Bcl-2 genes regulate noise-induced hearing loss

Proteins of the Bcl-2 family have been implicated in control of apoptotic pathways modulating neuronal cell death, including noise-induced hearing loss. In this study, we assessed the expressions of anti- and proapoptotic Bcl-2 genes, represented by Bcl-xL and Bak following noise exposures, which yielded temporary threshold shift (TTS) or permanent threshold shift (PTS). Auditory brainstem responses (ABRs) were assessed at 4, 8, and 16 kHz before exposure and on days 1, 3, 7, and 10 following exposure to 100 dB SPL, 4 kHz OBN, 1 hr (TTS) or 120 dB SPL, 4 kHz OBN, 5 hr (PTS). On day 10, subjects were euthanized. ABR thresholds increased following both exposures, fully recovered following the TTS exposure, and showed a 22.6 dB (4 kHz), 42.5 dB (8 kHz), and 44.9 dB (16 kHz) mean shift on day 10 following the PTS exposure. PTS was accompanied by outer hair cell loss progressing epically and basally from the 4-kHz region. Additional animals were euthanized for immunohistochemical assessment. BcL-xL was robustly expressed in outer hair cells following TTS exposure, whereas Bak was expressed following PTS exposure. These results indicate an important role of the Bcl-2 family proteins in regulating sensory cell survival or death following intense noise. Bcl-xL plays an essential role in prevention of sensory cell death following TTS levels of noise, and PTS exposure provokes the expression of Bak and, with that, cell death. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58028/1/21533_ftp.pd

Hereditary deafness occurring in cd/1 mice

Different strains of mice provide a valuable research tool for studying both hereditary and acquired forms of deafness. The cd/1 strain has been found to demonstrate hereditary cochlear pathology. The characteristics of hearing loss in cd/1 mice have not previously been reported. In this investigation auditory thresholds were obtained by measuring evoked brain stem responses in subjects of three different ages: 3 weeks, 10 weeks and 6 months. The results were compared with thresholds obtained from CBA/Ca mice (which have normal hearing) and C57BL/6 mice (which are known to have a genetically determined pre-senile progressive cochlear hearing loss). A significant hearing loss was observed which progressed from high to low frequencies, and with age. Extensive degeneration was observed throughout the organ of Corti. cd/1 mice may provide a useful model for studying genetically determined deafness.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28997/1/0000025.pd

Deafferentiation-associated changes in afferent and efferent processes in the guinea pig cochlea and afferent regeneration with chronic intrascalar brain-derived neurotrophic factor and acidic fibroblast growth factor

Deafferentation of the auditory nerve from loss of sensory cells is associated with degeneration of nerve fibers and spiral ganglion neurons (SGN). SGN survival following deafferentation can be enhanced by application of neurotrophic factors (NTF), and NTF can induce the regrowth of SGN peripheral processes. Cochlear prostheses could provide targets for regrowth of afferent peripheral processes, enhancing neural integration of the implant, decreasing stimulation thresholds, and increasing specificity of stimulation. The present study analyzed distribution of afferent and efferent nerve fibers following deafness in guinea pigs using specific markers (parvalbumin for afferents, synaptophysin for efferent fibers) and the effect of brain derived neurotrophic factor (BDNF) in combination with acidic fibroblast growth factor (aFGF). Immediate treatment following deafness was compared with 3-week-delayed NTF treatment. Histology of the cochlea with immunohistochemical techniques allowed quantitative analysis of neuron and axonal changes. Effects of NTF were assessed at the light and electron microscopic levels. Chronic BDNF/aFGF resulted in a significantly increased number of afferent peripheral processes in both immediate- and delayed-treatment groups. Outgrowth of afferent nerve fibers into the scala tympani were observed, and SGN densities were found to be higher than in normal hearing animals. These new SGN might have developed from endogenous progenitor/stem cells, recently reported in human and mouse cochlea, under these experimental conditions of deafferentation-induced stress and NTF treatment. NTF treatment provided no enhanced maintenance of efferent fibers, although some synaptophysin-positive fibers were detected at atypical sites, suggesting some sprouting of efferent fibers. J. Comp. Neurol. 507:1602–1621, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58023/1/21619_ftp.pd

The vascular component of sodium salicylate ototoxicity in the guinea pig

Drugs of the salicylate family (aspirin-like drugs) are reversibly ototoxic. Electrophysiologic and ultrastructural evidence suggests an impairment of the sensory hair cells of the cochlea following salicylate treatment. In addition, since these drugs can cause vasoconstriction, the ototoxicity of salicylates may also involve an impairment of the blood circulation in inner ear. However, a vascular hypothesis of salicylate toxicity has not received much attention. In the current study, we simultaneously measured cochlear blood flow (by laser Doppler flowmetry) and the sound-evoked potentials from the round window. Sodium salicylate caused a decrease in cochlear blood flow that appeared within 30 min following an intramuscular injection of a low dose of sodium salicylate (100 mg/kg). This sodium salicylate dose did not cause a change in auditory sensitivity. For higher doses (200 mg/kg and 300 mg/kg), both cochlear blood flow and auditory sensitivity were affected. The 300 mg/kg dose decreased blood flow by about 25% and elevated compound action potential thresholds by 10 to 25 dB for high frequencies (>= 8 kHz). Further experiments showed that salicylate-induced threshold shifts were significantly reduced for the mid-frequencies when cochlear blood flow is increased by the vasodilating drug hydralazine (negating the flow reduction caused by salicylate). These data indicate that in addition to the direct effect of systemically administered salicylate on neurosensory function a decreased blood flow contributes to the ototoxicity of salicylates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30594/1/0000231.pd

Contribution of the anterior inferior cerebellar artery to cochlear blood flow in guinea pig: A model-based analysis

This study was performed to determine the contribution of the anterior inferior cerebellar artery (AICA) to cochlear blood flow (CBF) in guinea pig. The AICA and the basilar-vertebral arterial complex in twelve animals was exposed through the basal portion of the skull. The cochlea was ventrally approached and the CBF of the apical area monitored with laser Doppler flowmetry. A specially designed microclamp was held in a micromanipulator and used to obstruct the AICA. When the AICA was clamped, CBF decreased to approximately 60% of baseline (BL) (not to `biological zero'), followed by a gradual increase. When the clamp was released, CBF quickly increased to more than 160% BL and then slowly declined to baseline. To quantify the contribution of AICA to CBF, we formulated an electrical analog model of the cochlear vessel system. With this model, AICA contribution to CBF and the relationship among blood pressure, blood flow, and vascular resistance or vascular conductance in the cochlea can be explored. Results in the present study indicate that the AICA contributes only about 45% of CBF to the cochlea; 55% of CBF must come from other supplying vessels. Contrary to previous reports, CBF response to AICA clamping did not exhibit a stable or constant decrease but showed time-dependent dynamic changes. In addition, the cochlear vascular system showed a marked autoregulatory response, instead of a passive response, to the perfusion pressure change. AICA clamping is, therefore, not a suitable model for investigation of ischemia effects in the guinea pig cochlea, but it is a useful approach to study autoregulation and the myogenic mechanism of the cochlear vascular system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30403/1/0000023.pd

Effects of vasodilating agents on cochlear blood flow in mice

The mouse has several distinct advantages as an experimental model for study of the cochlear blood flow (CBF) in the mammal, particularly for studies involving genetic manipulation, development and aging factors. In this investigation we evaluated the effects of selected vasodilating agents on CBF using laser-Doppler flowmetry. Sodium nitroprusside, hydralazine and pentoxifylline were applied topically on the round window (RW) or systemically by a subcutaneous injection. Topical application of sodium nitroprusside and hydralazine elevated CBF significantly, while systemic administrations of these two drugs failed to elevate CBF consistently. Pentoxifylline did not change CBF following topical application but increased CBF slightly following systemic administration. Age and gender did not influence the CBF response to topical application of sodium nitroprusside.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31209/1/0000111.pd

Pure tone overstimulation changes the micromechanical properties of the inner hair cell stereocilia

The effect of permanent noise-induced hearing loss on the auditory brainstem response (ABR) and the micromechanical properties of cochlear hair cell stereocilia in guinea pigs was investigated. The threshold of movement of the stereocilia was measured by applying force from a fluid filled pipette. After exposure to a 1.0 kHz pure tone signal at 105 dB(A) for 72 h the threshold of the ABR was broadly elevated by approximately 50 dB. Inner hair cell stereocilia showed a decrease in threshold while the outer hair cell stereocilia bundles remained unaltered. This effect was localized to the 13-15 mm distance from the stapes corresponding to the region of maximal stimulation. The effect was recorded within 1 h of exposure and remained constant with exposures up to 7 days. Following a one month recovery period from sound exposure, normal threshold values of stereocilia movement were observed, indicating recovery. At this time, swelling of the afferent dendrites beneath the inner hair cells was observed throughout the cochlea together with approximately 30% scattered loss of outer hair cells in the 13 to 15 mm region. The ABR showed some recovery (approximately 20 dB), yet a threshold shift remained.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26868/1/0000433.pd

Chronic drug infusion into the scala tympani of the guinea pig cochlea

This research describes a unique, effective and inexpensive delivery system to provide discrete quantities of drugs on a chronic basis to the inner ear. The amount of the drug administered and specific timing of each administration are under investigator control. A micro-injection system mounted atop an animal's head is shown to permit repeated application of agents which effectively block neural responsiveness (tetrodotoxin) on a daily basis for periods up to 2 weeks. Cannulation of the inner ear and chronic delivery of control substances (artificial perilymph) do not affect function. This system may be used to administer drugs to other compartments of the body (e.g., the brain) on a chronic basis for neurophysiologic and neuropharmacologic investigations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29802/1/0000148.pd

Effect of anesthesia on acoustically evoked middle latency response in guinea pigs

Increased recent interest in the middle latency response (MLR) has necessitated a clarification of the possible effects of anesthesia on the response. Our study was designed to examine the changes, in the guinea pig MLR, which occurred during anesthesia with ketamine, xylazine or both ketamine and xylazine. Under anesthesia the response remained present and the threshold remained stable. After anesthesia, significant changes in amplitude, latency, and general morphology of the waveform took place, however these were consistent and predictable. For studies requiring the MLR, it is best to avoid anesthetic agents. However, with care the MLR can be used as a reliable measure of auditory system sensitivity under anesthesia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28810/1/0000644.pd

Autoregulation of cochlear blood flow in young and aged mice

Autoregulation is the capacity of an organ system to maintain organ blood flow constant in response to changes in arterial blood pressure (BP). The current study was carried out to investigate the effect of age on autoregulation of cochlear blood flow (CBF) in mice. CBF was measured using a laser-Doppler flowmeter while BP was increased by angiotensin 11 injections and decreased by exsanguination in 2-month-old, 10-month-old and 18-month-old CBA mice. Autoregulation of CBF was significantly weaker in the 2-month-old mice when compared to the older mice. Although CBF autoregulation was weaker in the 18-month-old mice compared to the 10-month-old mice, this difference was not statistically significant. These results suggest that autoregulation changes with maturation and age. Findings are discussed in relationship to the possible development of presbycusis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47278/1/405_2004_Article_BF00185395.pd