Auditory Research publications

Prediction provides key advantages for survival, and cognitive studies have demonstrated that the brain computes multilevel predictions. Evidence for predictions remains elusive at the neuronal level because of the complexity of separating neural activity into predictions and stimulus responses. We overcome this challenge by recording from single neurons from cortical and subcortical auditory regions in anesthetized and awake preparations, during unexpected stimulus omissions interspersed in a regular sequence of tones. We find a subset of neurons that responds reliably to omitted tones. In awake animals, omission responses are similar to anesthetized animals, but larger and more frequent, indicating that the arousal and attentional state levels affect the degree to which predictions are neuronally represented. Omission-sensitive neurons also responded to frequency deviants, with their omission responses getting emphasized in the awake state. Because omission responses occur in the absence of sensory input, they provide solid and empirical evidence for the implementation of a predictive process.

The ability to localize a sound source in complex environments is essential for communication and navigation. Spatial hearing relies predominantly on the comparison of differences in the arrival time of sound between the two ears, the interaural time differences (ITDs). Hearing impairments are highly detrimental to sound localization. While cochlear implants (CIs) have been successful in restoring many crucial hearing capabilities, sound localization via ITD detection with bilateral CIs remains poor. The underlying reasons are not well understood. Neuronally, ITD sensitivity is generated by coincidence detection between excitatory and inhibitory inputs from the two ears performed by specialized brainstem neurons. Due to the lack of electrophysiological brainstem recordings during CI stimulation, it is unclear to what extent the apparent deficits are caused by the binaural comparator neurons or arise already on the input level. Here, we use a bottom-up approach to compare response features between electric and acoustic stimulation in an animal model of CI hearing. Conducting extracellular single neuron recordings in gerbils, we find severe hyper-precision and moderate hyper-entrainment of both the excitatory and inhibitory brainstem inputs to the binaural comparator neurons during electrical pulse-train stimulation. This finding establishes conclusively that the binaural processing stage must cope with highly altered input statistics during CI stimulation. To estimate the consequences of these effects on ITD sensitivity, we used a computational model of the auditory brainstem. After tuning the model parameters to match its response properties to our physiological data during either stimulation type, the model predicted that ITD sensitivity to electrical pulses is maintained even for the hyper-precise inputs. However, the model exhibits severely altered spatial sensitivity during electrical stimulation compared to acoustic: while resolution of ITDs near midline was increased, more lateralized adjacent source locations became inseparable. These results directly resemble recent findings in rodent and human CI listeners. Notably, decreasing the phase-locking precision of inputs during electrical stimulation recovered a wider range of separable ITDs. Together, our findings suggest that a central problem underlying the diminished ITD sensitivity in CI users might be the temporal hyper-precision of inputs to the binaural comparator stage induced by electrical stimulation.

The lateral superior olive (LSO) is a key structure in the central auditory system of mammals that exerts efferent control on cochlear sensitivity and is involved in the processing of binaural level differences for sound localization. Understanding how the LSO contributes to these processes requires knowledge about the resident cells and their connections with other auditory structures. We used standard histological stains and retrograde tracer injections into the inferior colliculus (IC) and cochlea in order to characterize two basic groups of neurons: (1) Principal and periolivary (PO) neurons have projections to the IC as part of the ascending auditory pathway; and (2) lateral olivocochlear (LOC) intrinsic and shell efferents have descending projections to the cochlea. Principal and intrinsic neurons are intermixed within the LSO, exhibit fusiform somata, and have disk-shaped dendritic arborizations. The principal neurons have bilateral, symmetric, and tonotopic projections to the IC. The intrinsic efferents have strictly ipsilateral projections, known to be tonotopic from previous publications. PO and shell neurons represent much smaller populations (<10% of principal and intrinsic neurons, respectively), have multipolar somata, reside outside the LSO, and have non-topographic, bilateral projections. PO and shell neurons appear to have widespread projections to their targets that imply a more diffuse modulatory function. The somata and dendrites of principal and intrinsic neurons form a laminar matrix within the LSO and share quantifiably similar alignment to the tonotopic axis. Their restricted projections emphasize the importance of frequency in binaural processing and efferent control for auditory perception. This study addressed and expanded on previous findings of cell types, circuit laterality, and projection tonotopy in the LSO of the mouse.

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.

Noise induced synaptopathy (NIS) has been researched extensively since a large amount of synaptic loss without permanent threshold shift (PTS) was found in CBA mice after a brief noise exposure. However, efforts to translate these results to humans have met with little success—and might not be possible since noise exposure used in laboratory animals is generally different from what is experienced by human subjects in real life. An additional problem is a lack of morphological data and reliable functional methods to quantify loss of afferent synapses in humans. Based on evidence for disproportionate synaptic loss for auditory nerve fibers (ANFs) with low spontaneous rates (LSR), coding-in-noise deficits (CIND) have been speculated to be the major difficulty associated with NIS without PTS. However, no robust evidence for this is available in humans or animals. This has led to a re-examination of the role of LSR ANFs in signal coding in high-level noise. The fluctuation profile model has been proposed to support a role for high-SR ANFs in the coding of high-level noise in combination with efferent control of cochlear gain. This study aimed to induce NIS by a low-level, intermittent noise exposure mimicking what is experienced in human life and examined the impact of the NIS on temporal processing under masking. It also evaluated the role of temporal fluctuation in evoking efferent feedback and the effects of NIS on this feedback.

Aims We aimed to find where and how noise‐induced cochlear hearing loss affects the central nervous system during the early state and identify the neural substrate for aberrant patterns that mediating noise‐related anxiety−/depression‐ like behaviors. Methods Broad band noise with 122 dB for 2 hours was conducted to induce hearing loss. We defined 0 day (N0D) and 10 days (N10D) post noise as the acute and sub‐acute period. Behavioral tests (Open field test and light/dark test) and resting‐state fMRI were computed to evaluate emotional conditions and aberrant neural activity. Functional connectivity analysis using the anterior cingulate cortex as a seed was computed to reveal the spatial distribution beyond auditory network during both periods. Results Anxiety−/depression‐like behaviors were found in rats with noise exposure. Between‐group analysis revealed that N0D rats displayed widespread reductions in functional connectivity, spanning primary somatosensory cortex, medial geniculate body, inferior colliculus, cingulate cortex, cerebellar lobule comparing with N10D rats and a similar pattern was also occurred in comparison with the control group. Conclusion Taken together, an “acoustic‐causing” network accounting for distress and gating of noise exposure related anxiety/depression was proposed.

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brain stem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure the hearing range, and monaural and binaural auditory responses in hemizygous males, homozygous females, and heterozygous females compared with those in wild-type mice. Consistent with previous study, we showed no difference in morphological parameters across genotypes or sexes. There was no significant difference in hearing range between the sexes or genotypes, however there was a trend towards high frequency hearing loss in male FXS mice. In contrast, female mice with homozygous FXS had a decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Finally, males with FXS had an increased latency of the binaural interaction component (BIC) at 0 interaural timing difference compared with that in wild-type males. These findings further clarify auditory brain stem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

Noise-induced hearing loss (NIHL) is one of the most prevalent forms of acquired hearing loss, and it is associated with aberrant microglial status and reduced hippocampal neurogenesis; however, the nature of these associations is far from being elucidated. Beyond its direct effects on the auditory system, exposure to intense noise has previously been shown to acutely activate the stress response, which has increasingly been linked to both microglial activity and adult hippocampal neurogenesis in recent years. Given the pervasiveness of noise pollution in modern society and the important implications of either microglial activity or hippocampal neurogenesis for cognitive and emotional function, this study was designed to investigate how microglial status and hippocampal neurogenesis change over time following acoustic exposure and to analyze the possible roles of the noise exposure-induced stress response and hearing loss in these changes. To accomplish this, adult male C57BL/6J mice were randomly assigned to either a control or noise exposure (NE) group. Auditory function was assessed by measuring ABR thresholds at 20 days post noise exposure. The time-course profile of serum corticosterone levels, microglial status, and hippocampal neurogenesis during the 28 days following noise exposure were quantified by ELISA or immunofluorescence staining. Our results illustrated a permanent moderate-to-severe degree of hearing loss, an early but transient increase in serum corticosterone levels, and time-dependent dynamic alterations in microglial activation status and hippocampal neurogenesis, which both present an early but transient change and a late but enduring change. These findings provide evidence that both the stress response and hearing loss contribute to the dynamic alterations of microglia and hippocampal neurogenesis following noise exposure; moreover, noise-induced permanent hearing loss rather than noise-induced transient stress is more likely to be responsible for perpetuating the neurodegenerative process associated with many neurological diseases.

The protective effect of the efferent system against acoustic trauma (AT) has been shown by several experimental approaches, including damage to one ear, sectioning of the olivocochlear bundle (OCB) in the floor of the IV ventricle, and knock-in mice overexpressing outer hair cell (OHC) cholinergic receptors, among others. Such effects have been related to changes in the regulation of the cholinergic efferent system and in cochlear amplification, which ultimately reverse upon protective hearing suppression. In addition to well-known circuits of the brainstem, the descending corticofugal pathway also regulates efferent neurons of the olivary complex. In this study, we applied our recently developed experimental paradigm of multiple sessions of electrical stimulation (ES) to activate the efferent system in combination with noise overstimulation. ABR thresholds increased 1 and 2 days after AT (8–16 kHz bandpass noise at 107 dB for 90 min) recovering at AT + 14 days. However, after multiple sessions of epidural anodal stimulation, no changes in thresholds were observed following AT. Although an inflammatory response was also observed 1 day after AT in both groups, the counts of reactive macrophages in both experimental conditions suggest decreased inflammation in the epidural stimulation group. Quantitative immunocytochemistry for choline acetyltransferase (ChAT) showed a significant decrease in the size and optical density of the efferent terminals 1 day after AT and a rebound at 14 days, suggesting depletion of the terminals followed by a long-term compensatory response. Such a synthesis recovery was significantly higher upon cortical stimulation. No significant correlation was found between ChAT optical density and size of the buttons in sham controls (SC) and ES/AT + 1day animals; however, significant negative correlations were shown in all other experimental conditions. Therefore, our comparative analysis suggests that cochleotopic cholinergic neurotransmission is also better preserved after multisession epidural stimulation.

Spiral ganglion neurons (SGNs) are auditory neurons that relay sound signals from the inner ear to the brainstem. The ototoxic drug cisplatin can damage SGNs and thus lead to sensorineural hearing loss (SNHL), and there are currently no methods for preventing or treating this. Macroautophagy/autophagy plays a critical role in SGN development, but the effect of autophagy on cisplatin-induced SGN injury is unclear. Here, we first found that autophagic flux was activated in SGNs after cisplatin damage. The SGN apoptosis and related hearing loss induced by cisplatin were alleviated after co-treatment with the autophagy activator rapamycin, whereas these were exacerbated by the autophagy inhibitor 3-methyladenine, indicating that instead of inducing SGN death, autophagy played a neuroprotective role in SGNs treated with cisplatin both in vitro and in vivo. We further demonstrated that autophagy attenuated reactive oxygen species (ROS) accumulation and alleviated cisplatin-induced oxidative stress in SGNs to mediate its protective effects. Notably, the role of the antioxidant enzyme PRDX1 (peroxiredoxin 1) in modulating autophagy in SGNs was first identified. Deficiency in PRDX1 suppressed autophagy and increased SGN loss after cisplatin exposure, while upregulating PRDX1 pharmacologically or by adeno-associated virus activated autophagy and thus inhibited ROS accumulation and apoptosis and attenuated SGN loss induced by cisplatin. Finally, we showed that the underlying mechanism through which PRDX1 triggers autophagy in SGNs was, at least partially, through activation of the PTEN-AKT signaling pathway. These findings suggest potential therapeutic targets for the amelioration of drug-induced SNHL through autophagy activation. Abbreviations: 3-MA: 3-methyladenine; AAV : adeno-associated virus; ABR: auditory brainstem responses; AKT/protein kinase B: thymoma viral proto-oncogene; Baf: bafilomycin A1; CAP: compound action potential; COX4I1: cytochrome c oxidase subunit 4I1; Cys: cysteine; ER: endoplasmic reticulum; H2O2: hydrogen peroxide; HC: hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; NAC: N-acetylcysteine; PRDX1: peroxiredoxin 1; PTEN: phosphatase and tensin homolog; RAP: rapamycin; ROS: reactive oxygen species; SGNs: spiral ganglion neurons; SNHL: sensorineural hearing loss; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling; WT: wild type.

The present study aimed to observe the changes in the cochlea ribbon synapses after repeated exposure to moderate-to-high intensity noise. Guinea pigs received 95 dB SPL white noise exposure 4 h a day for consecutive 7 days (we regarded it a medium-term and moderate-intensity noise, or MTMI noise). Animals were divided into four groups: Control, 1DPN (1-day post noise), 1WPN (1-week post noise), and 1MPN (1-month post noise). Auditory function analysis by auditory brainstem response (ABR) and compound action potential (CAP) recordings, as well as ribbon synapse morphological analyses by immunohistochemistry (Ctbp2 and PSD95 staining) were performed 1 day, 1 week, and 1 month after noise exposure. After MTMI noise exposure, the amplitudes of ABR I and III waves were suppressed. The CAP threshold was elevated, and CAP amplitude was reduced in the 1DPN group. No apparent changes in hair cell shape, arrangement, or number were observed, but the number of ribbon synapse was reduced. The 1WPN and 1MPN groups showed that part of ABR and CAP changes recovered, as well as the synapse number. The defects in cochlea auditory function and synapse changes were observed mainly in the high-frequency region. Together, repeated exposure in MTMI noise can cause hidden hearing loss (HHL), which is partially reversible after leaving the noise environment; and MTMI noise-induced HHL is associated with inner hair cell ribbon synapses.

Polychlorinated biphenyls (PCBs) are enduring environmental toxicants and exposure is associated with neurodevelopmental deficits. The auditory system appears particularly sensitive, as previous work has shown that developmental PCB exposure causes both hearing loss and gross disruptions in the organization of the rat auditory cortex. However, the mechanisms underlying PCB-induced changes are not known, nor is it known whether the central effects of PCBs are a consequence of peripheral hearing loss. Here, we study changes in both peripheral and central auditory function in rats with developmental PCB exposure using a combination of optical and electrophysiological approaches. Female rats were exposed to an environmental PCB mixture in utero and until weaning. At adulthood, auditory brainstem responses (ABRs) were measured, and synaptic currents were recorded in slices from auditory cortex layer 2/3 neurons. Spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) were more frequent in PCB-exposed rats compared with controls and the normal relationship between IPSC parameters and peripheral hearing was eliminated in PCB-exposed rats. No changes in spontaneous EPSCs were found. Conversely, when synaptic currents were evoked by laser photostimulation of caged-glutamate, PCB exposure did not affect evoked inhibitory transmission, but increased the total excitatory charge, the number and distance of sites that evoke a significant response. Together, these findings indicate that early developmental exposure to PCBs causes long-lasting changes in both inhibitory and excitatory neurotransmission in the auditory cortex that are independent of peripheral hearing changes, suggesting the effects are because of the direct impact of PCBs on the developing auditory cortex.

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with “no-repetition” controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection.

Large-scale epidemiological surveys suggest that hearing loss (HL) is a significant risk factor for dementia. We previously showed that noise-induced HL (NIHL) impairs hippocampal cognitive function and decreases hippocampal neurogenesis and neuronal complexity, suggesting a causal role of HL in dementia. To further investigate the influence of acquired peripheral HL on hippocampal neurogenesis with the aging process as well as the underlying mechanism, we produced NIHL in male CBA/J mice and assessed hippocampal neurogenesis and microglial morphology in the auditory brain and hippocampus at 4 days post-noise exposure (DPN) or 1, 3, 6, or 12 months post-noise exposure (MPN) by immunofluorescence labeling. We found that the age-related decline in hippocampal neurogenesis was accelerated in mice with NIHL. Furthermore, in mice with NIHL, prolonged microglial activation occurred from 1 MPN to 12 MPN across multiple auditory nuclei, while aggravated microglial deterioration occurred in the hippocampus and correlated with the age-related decline in hippocampal neurogenesis. These results suggest that acquired peripheral HL accelerates the age-related decline in hippocampal neurogenesis and that hippocampal microglial degeneration may contribute to the development of neurodegeneration following acquired peripheral HL.

Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that selectively increasing NMDA receptor activity in inhibitory neurons using an NMDAR positive allosteric modulator (PAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. In vivo infusion of PAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. In addition, PAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. These results reveal that selectively enhancing endogenous NMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory–inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.

Dopamine guides behavior and learning through pleasure, according to classic understanding. Dopaminergic neurons are traditionally thought to signal positive or negative prediction errors (PEs) when reward expectations are, respectively, exceeded or not matched. These signed PEs are quite different from the unsigned PEs, which report surprise during sensory processing. But mounting theoretical accounts from the predictive processing framework postulate that dopamine, as a neuromodulator, could potentially regulate the postsynaptic gain of sensory neurons, thereby scaling unsigned PEs according to their expected precision or confidence. Despite ample modeling work, the physiological effects of dopamine on the processing of surprising sensory information are yet to be addressed experimentally. In this study, we tested how dopamine modulates midbrain processing of unexpected tones. We recorded extracellular responses from the rat inferior colliculus to oddball and cascade sequences, before, during, and after the microiontophoretic application of dopamine or eticlopride (a D2-like receptor antagonist). Results demonstrate that dopamine reduces the net neuronal responsiveness exclusively to unexpected sensory input without significantly altering the processing of expected input. We conclude that dopaminergic projections from the thalamic subparafascicular nucleus to the inferior colliculus could encode the expected precision of unsigned PEs, attenuating via D2-like receptors the postsynaptic gain of sensory inputs forwarded by the auditory midbrain neurons. This direct dopaminergic modulation of sensory PE signaling has profound implications for both the predictive coding framework and the understanding of dopamine function.

Visual cortex (VC) over-activation analysed by evoked responses has been demonstrated in congenital deafness and after long-term acquired hearing loss in humans. However, permanent hearing deprivation has not yet been explored in animal models. Thus, the present study aimed to examine functional and molecular changes underlying the visual and auditory cross-modal reaction. For such purpose, we analysed cortical visual evoked potentials (VEPs) and the gene expression (RT-qPCR) of a set of markers for neuronal activation (c-Fos) and activity-dependent homeostatic compensation (Arc/Arg3.1). To determine the state of excitation and inhibition, we performed RT-qPCR and quantitative immunocytochemistry for excitatory (receptor subunits GluA2/3) and inhibitory (GABAA-α1, GABAB-R2, GAD65/67 and parvalbumin-PV) markers. VC over-activation was demonstrated by a significant increase in VEPs wave N1 and by up-regulation of the activity-dependent early genes c-Fos and Arc/Arg3.1 (thus confirming, by RT-qPCR, our previously published immunocytochemical results). GluA2 gene and protein expression were significantly increased in the auditory cortex (AC), particularly in layers 2/3 pyramidal neurons, but inhibitory markers (GAD65/67 and PV-GABA interneurons) were also significantly upregulated in the AC, indicating a concurrent increase in inhibition. Therefore, after permanent hearing loss in the rat, the VC is not only over-activated but also potentially balanced by homeostatic regulation, while excitatory and inhibitory markers remain imbalanced in the AC, most likely resulting from changes in horizontal intermodal regulation.

Key points Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system. The neuromodulatory peptide urocortin‐3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem. Lack of UCN3 facilitates age‐induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities. Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms. Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress‐related auditory deficits, including recovery from acoustic trauma. Abstract Environmental acoustic noise is omnipresent in our modern society, with sound levels that are considered non‐damaging still causing long‐lasting or permanent changes in the auditory system. The small neuromodulatory peptide urocortin‐3 (UCN3) is the endogenous ligand for corticotropin‐releasing factor receptor type 2 and together they are known to play an important role in stress recovery. UCN3 expression has been observed in the auditory brainstem, but its role remains unclear. Here we describe the detailed distribution of UCN3 expression in the murine auditory brainstem and provide evidence that UCN3 is expressed in the synaptic region of inner hair cells in the cochlea. We also show that mice with deficient UCN3 signalling experience premature ageing of the auditory system starting at an age of 4.7 months with significantly elevated thresholds of auditory brainstem responses (ABRs) compared to age‐matched wild‐type mice. Following a single, 2 h exposure to moderate (84 or 94 dB SPL) noise, UCN3‐deficient mice exhibited significantly larger shifts in ABR thresholds combined with maladaptive recovery. In wild‐type mice, the same noise exposure did not cause lasting changes to auditory thresholds. The presence of UCN3‐expressing neurons throughout the auditory brainstem and the predisposition to hearing loss caused by preventing its normal expression suggests UCN3 as an important neuromodulatory peptide in the auditory system's response to loud sounds.

In this study, we investigated the role of MAP kinase phosphatase-1 (MKP-1) and rosiglitazone (RSG) in glucocorticoid resistance and glucocorticoid sensitivity, respectively, using a guinea pig model of lipopolysaccharide- (LPS-) induced sudden sensorineural hearing loss (SSHL). The pigs were divided into control, LPS, LPS+dexamethasone (DEX), LPS+RSG, and LPS+DEX+RSG groups. Their hearing was screened by auditory brainstem response measurement. Immunofluorescence staining was used to identify the location of MKP-1 in the inner ear. The expression levels of MKP-1 and the related proteins in the inner ear were detected using western blotting. The morphological changes in the cochlea were observed via hematoxylin-eosin staining. Severe hearing loss was observed in the LPS group, as opposed to the protection from hearing loss observed in the LPS+DEX+RSG group. A positive correlation was observed between MKP-1 expression levels and protection from hearing loss. RSG and DEX synergistically influenced inner ear inflammation. In conclusion, resistance of LPS-induced SSHL guinea pig models to glucocorticoids may result from impaired MKP-1 function in inner ear tissues, induced by glucocorticoids, impairing the inhibition of inflammation. Our findings present novel targets to develop potential therapeutics to treat inflammatory diseases of the inner ear.

Rat auditory cortex was subjected to 0.1 mA anodal direct current in seven 10-min sessions on alternate days. Based on the well-known auditory cortex control of olivocochlear regulation through corticofugal projections, auditory brainstem responses (ABRs) were recorded as an indirect test of the effectiveness and reversibility of the multisession protocol of epidural stimulation. Increases of 20-30 dB ABR auditory thresholds shown after epidural stimulation reverted back to control levels 10 min after a single session. However, increases in thresholds revert 4 days after multisession stimulation. Less changes in wave amplitudes and threshold shifts were shown in ABR recorded contralaterally to the electrically stimulated side of the brain. To assess tissue effects of epidural electric stimulation on the brain cortex, well characterized functional anatomical markers of glial cells (GFAP/astrocytes and Iba1/microglial cells) and neurons (c-Fos) were analyzed in alternate serial sections by quantitative immunocytochemistry. Restricted astroglial and microglial reactivity was observed within the cytoarchitectural limits of the auditory cortex. However, interstitial GFAP overstaining was also observed in the ventricular surface and around blood vessels, thus supporting a potential global electrolytic stimulation of the brain. These results correlate with extensive changes in the distribution of c-Fos immunoreactive neurons among layers along sensory cortices after multisession stimulation. Quantitative immunocytochemical analysis supported this idea by showing a significant increase in the number of positive neurons in supragranular layers and a decrease in layer 6 with no quantitative changes detected in layer 5. Our data indicate that epidural stimulation of the auditory cortex induces a reversible decrease in hearing sensitivity due to local, restricted epidural stimulation. A global plastic response of the sensory cortices, also reported here, may be related to electrolytic effects of electric currents.