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• Small arms fire-like noise induced loss of inner hair cell synaptic ribbons in rat cochleae. • Small arms fire-like noise also reduced Gap Detection many noise-induced rats, this can be associated with Tinnitus. • Noise-exposed rats with reduced Gap Detection had greater loss of hair cell ribbons than those with normal Gap Detection. • Piribedil, memantine, and ACEMg treatment significantly reduced the noise-induced loss of ribbons. • A treatment induced reduction in incidence of noise-induced reduced Gap Detection did not reach significance. A noise-induced loss of inner hair cell (IHC) – auditory nerve synaptic connections has been suggested as a factor that can trigger the progression of maladaptive plastic changes leading to noise-induced tinnitus. The present study used a military relevant small arms fire (SAF)-like noise (50 biphasic impulses over 2.5 min at 152 dB SPL given unilaterally to the right ear) to induce loss (∼1/3) of IHC synaptic ribbons (associated with synapse loss) in rat cochleae with only minor (less than 10%) loss of outer hair cells. Approximately half of the noise-exposed rats showed poorer Gap Detection post-noise, a behavioral indication suggesting the presence of tinnitus. There was significantly greater loss of IHC ribbons in noise-exposed rats with reduced Gap Detection compared to noise-exposed rats retaining normal Gap Detection. We have previously shown systemic administration of piribedil, memantine, and/or ACEMg significantly reduced loss of IHC ribbons induced by a 3 h 4 kHz octave band 117 dB (SPL) noise. The present study examined if this treatment would also reduce ribbon loss from the SAF-like noise exposure and if this would prevent the reduced Gap Detection. As in the previous study, piribedil, memantine, and ACEMg treatment significantly reduced the noise-induced loss of ribbons, such that it was no longer significantly different from normal. However, it did not prevent development of the reduced Gap Detection indication of tinnitus in all treated noise-exposed rats, reducing the incidence but not reaching significance. [ABSTRACT FROM AUTHOR]

• A single exposure to noise given to young mice that does not cause immediate permanent hearing loss will accelerate and enhance later age-related hearing loss. • The effects of noise in youth on age-related hearing loss is largely an acceleration, with age-related hearing appearing earlier. • Different noise exposure conditions cause different paces and patterns of accelerated age-related hearing loss. Many factors contribute to hearing loss commonly found in older adults. There can be natural aging of cellular elements, hearing loss previously induced by environmental factors such as noise or ototoxic drugs as well as genetic and epigenetic influences. Even when noise overstimulation does not immediately cause permanent hearing loss it has recently been shown to increase later age-related hearing loss (ARHL). The present study further investigated this condition in the UMHET4 mouse model by comparing a small arms fire (SAF)-like impulse noise exposure that has the greatest immediate effect in more apical cochlear regions to a broadband noise (BBN) exposure that has the greatest immediate effect in more basal cochlear regions. Both noise exposures were given at levels that only induced temporary auditory brainstem response (ABR) threshold shifts (TS). Mice were noise exposed at 5 months of age followed by ABR assessment at 6, 12, 18, 21, and 24 months of age. Mice that received the SAF-like impulse noise had accelerated age-related TS at 4 kHz that appeared at 12 months of age (significantly increased compared to no-noise controls). This increased TS at 4 kHz continued at 18 and 21 months but was no longer significantly greater at 24 months of age. The SAF-like impulse noise also induced a significantly greater mean TS at 48 kHz, first appearing at 18 months of age and continuing to be significantly greater than controls at 21 and 24 months. The BBN induced a different pace and pattern of enhanced age-related ABR TS. The mean TS for the BBN group first became significantly greater than controls at 18 months of age and only at 48 kHz. It remained significantly greater than controls at 21 months but was no longer significantly greater at 24 months of age. Results, therefore, show different influences on ARHL for the two different noise exposure conditions. Noise-induced enhancement appears to provide more an acceleration than overall total increase in ARHL. [ABSTRACT FROM AUTHOR]

Abstract: The successful function of cochlear prostheses depends on activation of auditory nerve. The survival of auditory nerve neurons, however, can vary widely in candidates for cochlear implants and influence implant efficacy. Stem cells offer the potential for improving the function of cochlear prostheses and increasing the candidate pool by replacing lost auditory nerve. The first phase of studies for stem cell replacement of auditory nerve has examined the in vitro survival and differentiation as well as in vivo differentiation and survival of exogenous embryonic and tissue stem cells placed into scala tympani and/or modiolus. These studies are reviewed and new results on in vivo placement of B-5 mouse embryonic stem cells into scala tympani of the guinea pig cochleae with differentiation into a glutamatergic neuronal phenotype are presented. Research on the integration and connections of stem cell derived neurons in the cochlea is described. Finally, an alternative approach is considered, based on the use of endogenous progenitors rather than exogenous stem cells, with a review of promising findings that have identified stem cell-like progenitors in cochlear and vestibular tissues to provide the potential for auditory nerve replacement. [Copyright &y& Elsevier]

Abstract: Tyrosine hydroxylase (TH), a key enzyme in the catecholaminergic pathway, allows for the differentiation of dopaminergic neurons. We previously showed decreases in TH gene expression in the rat inferior colliculus (IC) 3 and 21 days following deafness. In the present study, we characterized the normal distribution of TH as well as changes following deafness (bilateral cochlear ablation) in the IC and nuclei of the lateral lemniscus. Immunostaining was compared in three groups of rats: normal hearing (n =8), 21 day deaf (n =5) and 90 days following deafening (n =5). Many TH immunoreactive fibers and puncta were identified in the IC and nuclei of the lateral lemniscus of normal hearing animals and labeling was most dense in the external cortex of the IC. We also identified immunolabeling for fibers and puncta for another catecholaminergic enzyme, dopamine β hydroxylase (DBH), but not phenylethanolamine-N-methyltranferase (PNMT). Neurons immunopositive for TH but not DBH or PNMT were observed in the dorsal cortex and dorsal horn of the central nucleus of the IC and ventral and intermediate lemniscus. In the central nucleus of the IC and dorsal lateral lemniscus many lightly labeled TH neurons were also DBH positive. Although the number of immunopositive cells in the IC and lemniscus declined 3 weeks and 3 months after deafening, the decline was not significant at three weeks in the VNLL nor after three months in the dorsal cortex. Immunolabeling for TH decreased significantly in IC and lemniscus 3 weeks and 3 months following deafening. These results suggest a role for dopaminergic neurons and fibers in deafness-related plasticity. [Copyright &y& Elsevier]

The role of the cochlea is to transduce complex sound waves into electrical neural activity in the auditory nerve. Hair cells of the organ of Corti are the sensory cells of hearing. The inner hair cells perform the transduction and initiate the depolarization of the spiral ganglion neurons. The outer hair cells are accessory sensory cells that enhance the sensitivity and selectivity of the cochlea. Neural feedback loops that bring efferent signals to the outer hair cells assist in sharpening and amplifying the signals. The stria vascularis generates the endocochlear potential and maintains the ionic composition of the endolymph, the fluid in which the apical surface of the hair cells is bathed. The mechanical characteristics of the basilar membrane and its related structures further enhance the frequency selectivity of the auditory transduction mechanism. The tectorial membrane is an extracellular matrix, which provides mass loading on top of the organ of Corti, facilitating deflection of the stereocilia. This review deals with the structure of the normal mature mammalian cochlea and includes recent data on the molecular organization of the main cell types within the cochlea. [Copyright &y& Elsevier]

Abstract: A genetically heterogeneous population of mice was tested for hearing at 8, 18, and 22 months by auditory brainstem response (ABR), and genotyped at 128 markers to identify loci that modulate late life hearing loss. Half of the test mice were exposed to noise for 2 hours at age 20 months. Polymorphisms affecting hearing at 18 months were noted on chromosomes 2, 3, 7, 10, and 15. Most of these loci had effects only on responses to 48 kHz stimuli, but a subset also influenced the auditory brainstem response at lower frequencies. Loci on chromosomes 4, 10, 12, and 14 had significant effects on hearing at 22 months in noise-exposed mice, and loci on chromosomes 10 and 11 had effects on mice not exposed to noise. Outer hair cell loss was modulated by polymorphisms on chromosomes 10, 11, 12, 17, and 19. Resistance to age-related hearing loss is thus modulated by a set of genetic effects, some age-specific, some frequency specific, some dependent on prior exposure to noise, and some of which compromise survival of cochlear hair cells. [Copyright &y& Elsevier]

In order to assess the role of L-type voltage-gated calcium channels in electrical stimulation-mediated neuroprotection in vivo, we assessed survival of primary auditory afferents (spiral ganglion cells) in systemically deafened guinea pigs following chronic electrical stimulation with or without intracochlear infusion of verapamil, an L-type voltage-gated calcium channel antagonist. Continuous intracochlear drug delivery (0.5 μl/h) was provided using a delivery system developed previously in our laboratory using Alzet® mini-osmotic pumps. In the absence of chronic stimulation, spiral ganglion cell survival was relatively symmetric in animals treated unilaterally with either artificial perilymph or verapamil (50 μg/ml). In the presence of unilateral chronic electrical stimulation, spiral ganglion cell survival was significantly greater in stimulated, perilymph-infused ears, relative to the contralateral ear. In contrast, spiral ganglion cell survival was bilaterally symmetric in chronically stimulated, verapamil-infused animals. The difference in symmetry of spiral ganglion cell survival between the two groups was statistically significant. In vitro, passive depolarization has been demonstrated to enhance survival of cultured neurons via activation of L-type calcium channels. The results of this study indicate that, as suggested by in vitro depolarization models, in vivo electrical stimulation-mediated neuroprotection requires the activation of L-type voltage-gated calcium channels. Chronic electrical stimulation of the deaf ear is an ideal preparation for further studies in which to extrapolate findings from in vitro depolarization models. [Copyright &y& Elsevier]

Neurons of the lateral olivocochlear (LOC) system project from the auditory brainstem to the cochlea, where they synapse on radial dendrites of auditory nerve fibers. Selective LOC disruption depresses sound-evoked auditory nerve activity in the guinea pig, but enhances it in the mouse. Here, LOC disruption depressed spontaneous auditory nerve activity in the guinea pig. Recordings from single auditory nerve fibers revealed a significantly reduced proportion of fibers with the highest spontaneous firing rates (SRs) and an increased proportion of neurons with lower SRs. Ensemble activity, estimated using round window noise, also decreased after LOC disruption. Decreased spontaneous activity after LOC disruption may be a consequence of reduced tonic release of excitatory transmitters from the LOC terminals in guinea pigs. [ABSTRACT FROM AUTHOR]

Abstract: Commercially obtained aged male CBA/J mice presented a complex pattern of hearing loss and morphological changes. A significant threshold shift in auditory brainstem responses (ABR) occurred at 3 months of age at 4kHz without apparent loss of hair cells, rising slowly at later ages accompanied by loss of apical hair cells. A delayed high-frequency deficit started at 24kHz around the age of 12 months. At 20–26 months, threshold shifts at 12 and 24kHz and the accompanying hair cell loss at the base of the cochlea were highly variable with some animals appearing almost normal and others showing large deficits. Spiral ganglion cells degenerated by 18 months in all regions of the cochlea, with cell density reduced by approximately 25%. There was no degeneration of the stria vascularis and the endocochlear potential remained stable from 3 to 25 months of age regardless of whether the animals had normal or highly elevated ABR thresholds. The slow high-frequency hearing loss combined with a modest reduction of ganglion cell density and an unchanged endocochlear potential suggest sensorineural presbycusis. The superimposed early hearing loss at low frequencies, which is not seen in animals bred in-house, may complicate the use of these animals as a presbycusis model. [Copyright &y& Elsevier]

Abstract: Two-pore domain potassium channels play an important role in setting resting membrane potential by regulating background leakage of potassium ions, which in turn controls neuronal excitability. To determine whether these channels contribute to activity-dependent plasticity following deafness, we used quantitative real-time PCR to examine the expression of 10 subunits in the rat cochlear nucleus at 3 days, 3 weeks and 3 months after bilateral cochlear ablation. There was a large sustained decrease in the expression of TASK-5, a subunit that is predominantly expressed in auditory brain stem neurons, and in the TASK-1 subunit which is highly expressed in several types of cochlear nucleus neurons. TWIK-1 and THIK-2 also showed significant decreases in expression that were maintained across all time points. TWIK-2, TREK-1 and TREK-2 showed no significant change in expression at 3 days but showed large decreases at 3 weeks and 3 months following deafness. TRAAK and TASK-3 subunits showed significant decreases at 3 days and 3 weeks following deafness, but these differences were no longer significant at 3 months. Dramatic changes in expression of subunits suggest these channels may play a role in deafness-associated changes in the excitability of cochlear nucleus neurons. [Copyright &y& Elsevier]

In mammals, exposure to intense noise produces a permanent hearing loss called permanent threshold shift (PTS), whereas a moderate noise produces only a temporary threshold shift (TTS). Little is known about the molecular responses to such high intensity noise exposures. In this study we used gene arrays to examine the early response to acoustic overstimulation in the rat cochlea. We compared cochlear RNA from noise-exposed rats with RNA from unexposed controls. The intense PTS noise induced several immediate early genes encoding both transcription factors (c-FOS, EGR1, NUR77/TR3) and cytokines (PC3/BTG2, LIF and IP10). In contrast, the TTS noise down-regulated the gene for growth hormone. The response of these genes to different noise intensities was examined by quantitative RT-PCR 2.5 h after the 90-min noise exposure. For most genes, the extent of induction correlates with the intensity of the noise exposure. Three proteins (EGR1, NUR77/TR3, and IP10) were detected in many regions of the unexposed cochlea. After exposure to 120 dB noise, these proteins were present at higher levels or showed extended expression in additional regions of the cochlea. LIF was undetectable in the cochlea of unexposed rats, but could be seen in the organ of Corti and spiral ganglion neurons following noise. NUR77/TR3 was a nuclear protein before noise, but following noise translocated to the cytoplasm. These studies provide new insights into the molecular response to noise overstimulation in the mammalian cochlea. [Copyright &y& Elsevier]

The genes for heat shock proteins (Hsps) can be upregulated in response to cellular trauma, resulting in enhanced cell survival and protection. Hsp32, also known as heme oxygenase 1, catalyzes the degradation of heme to produce carbon monoxide and bilirubin, which play a variety of cytoprotective functions at physiological concentrations, and iron, which is rapidly sequestered by the iron-binding protein ferritin. In the present study we examined the expression and localization of Hsp32 in the rat cochlea after heat shock using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunocytochemistry. Low levels of constitutive Hsp32 expression were observed in the normal rat cochlea by RT-PCR and Western blot. Hsp32 mRNA (messenger RNA) was present at higher levels in a subfraction containing sensorineural epithelium and lateral wall than in a subfraction containing modiolus. Western blot revealed that Hsp32 protein levels increase in the rat cochlea following heat shock. Immunocytochemistry showed scattered staining of outer hair cells in the organ of Corti of normal untreated rats. Following heat shock Hsp32 is upregulated in outer hair cells and the cells of the stria vascularis. These results suggest a potential role for Hsp32 as a component of the oxidative stress response pathway in the rat cochlea. [Copyright &y& Elsevier]

Activation of heat shock factors (Hsfs) is one of the potential mechanisms for regulating the transcription of the heat shock proteins (Hsps) and certain other stress-responsive genes. Reverse transcription polymerase chain reaction (RT-PCR), Western blot and immunocytochemistry were used to examine the expression and localization of Hsf1, the stress-responsive member of the Hsf family, in the rat and mouse cochlea. Cerebellum was used as a positive control. Semi-quantitative RT-PCR of cochlear RNA revealed that Hsf1 was more highly expressed in a subfraction containing sensorineural epithelium and lateral wall than in a subfraction containing modiolus, with the α splice form predominant over the β in both subfractions. Immunocytochemistry showed selective staining in the rodent cochlea. Hsf1 immunostaining was found in the nuclei of inner and outer hair cells in the organ of Corti, spiral ganglion cells in the modiolus, and cells in the marginal and intermediate layers of the stria vascularis. This is largely consistent with where Hsp70 induction is reported. Hsf1 activation following heat shock was examined by Western blot. Hyperthermia resulted in stress-induced Hsf1 hyperphosphorylation in cochlea as well as cerebellum. This hyperphosphorylation as well as the correlation of its localization with Hsp70 induction supports a role for Hsf1 in the cochlear stress response. [Copyright &y& Elsevier]

Heat shock protein-27 (Hsp27) is known to function as both a stress-inducible molecular chaperone and regulator of actin polymerization. For many cells in the cochlea, actin is part of the cytoskeleton and plays an important role in the maintenance of cochlear function. To understand the molecular processes by which the cochlear actin cytoskeleton is maintained and regulated during normal auditory function, we examined the expression and localization of Hsp27 in the normal rat cochlea. Reverse transcription-polymerase chain reaction and Western blot showed constitutive expression of Hsp27 in the normal rat cochlea. Immunofluorescence microscopy showed Hsp27-like staining is localized to the cuticular plate and lateral wall of outer hair cells. Hsp27-like immunostaining is also found in tension fibroblasts, in the root cells of the spiral limbus and in Reissner’s membrane. The presence of Hsp27 in the actin-rich tension fibroblasts and outer hair cells suggests a potential role in the regulation and maintenance of the actin cytoskeleton in these cells. The presence of high levels of constitutive Hsp27 may also provide a mechanism for pre-protecting these cells against environmental stressors. [Copyright &y& Elsevier]