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

L-PGDS (Betatrace Protein) Inhibits Astrocyte Proliferation and Mitochondrial ATP Production in Vitro

L-PGDS is the most abundant protein present in the cerebrospinal fluid (CSF). Although CSF was believed to be homogenous in content, a previous study has showed that a marked concentration gradient of L-PGDS exists between the spinal CSF and the CSF in the subarachnoid space of patients with optic nerve disease (papilledema and normal-tension glaucoma). Astrocytes play a critical role in maintaining the integrity of axon function in the central nervous system and specifically in the optic nerve, and we therefore investigated the biochemical effects of L-PGDS on the proliferation of astrocytes and on the production of adenosine triphosphate (ATP) by astrocyte mitochondria. We found an inhibitory effect of L-PGDS on both proliferation of astrocytes and production of astrocyte ATP. The concentrations that inhibited astrocyte proliferation and ATP production were in the range measured in patients with idiopathic intracranial hypertension and in patients with normal-tension glaucoma. As the CSF is in contact with axons and mitochondria of the optic nerve (Bristow et al. Archives of Ophthalmology, 120, 791-796, 2002), we postulate that a change in the concentration of CSF protein such as L-PGDS could exercise a harmful effect on these structure

Towards a reflexive turn in the governance of global environmental expertise the cases of the IPCC and the IPBES

The role and design of global expert organizations such as the Intergovernmental Panel on Climate Change (IPCC) or the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) needs rethinking. Acknowledging that a one-size-fits-all model does not exist, we suggest a reflexive turn that implies treating the governance of expertise as a matter of political contestation

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