Noise-induced cell death in the mouse medial geniculate body and primary auditory cortex

Noise-induced effects within the inner ear have been well investigated for several years. However, this peripheral damage cannot fully explain the audiological symptoms in noise-induced hearing loss (NIHL), e.g. tinnitus, recruitment, reduced speech intelligibility, hyperacusis. There are few reports on central noise effects. Noise can induce an apoptosis of neuronal tissue within the lower auditory pathway. Higher auditory structures (e.g. medial geniculate body, auditory cortex) are characterized by metabolic changes after noise exposure. However, little is known about the microstructural changes of the higher auditory pathway after noise exposure. The present paper was therefore aimed at investigating the cell density in the medial geniculate body (MGB) and the primary auditory cortex (AI) after noise exposure. Normal hearing mice were exposed to noise (10 kHz center frequency at 115 dB SPL for 3 h) at the age of 21 days under anesthesia (Ketamin/Rompun, 10:1). After 1 week, auditory brainstem response recordings (ABR) were performed in noise exposed and normal hearing animals. After fixation, the brain was microdissected and stained (Kluever-Barrera). The cell density in the MGB subdivisions and the AI were determined by counting the cells within a grid. Noise-exposed animals showed a significant ABR threshold shift over the whole frequency range. Cell density was significantly reduced in all subdivisions of the MGB and in layers IV-VI of AI. The present findings demonstrate a significant noise-induced change of the neuronal cytoarchitecture in central key areas of auditory processing. These changes could contribute to the complex psychoacoustic symptoms after NIHL.     

Salicylate increases the gain of the central auditory system

High doses of salicylate, the anti-inflammatory component of aspirin, induce transient tinnitus and hearing loss. Systemic injection of 250 mg/kg of salicylate, a dose that reliably induces tinnitus in rats, significantly reduced the sound evoked output of the rat cochlea. Paradoxically, salicylate significantly increased the amplitude of the sound-evoked field potential from the auditory cortex (AC) of conscious rats, but not the inferior colliculus (IC). When rats were anesthetized with isoflurane, which increases GABA-mediated inhibition, the salicylate-induced AC amplitude enhancement was abolished, whereas ketamine, which blocks N-methyl-d-aspartate receptors, further increased the salicylate-induced AC amplitude enhancement. Direct application of salicylate to the cochlea, however, reduced the response amplitude of the cochlea, IC and AC, suggesting the AC amplitude enhancement induced by systemic injection of salicylate does not originate from the cochlea. To identify a behavioral correlate of the salicylate-induced AC enhancement, the acoustic startle response was measured before and after salicylate treatment. Salicylate significantly increased the amplitude of the startle response. Collectively, these results suggest that high doses of salicylate increase the gain of the central auditory system, presumably by down-regulating GABA-mediated inhibition, leading to an exaggerated acoustic startle response. The enhanced startle response may be the behavioral correlate of hyperacusis that often accompanies tinnitus and hearing loss.     

Up-regulation of cochlear Hes1 expression in response to noise exposure

Hes1, a hairy and enhancer of split homolog, negatively regulates inner ear hair cell differentiation. The main objective of this study was to investigate the status of the Hes1 gene in the noise-damaged cochlea in relation to the degree of noise-induced hearing loss (NIHL). Adult albino guinea pigs were exposed to white-band noise (115 dB sound pressure level). Noise exposure for either 1 or 3 hours induced significant elevations of threshold in auditory brainstem response (ABR) compared with unexposed controls. Succinate dehydrogenase staining showed that white-band noise exposure caused significant outer hair cell losses. In addition, we found significant up-regulations of cochlear Hes1 mRNA and protein expressions following acoustic trauma, and Hes1 mRNA expression was positively correlated with NIHL. These findings suggest that up-regulation of Hes1 expression in response to noise exposure may be one of the underlying mechanisms of NIHL.     

Post-exposure treatment with ginsenoside compound K ameliorates auditory functional injury associated with noise-induced hearing loss in mice

Noise-induced hearing loss (NIHL) is thought to primarily involve damage to the sensory hair cells of the cochlea via mechanical and metabolic mechanisms. Unfortunately, initial studies assessing the effectiveness of post-exposure treatment after hearing loss have yielded largely disappointing results. This study explored the effects of oral treatment with Korean red ginseng (RG) and with two bioavailable ginsenoside metabolites, ginsenoside Rh1 and ginsenoside compound K (GCK), in response to NIHL in a murine model. Pharmacological treatments began 24h after noise exposure and were continued once daily for 7 days. Central auditory function was evaluated using auditory middle latency responses, and cochlear function was determined based on transient evoked otoacoustic emissions. Additionally, cochlear hair cell morphology was investigated after noise exposure. Both Korean red ginseng and compound K reduced threshold shifts, central auditory function damage, and cochlear functional and morphological deficits. In contrast, treatment with ginsenoside Rh1 did not result in recovery of NIHL in mice. These results suggest that consumption of Korean red ginseng may facilitate recovery from noise-induced hearing loss. Furthermore, one of the active constituents in ginseng is likely ginsenoside compound K.     

Limitation of Conventional Audiometry in Identifying Hidden Hearing Loss in Acute Noise Exposure

PurposeThe concept of hidden hearing loss can explain the discrepancy between a listener''s perception of hearing ability and hearing evaluation using pure tone audiograms. This study investigated the utility of the suprathreshold auditory brainstem response (ABR) for the evaluation of hidden hearing loss in noise-exposed ear with normal audiograms.Materials and MethodsA total of 15 patients (24 ears) with normal auditory thresholds and normal distortion product otoacoustic emissions were included in a retrospective analysis of medical records of 80 patients presenting with histories of acute noise exposure. The control group included 12 subjects (24 ears) with normal audiograms and no history of noise exposure. Pure tone audiometry and suprathreshold ABR testing at 90 dB peSPL were performed. The amplitudes and latencies of ABR waves I and V were compared between the noise-exposed and control groups.ResultsWe found no significant difference in the wave I or V amplitude, or the wave I/V ratio, between the two groups. The latencies of ABR wave I, V, and I-V interpeak interval were compared, and no significant intergroup difference was observed.ConclusionThe results suggest that either hidden hearing loss may not be significant in this cohort of patients with acute noise exposure history, or the possible damage by noise exposure is not reflected in the ABRs. Further studies are needed to inquire about the role of ABR in identification of hidden hearing loss.     

Doxepin Mitigates Noise‐induced Neuronal Damage in Primary Auditory Cortex of Mice via Suppression of Acid Sphingomyelinase/Ceramide Pathway

Neuronal damage in primary auditory cortex (A1) underlies complex manifestations of noise exposure, prevention of which is critical for health maintenance. Acid sphingomyelinase (ASM) catalyzes generation of ceramide (Cer) which if over‐activated mediates neuronal disorders in various diseases. Tricyclic antidepressants (TCAs), by restraining ASM/Cer, benefits multiple neuronal anomalies, so we aimed to elucidate the effect of TCA on noise induced hearing loss and auditory cortex derangement, unraveling mechanism involved. The mice were exposed to noise with frequencies of 20–20 KHz and intensity of 95 dB. Doxepin hydrochloride (DOX), a kind of TCAs, was given intragastrically by 5 mg kg^?1 days^?1. Morphology of neurons was examined using hematoxylin‐eosin (HE) and Nissl staining. Apoptosis was assayed through transferase‐mediated dUTP nick end labeling (TUNEL). The content of ASM, Cer or acid ceramidase (AC) was detected by western blot and immunohistochemistry analysis. We demonstrated intense, broad band noise caused upward shift of auditory brainstem response (ABR) threshold to sound over frequencies 4–32 KHz, with prominent morphologic changes and enhanced apoptosis in neurons of primary auditory cortex (A1) (P < 0.05). DOX partly restored noise‐caused hearing loss alleviating morphologic changes or apoptosis remarkably (P < 0.05). Both ASM and Cer abundance were elevated significantly by noise which was reversed upon DOX treatment (P < 0.05), but neither noise nor DOX altered AC content. DOX had no influence on hearing, neuronal morphology or ASM/Cer in control mice. Our result suggests DOX palliates noise induced hearing loss and neuronal damage in auditory cortex by correcting over‐activation of ASM/Cer without hampering intrinsic behavior of it. Anat Rec, 300:2220–2232, 2017. © 2017 Wiley Periodicals, Inc.     

Long-term exposure to noise impairs cortical sound processing and attention control

Long-term exposure to noise impairs human health, causing pathological changes in the inner ear as well as other anatomical and physiological deficits. Numerous individuals are daily exposed to excessive noise. However, there is a lack of systematic research on the effects of noise on cortical function. Here we report data showing that long-term exposure to noise has a persistent effect on central auditory processing and leads to concurrent behavioral deficits. We found that speech-sound discrimination was impaired in noise-exposed individuals, as indicated by behavioral responses and the mismatch negativity brain response. Furthermore, irrelevant sounds increased the distractibility of the noise-exposed subjects, which was shown by increased interference in task performance and aberrant brain responses. These results demonstrate that long-term exposure to noise has long-lasting detrimental effects on central auditory processing and attention control.     

Noise-induced changes of neuronal spontaneous activity in mice inferior colliculus brain slices

The inferior colliculus (IC) in vivo is reportedly subject to a noise-induced decrease of GABA-related inhibitory synaptic transmission accompanied by an amplitude increase of auditory evoked responses, a widening of tuning curves and a higher neuronal discharge rate at suprathreshold levels. However, other in vivo experiments which demonstrated constant neuronal auditory thresholds or unchanged spontaneous activity in the IC after noise exposure did not confirm those findings. Perhaps this can be the result of complex noise-induced interactions between different central auditory structures. It was, therefore, the aim of the present study to investigate the effects of noise exposure on the spontaneous electrical activity of single neurons in a slice preparation of the isolated mouse IC. Normal hearing mice were exposed to noise (10 kHz center frequency at 115 dB SPL for 3 h) at the age of 21 days under anesthesia (Ketamin/Rompun 10:1). After one week, auditory brainstem response (ABR) recordings and extracellular single-unit recordings from spontaneously active neurons within the IC slice were performed in noise-exposed and in normal hearing control mice. Noise-exposed animals showed a significant ABR threshold shift in the whole tested frequency range and a significant lower neuronal spontaneous activity in all investigated isofrequency laminae compared to controls. In both groups, the firing rate of 80% of IC neurons (approximately) increased significantly during the application of the GABA(A) receptor antagonist Bicucullin (10 microM). The present findings demonstrate a noise-related modulation of spontaneous activity in the IC, which possibly contribute to the generation of noise-induced tinnitus and hearing loss.     

Erratum to "Noise-induced changes of neuronal spontaneous activity in mice inferior colliculus brain slices"

The inferior colliculus (IC) in vivo is reportedly subject to a noise-induced decrease of GABA-related inhibitory synaptic transmission accompanied by an amplitude increase of auditory evoked responses, a widening of tuning curves and a higher neuronal discharge rate at suprathreshold levels. However, other in vivo experiments which demonstrated constant neuronal auditory thresholds or unchanged spontaneous activity in the IC after noise exposure did not confirm those findings. Perhaps this can be the result of complex noise-induced interactions between different central auditory structures. It was, therefore, the aim of the present study to investigate the effects of noise exposure on the spontaneous electrical activity of single neurons in a slice preparation of the isolated mouse IC. Normal hearing mice were exposed to noise (10 kHz center frequency at 115 dB SPL for 3 h) at the age of 21 days under anesthesia (Ketamin/Rompun 10:1). After one week, auditory brainstem response (ABR) recordings and extracellular single-unit recordings from spontaneously active neurons within the IC slice were performed in noise-exposed and in normal hearing control mice. Noise-exposed animals showed a significant ABR threshold shift in the whole tested frequency range and a significant lower neuronal spontaneous activity in all investigated isofrequency laminae compared to controls. In both groups, the firing rate of 80% of IC neurons (approximately) increased significantly during the application of the GABA(A) receptor antagonist Bicucullin (10 microM). The present findings demonstrate a noise-related modulation of spontaneous activity in the IC, which possibly contribute to the generation of noise-induced tinnitus and hearing loss.     

Post-exposure treatment attenuates noise-induced hearing loss

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in sensory cell and neural death in the peripheral nervous system, including damage induced by noise trauma. Antioxidant administration prior to or concomitant with noise exposure can prevent auditory deficits, but the efficacy of a delayed treatment is not known. We have recently found continued reactive oxygen species/reactive nitrogen species formation in the ear for 7-10 days following noise exposure and reasoned that antioxidant intervention during this period should also reduce noise-induced hearing loss. Guinea-pigs were subjected to 4 kHz octave band noise at 120 decibels sound- pressure-level (dB SPL) for 5 hours and received treatment with ROS and RNS scavengers (salicylate and trolox) beginning 3 days prior, 1 hour, 1, 3, or 5 days after noise exposure. Auditory thresholds were assessed by sound-evoked auditory brainstem response at 4, 8, and 16 kHz, before and 10 days after noise exposure. Hair cell damage was analyzed by quantitative histology, and free radical activity was determined immunohistochemically via 4-hydroxynonenal and nitrotyrosine as markers of reactive oxygen species and reactive nitrogen species action. Delivered up to 3 days after noise exposure, salicylate and trolox significantly reduced auditory brainstem response deficits, reduced hair cell damage, and decreased reactive oxygen species and reactive nitrogen species formation. Earlier drug treatment was more effective than later treatment. Our results detail a window of opportunity for rescue from noise trauma, and provide evidence for both morphological and functional protection by delayed pharmacological intervention.     

Hearing Preservation Following Repeated Adenovector Delivery

Factors influencing the damage to the inner ear can include the surgical approach used for vector delivery, the volume of vector used, the buffer that the vector is suspended in as well as the host response to the vector capsid and vector genes that are transferred. We evaluated the effect of Ad5 capsid adenovectors on hearing function after delivery to the perilymph of adult C57Bl/6 mice. Hearing was evaluated before surgery and 3 days post-surgery by auditory brain stem response (ABR) and distortion product otoacoustic emissions (DPOAE). A second group of mice underwent repeated delivery of adenovector two times to determine if a preliminary exposure to an Ad vector could induce an inflammatory response leading to further loss. The first adenovector (Ad.11D.LacZ) was delivered to the posterior semicircular canal or via round window. In the second surgery, a second adenovector (Ad.11D.gfp) was delivered to the horizontal semicircular canal. The functional outcome was tested prior, 7 days post first vector delivery, and 3 days post second vector delivery via ABR and DPOAE. Dual delivery via the semicircular canals resulted in preservation of hearing suggesting that pre-exposure to Ad5 capsid does not predispose to hearing loss. Delivery to the round window resulted in hearing loss that was worsened after the second vector delivery, suggesting that delivery route and prior injury to the inner ear rather than the repetition of delivery predisposes to further hearing loss. Anat Rec, 303:600–607, 2020. © 2019 American Association for Anatomy     

Variations in HSP70 genes associated with noise-induced hearing loss in two independent populations

Noise-induced hearing loss (NIHL) is one of the most important occupational health hazards. Millions of people worldwide are exposed daily to harmful levels of noise. NIHL is a complex disease resulting from an interaction between genetic and environmental factors. Although the environmental risk factors have been studied extensively, little is known about the genetic factors. Heat-shock proteins (HSPs) are induced after exposure to severe noise. When first induced by exposure to moderate sound levels, they can protect the ear from damage from excessive noise exposure. This protection is highly variable between individuals. An association of HSP70 genes with NIHL has been described by Yang et al (2006) in a Chinese sample set of noise-exposed workers. In this study, three polymorphisms (rs1043618, rs1061581 and rs2227956) in HSP70-1, HSP70-2 and HSP70-hom, respectively, were genotyped in 206 Swedish and 238 Polish DNA samples of noise-exposed subjects and analyzed. One SNP, rs2227956 in HSP70-hom, resulted in a significant association with NIHL in both sample sets. In addition, rs1043618 and rs1061581 were significant in the Swedish sample set. Analysis of the haplotypes composed of the three SNPs revealed significant associations between NIHL and haplotype GAC in both sample sets and with haplotype CGT in the Swedish sample set. In conclusion, this study replicated the association of HSP70 genes with NIHL in a second and third independent noise-exposed sample set, hereby adding to the evidence that HSP70 genes may be NIHL susceptibility genes.     

Unilateral auditory cortex ablation in macaques results in a contralateral hearing loss

1. The behavioral audiograms of four Japanese macaques (Macaca fuscata) were assessed before and after unilateral ablation of auditory cortex. The tones were presented via insertion earphones so that each ear could be tested separately. 2. Each animal had a hearing loss in the ear contralateral to the lesion, whereas the ipsilateral ear showed no change in sensitivity. The hearing loss initially appeared as a large shift in thresholds followed by rapid but incomplete recovery during the first 3-5 wk after surgery. The initial hearing loss ranged as high as 68 dB at some frequencies, although thresholds at other frequencies were occasionally unchanged. A threshold shift could be demonstrated with broadband noise as well as with tones. Although thresholds for some tones returned to normal within a few weeks, most were still elevated 16 wk after surgery when testing was discontinued. The largest long-term hearing losses occurred at frequencies from 4 to 25 kHz. 3. Analysis of the animals' psychophysical functions suggested that the hearing loss resembled a sensory deficit, as opposed to a nonsensory deficit in attention or vigilance. 4. Testing with binaural stimuli indicated that the hearing loss could best be described as a contralateral "ear" deficit, as opposed to a contralateral "auditory field" deficit. 5. It is suggested that a similar hearing loss occurs in humans after unilateral damage to auditory cortex.     

A recovery from enhancement of activation in auditory cortex of patients with idiopathic sudden sensorineural hearing loss

OBJECTIVE: We previously reported enhanced activation of auditory cortex in patients with bilateral chronic inner-ear hearing loss. To determine whether this enhancement can exhibit a short-term alteration, we measured auditory evoked magnetic fields (AEFs) in patients with idiopathic sudden sensorineural hearing loss (ISSHL) in the acute phase (AP) and recovery phases (RPs). METHODS: We recorded AEFs in two unilateral ISSHL patients at three time points (AP, RP1, and RP2) using a whole-head neuromagnetometer. Tone bursts of 1 kHz were presented monaurally to the affected and healthy ear at four different intensities (40-70 dB HL). RESULTS: Both patients showed the enhancement of N100 m moment at AP and not at RPs in response to the affected ear stimulation, and stronger N100 m moment in ipsilateral than contralateral hemisphere in response to the healthy ear stimulation at AP. CONCLUSIONS: Enhancement of N100 m amplitude occurs in ISSHL patients and disappears on the scale of days. Enhancement of activity in the auditory cortex derived from inner-ear hearing loss can thus exhibit short-term change. SIGNIFICANCE: The results of this study provide first evidence for a recovery from enhancement of activation in the auditory cortex following injury of peripheral hearing organ.     

F1 (CBA × C57) mice show superior hearing in old age relative to their parental strains: Hybrid vigor or a new animal model for “Golden Ears”?

Age-related hearing loss - presbycusis - is the most common communication problem and third most prevalent chronic medical disorder of the aged. The CBA and C57BL/6 mouse strains are useful for studying features of presbycusis. The CBA loses its hearing slowly, like most humans. Because the C57 develops a rapid, high frequency hearing loss by middle age, it has an “old” ear but a relatively young brain, a model that helps separate peripheral (cochlear) from central (brain) etiologies. This field of sensory neuroscience lacks a good mouse model for the 5-10% of aged humans with normal cochlear sensitivity, but who have trouble perceiving speech in background noise. We hypothesized that F1 (CBA × C57) hybrids would have better hearing than either parental strain. Measurements of peripheral auditory sensitivity supported this hypothesis, however, a rapid decline in the auditory efferent feedback system, did not. Therefore, F1s might be an optimal model for studying cases where the peripheral hearing is quite good in old age; thereby allowing isolation of central auditory changes due to brain neurodegeneration.     

Moderate noise induced cognition impairment of mice and its underlying mechanisms

Noise pollution is recognized as a serious human health problem in modern society. The aim of the present study was to explore the effects of moderate-intensity white noise exposure on learning and memory of mice, and the underlying mechanisms. The learning and memory ability of mice were evaluated by water maze and step-down inhibitory avoidance experiments respectively, following 1, 3, and 6 weeks noise exposure (80 dB SPL, 2 h/day). To explore potential mechanisms, we determined levels of oxidative stress in the inferior colliculus (IC), auditory cortex (AC), and hippocampus (the structures comprising the critical encephalic region associated with the acoustic lemniscal ascending pathway), the phosphorylation of microtubule-associated protein tau in the hippocampus (important role in learning and memory), and the basic auditory response properties of neurons in the IC. Moderate-intensity noise exposure impaired the learning and memory ability of mice in both water maze and step-down inhibitory avoidance experiments, and the longer the noise exposure time the greater the impairment. At 6 weeks after noise exposure, there was also evidence of oxidative damage in the IC, AC, and hippocampus, hyperphosphorylated tau protein in the hippocampus, and significant changes in the auditory response properties of neurons in the IC. These data results suggest that moderate-intensity noise can progressively impair the learning and memory ability of mice, which may result from peroxidative damage, tau hyperphosphorylation, and auditory coding alteration.     

Noise-induced tinnitus: auditory evoked potential in symptomatic and asymptomatic patients

OBJECTIVES:

We evaluated the central auditory pathways in workers with noise-induced tinnitus with normal hearing thresholds, compared the auditory brainstem response results in groups with and without tinnitus and correlated the tinnitus location to the auditory brainstem response findings in individuals with a history of occupational noise exposure.

METHOD:

Sixty individuals participated in the study and the following procedures were performed: anamnesis, immittance measures, pure-tone air conduction thresholds at all frequencies between 0.25–8 kHz and auditory brainstem response.

RESULTS:

The mean auditory brainstem response latencies were lower in the Control group than in the Tinnitus group, but no significant differences between the groups were observed. Qualitative analysis showed more alterations in the lower brainstem in the Tinnitus group. The strongest relationship between tinnitus location and auditory brainstem response alterations was detected in individuals with bilateral tinnitus and bilateral auditory brainstem response alterations compared with patients with unilateral alterations.

CONCLUSION:

Our findings suggest the occurrence of a possible dysfunction in the central auditory nervous system (brainstem) in individuals with noise-induced tinnitus and a normal hearing threshold.     

Effect of bilateral auditory cortex lesions on absolute thresholds in Japanese macaques

1. The behavioral audiograms of four Japanese macaques (Macaca fuscata) were assessed before and after receiving two-stage bilateral lesions of auditory cortex. Thresholds were assessed for each ear with the use of insertion earphones. 2. The bilateral lesions resulted in a large initial hearing loss followed by partial recovery that left the animals with a permanent hearing loss in both ears. 3. The initial hearing loss consisted of a total insensitivity to sound in the ear contralateral to the second lesion with limited hearing in the other ear. However, the animal with the most complete lesion was initially unable to hear sound in either ear. Broadband noise was often more effective in eliciting a behavioral response than tones. 4. Partial recovery occurred in all animals and was observed as early as the first week after surgery. Most of this recovery occurred during the first 3-7 wk after surgery. This rapid phase of recovery was sometimes followed by a more gradual phase although thresholds were still elevated after 94 wk. 5. The permanent hearing loss, which averaged from 30 to 44 dB, was not constant across frequency. Threshold shifts were smallest at 63 Hz and progressively increased with frequency to a maximum loss from 8 to 25 kHz with slightly less loss at 32 kHz. 6. Analysis of the psychophysical functions and threshold stability gave no indication of any nonsensory deficits in attention or vigilance. 7. These results, taken with those of previous experiments, indicate that each hemisphere is primarily involved in the detection of sound in the contralateral ear and secondarily involved in detection in the ipsilateral ear. This arrangement differs from that seen in sound localization where each hemisphere is involved with the contralateral hemifield as opposed to the contralateral ear. Thus it appears that the functional organization of auditory cortex for sound localization is different from that for the detection and identification of sound itself.