CaJ mice and APP/PS1 AD mice. AECP in mice usually appeared as three positive peaks, i.e., P1, P2, and P3, and three corresponding negative peaks, i.e., N1, N2, and N3. In normal aging CBA mice, the early sensory peaks P1, N1, and P2 were reduced as age increased, whereas the later cognitive peaks N2, P3, and N3 were increased or had no changes with aging. Moreover, the latency of the P1 peak was increased as age increased, although the latencies of later peaks had a significant reduction with aging. In AD mice, peak P1 was significantly reduced in comparison with wild-type (WT) littermates at young ages, proceeding AD phenotype presentation. In particular, the later cognitive peak P3 was diminished after 3 months old, different from the normal aging effect. However, the latencies of AECP peaks in AD mice generally had no significant delay or changes with aging. Finally, consistent with AECP changes, the accumulation of amyloid precursor protein (APP) at the AC was visible in AD mice as early as 2 months old. These data suggest that AECP could serve as an early, non-invasive, and objective biomarker for detecting AD and AD-related dementia (ADRD).