Biomedical subjects

Barbara Canlon

Publications and source records attributed to Barbara Canlon.

At least 19 recordsLinked to original sources

PubMed2006

Sound conditioning protects hearing by activating the hypothalamic-pituitary-adrenal axis.

Sound conditioning primes the auditory system to low levels of acoustic stimuli and reduces damage caused by a subsequent acoustic trauma. This priming activates the HPA axis resulting in the elevation of plasma corticosterone with a consequent upregulation of glucocorticoid receptors (GR) in the cochlea and the paraventricular nucleus (PVN) of the hypothalamus in the mouse. This protective effect is blocked by adrenalectomy or pharmacological treatment with RU486 + metyrapone. Sound conditioning prevents GR down-regulation induced by acoustic trauma and subsequently enhances GR activity in spiral ganglion neurons. Increased SRC-1 expression, triggered by sound conditioning, positively correlates with the upregulation of GR in the cochlea. These findings will help to define the cellular mechanisms responsible for protecting the auditory system from hearing loss by sound conditioning.

Acoustic Stimulation↗

PubMed2006

N-Acetyl L-cysteine does not protect against premature age-related hearing loss in C57BL/6J mice: a pilot study.

A compound capable of preventing age-related hearing loss would be very useful in an aging population. N-acetyl-L-cysteine (L-NAC) has been shown to be protective against noise exposure, a condition that leads to increased oxidative stress. Not withstanding environmental factors, there is evidence that age-related hearing loss (AHL) in the mouse is linked to more than one genetic loci and, by extension, in humans. Our hypothesis is that AHL defect results in increased sensitivity to oxidative stress and L-NAC would be able to protect the hearing of a mouse model of pre-mature AHL, the C57BL/6J (B6) mouse strain. L-NAC was added to the regular water bottle of B6 mice (experimental group) and available ad lib. The other group received normal tap water. Hearing was tested monthly by the ability to generate the auditory brainstem response (ABR). After the final ABR test, mice were sacrificed by an overdose of Avertin, ears were harvested and hair cell loss was quantified. There was no difference in ABR thresholds or in histopathology between the control group and the group receiving L-NAC in their drinking water. In contrast to the protective effects of L-NAC against noise-induced hearing loss, the lack of protective effect in this study may be due to (i) the dosage level; (ii) the duration of treatment; (iii) the biochemical mechanisms underlying age-induced hearing loss; or (iv) how the mouse metabolizes L-NAC.

Acetylcysteine↗

PubMed2006

Glucocorticoid receptors modulate auditory sensitivity to acoustic trauma.

Glucocorticoids are widely used to treat different hearing disorders yet the exact mechanisms of glucocorticoid action on the inner ear are not known. The inner ear of both humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GRs) in both neuronal and non-neuronal tissues. In this review, we discuss how activation of the hypothalamic-pituitary-adrenal axis can directly modulate hearing sensitivity. Recent findings indicate that several factors define the responsiveness of the peripheral auditory system to glucocorticoids including the concentration of agonist, availability of the GR, and the activation of GR and NF-kappaB. These findings will further our understanding of individual glucocorticoid responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Animals↗

PubMed2006

Restraint stress modulates glucocorticoid receptors and nuclear factor kappa B in the cochlea.

The regulation of glucocorticoid receptors and nuclear factor kappaB was evaluated in the spiral ganglion neurons after 4 h of restraint stress in the mouse cochlea. Immediately after restraint stress, glucocorticoid receptor protein expression was not altered in spiral ganglion neurons even though both the plasma corticosterone levels and glucocorticoid receptor nuclear translocation increased. By 24 h after restraint stress, the protein expression of glucocorticoid receptors was decreased in spiral ganglion neurons. Pre-treatment with RU486 and metyrapone prevented nuclear translocation of glucocorticoid receptors and nuclear factor kappaB. Moreover, the synthesis of nuclear factor kappaB protein (p65) and inhibitory factor kappaBalpha decreased when RU486 and metyrapone treatment was given before restraint stress. These findings suggest that restraint stress modulates glucocorticoid receptor and nuclear factor kappaB activity in the spiral ganglion neurons, resulting in an altered response to stress.

Analysis of Variance↗

PubMed2006

Glucocorticoid receptor and nuclear factor-kappa B interactions in restraint stress-mediated protection against acoustic trauma.

The role of glucocorticoid receptors (GRs) in the protective effect of restraint stress (RS) before acoustic trauma was studied in spiral ganglion neurons of CBA mice. RS increased corticosterone and protected against elevated auditory brain stem thresholds caused by acoustic trauma. This protection was inhibited by the pretreatment with a corticosterone synthesis inhibitor, metyrapone (MET), and a GR antagonist (RU486). RS followed by acoustic trauma caused an immediate increase in corticosterone that triggered nuclear translocation of GR, without a change in the expression of GR protein. RU486 + MET before RS and acoustic trauma caused an immediate increase in GR mRNA followed by increased GR protein expression (24 h after trauma). GR signaling was further characterized by analyzing nuclear factor-kappaB (NF kappaB) nuclear translocation and protein expression. NF kappaB nuclear translocation was reduced after acoustic trauma or pretreatment with RU486 + MET before RS and acoustic trauma. On the contrary, RS protected against the trauma-induced NF kappaB reduction of its nuclear translocation in inhibitory-kappaB (I kappaB)-dependent manner. RU486 + MET caused a simultaneous decreased I kappaB expression and NF kappaB nuclear translocation, demonstrating an interference with the I kappaB-mediated activation of NF kappaB. In summary, RS protects the cochlea from acoustic trauma by increasing corticosterone and activating GRs. These results emphasis how GR activity modulates hearing sensitivity and its importance for the rationale use of glucocorticoids in inner ear diseases.

Animals↗

PubMed2006

NF-kappaB mediated glucocorticoid response in the inner ear after acoustic trauma.

The inner ear of humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GR). Glucocorticoids (GC) are widely used to treat different hearing disorders; yet the mechanisms of GC action on the inner ear are unknown. We demonstrate how GR can directly modulate hearing sensitivity in response to a moderate acoustic trauma that results in a hearing loss (10-30 dB). The GC agonist (dexamethasone) and the drugs (metyrapone + RU 486) showed opposing effects on hearing threshold shifts. GC agonist (dexamethasone) decreased the hearing threshold whereas pre-treatment with a GC synthesis inhibitor (metyrapone) in combination with a GR antagonist (RU 486) exacerbated auditory threshold shifts (25-60 dB) after acoustic trauma with statistically significant increase in GR mRNA and GR protein compared with the vehicle and acoustic trauma group. Acoustic trauma caused a significant increase in the nuclear transport of NF-kappaB, whereas pre-treatment with the drugs (metyrapone and RU 486) blocked NF-kappaB nuclear transport into spiral ganglion nuclei. An NF-kappaB inhibitor, pyrrolidine dithiocarbamate ammonium blocked the trauma-induced translocation of NF-kappaB and resulted in a hearing loss (45-60) dB. These results indicate that several factors define the responsiveness of the inner ear to GC, including the availability of ligand or receptor, and the nuclear translocation of GR and NF-kappaB. These findings will further our understanding of individual GC responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Acoustic Stimulation↗

PubMed2005

Age-related changes in cochlear and brainstem auditory functions in Fischer 344 rats.

Auditory function in Fischer 344 (F344) and Long Evans (LE) rats was monitored during their lifespan by evaluating hair cell loss, middle-ear compliance and the recording of otoacoustic emissions and auditory brainstem responses. The results revealed a faster deterioration of hearing function in F344 rats compared with LE rats, resulting in larger hearing threshold shifts, a decrease in the latency and amplitude of click-evoked auditory brainstem responses, diminution of the distortion product otoacoustic emissions and a decrease in middle-ear compliance. However, hair cell loss, observed only at the most basal and apical parts of the organ of Corti, was comparable in older individuals of both rat strains. The results suggest involvement of cochlear (stria vascularis) and extracochlear (middle-ear) pathological changes during ageing. Thus, F344 rats represent a complex mix of conductive hearing loss (with low-frequency threshold shift, declining parameters of the middle-ear admittance and asymmetric otoacoustic emissions) and sensorineural hearing loss (with a decrease in the amplitudes of auditory brainstem response and a high-frequency threshold shift).

Aging↗

PubMed2004

Protection against acoustic trauma by forward and backward sound conditioning.

The purpose of the present study was to determine if short-term sound conditioning provides protection when delivered either before (forward sound conditioning) or after (backward sound conditioning) a traumatic exposure in the guinea pig. Two different sound conditioning paradigms were studied (1 kHz, 81 dB SPL, 24 h; 6.3 kHz, 78 dB SPL, 24 h). The 1-kHz forward sound conditioning paradigm (81 dB SPL, 24 h) protected distortion product otoacoustic emissions (DPOAEs) against a short-duration acoustic trauma (2.7 kHz, 103 dB SPL, 5 min) compared to the group exposed to the acoustic trauma alone. The 1-kHz forward sound conditioning paradigm (81 dB SPL, 24 h) also protected both the auditory brainstem response (ABR) thresholds and DPOAEs against a longer-duration acoustic trauma (2.7 kHz, 103 dB SPL, 30 min). The group exposed to the acoustic trauma alone showed ABR threshold shifts between 15 and 24 dB, and DPOAE amplitude shifts between 11 and 24 dB, while the group with 1-kHz forward sound conditioning showed statistically significant protection at all ABR frequencies and at all DPOAE frequencies. The 1-kHz backward sound conditioning paradigm protected against acoustic trauma (2.7 kHz, 103 dB SPL, 30 min). The ABR thresholds were protected at 1, 2 and 4 kHz, and DPOAEs at all frequencies (except 8 kHz) when compared to the group exposed only to the acoustic trauma. The 6.3-kHz forward sound conditioning paradigm protected against acoustic trauma (5.5 kHz, 109 dB SPL, 30 min) at 6.3, 8 and 10 kHz. The 6.3-kHz backward sound conditioning paradigm showed no protection against acoustic trauma at any DPOAE frequency. Taken together, these findings are important for understanding how the auditory system can be modulated by acoustic stimulation and highlights the importance of the acoustic environment during the recovery process of the auditory system.

Acoustic Stimulation↗

PubMed2004

The guide to plotting a cochleogram.

The cochleogram is commonly used for illustrating hair cell loss after insult, yet standardized procedures for plotting either individual or averaged cochleograms are lacking despite more than 40 years of use. Due to the intra-species variation in basilar membrane (BM) length, it is important that length is plotted on the cochleogram in percent and not millimeter. It is also of interest to correlate the location of lesion to frequency by using a frequency-place equation. However, there is no consensus as which equation is most suitable for the species under study. This is an important issue since two different equations can result in significantly different frequency-place maps for the same cochlea. The purpose of this presentation is to suggest procedures for standardizing the cochleogram. The guidelines include: (i) basilar membrane length should be plotted as percent instead of millimeter due to the biological variation that exists in BM length within a particular species and strain, and the total length in millimeter stated on the cochleogram; (ii) the equations used for frequency-place maps should be stated on the cochleogram; (iii) different basilar membrane lengths should be normalized to percent before averaged cochleograms are made. These procedures are illustrated and discussed.

Animals↗

PubMed2004

Age-related increases in calcium-binding protein immunoreactivity in the cochlear nucleus of hearing impaired C57BL/6J mice.

Aging C57BL/6J (C57) mice (1-30 months old), were used to study calcium-binding protein immunoreactivity (parvalbumin, calbindin and calretinin) in the cochlear nucleus. A quantitative stereological method, the optical fractionator was used to determine the total number of neurons, and the total number of immunostained neurons in the posteroventral- and dorsal cochlear nuclei (PVCN and DCN). A statistically significant age-related decrease of the total number of neurons was found in the PVCN and DCN using Nissl staining. In the DCN, an age-related increase in the total number of parvalbumin-positive neurons was found, while no changes in the total number of calbindin or calretinin positive neurons were demonstrated. In the PVCN, the total number of parvalbumin, calbindin, or calretinin positive neurons remained stable with increasing age. The percentage of parvalbumin, calbindin, and calretinin positive neurons significantly increased in the DCN, and the percentage of parvalbumin and calbindin-positive neurons increased in the PVCN. These findings imply that there is a relative up-regulation of calcium-binding proteins in neurons that had not previously expressed these proteins. This plastic response in the profoundly hearing impaired C57 mouse may be a survival strategy for cochlear nucleus neurons.

Adaptation, Physiological↗

PubMed2003

Suppression of apoptosis occurs in the cochlea by sound conditioning.

Apoptosis plays a critical role in the pathogenesis of noise-induced hearing loss. The goal of this study was to determine if apoptotic pathways are suppressed by sound conditioning. Sound conditioning is a pretreatment to low-level non-damaging sound that protects against a subsequent damaging acoustic trauma. Sound conditioning protects against hair cell death and thereby preserves hearing after a subsequent acoustic trauma. Using a combination of immunocytochemical and Western blotting techniques we show that acoustic trauma causes the release of cytochrome c from the mitochondria into the cytoplasm, and a decrease in bcl-2 immunoreactivity in the outer hair cells. Sound conditioning was found to trigger a protection against these detrimental changes. These data suggest that bcl-2 plays an important role in the regulation of hair cell death, and provides evidence that bcl-2 acts as an inducible neuroprotective gene that is upregulated by sound conditioning.

Acoustic Stimulation↗

PubMed2003

Auditory peripheral influences on calcium binding protein immunoreactivity in the cochlear nucleus during aging in the C57BL/6J mouse.

The C57BL/6J (C57) mouse was selected as a suitable model for early presbyacusis to determine if there were correlations between peripheral pathology (spiral ganglion loss, inner and outer hair cell loss) and calcium binding immunoreactivity in the cochlear nucleus during aging. The quantitative stereological method, the optical fractionator, was used for determining the total number of neurons and calcium binding immunopositive neurons (calbindin, parvalbumin and calretinin) during aging in the posteroventral- and dorsal cochlear nucleus (PVCN and DCN) in C57 mice. Comparing 30-month-old to 1-month-old C57 mice, a percent increase in parvalbumin and calbindin immunoreactivity was evident in both the PVCN and DCN. Correlations were made between peripheral pathology (spiral ganglion and inner and outer hair cell loss) and calcium binding protein expression. Significant correlations between cochlear pathology and the percentage of parvalbumin and calretinin immunoreactive neurons were demonstrated in the DCN. Moreover, significant correlations were found between cochlear pathology and parvalbumin and calbindin in the PVCN. In summary, the findings imply that degenerative changes in the auditory periphery can modulate neuronal homeostasis by increasing calcium binding proteins in the PVCN and DCN during aging. Taken together, these findings suggest a role for calcium binding proteins in protecting against age-induced calcium toxicity.

Aging↗

PubMed2003

Alterations in the intrauterine environment by glucocorticoids modifies the developmental programme of the auditory system.

Prenatal exposure to excessive glucocorticoids alters the programming of the metabolic and endocrine balance of various organs, including the nervous system. In the present study, prenatal glucocorticoid treatment was shown to increase the susceptibility of the inner ear to acoustic noise trauma in adult life. Acute auditory brainstem response thresholds were not different between the age-matched groups. However, when measured at 48 h and 4 weeks postexposure, the dexamethasone (DEX)-treated rats showed little or no recovery from the trauma. In contrast, normal rats showed a significant amount of recovery by 48 h postexposure and continued to show further recovery over 4 weeks. In addition, acoustic trauma resulted in a massive outer hair cell loss in the DEX rats compared to minor loss in the normal rats. To determine whether oxidative stress plays a role in the recovery phase of acoustic trauma, the free radical scavenger PBN (100 mg/kg) was administered before, during and several times after noise exposure. PBN treatment significantly reduced the physiological and morphological cochlear differences which were observed between DEX and control rats after acoustic trauma. These data support the hypothesis that alterations in the intrauterine environment may modify the developmental programme of the cochlea, inducing dysfunction later in adult life. Excessive prenatal exposure to dexamethasone decreased the potential for recovery of the cochlea to oxidative stress induced by acoustic trauma; this decreased recovery potential can be counteracted by treatment with antioxidants.

Animals↗

PubMed2003

BDNF gene replacement reveals multiple mechanisms for establishing neurotrophin specificity during sensory nervous system development.

Neurotrophins have multiple functions during peripheral nervous system development such as controlling neuronal survival, target innervation and synaptogenesis. Neurotrophin specificity has been attributed to the selective expression of the Trk tyrosine kinase receptors in different neuronal subpopulations. However, despite overlapping expression of TrkB and TrkC in many sensory ganglia, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) null mutant mice display selective losses in neuronal subpopulations. In the present study we have replaced the coding part of the BDNF gene in mice with that of NT3 (BDNF(NT3/NT3)) to analyse the specificity and selective roles of BDNF and NT3 during development. Analysis of BDNF(NT3/NT3) mice showed striking differences in the ability of NT3 to promote survival, short-range innervation and synaptogenesis in different sensory systems. In the cochlea, specificity is achieved by a tightly controlled spatial and temporal ligand expression. In the vestibular system TrkB or TrkC activation is sufficient to promote vestibular ganglion neuron survival, while TrkB activation is required to promote proper innervation and synaptogenesis. In the gustatory system, NT3 is unable to replace the actions of BDNF possibly because of a temporally selective expression of TrkB in taste neurons. We conclude that there is no general mechanism by which neurotrophin specificity is attained and that specificity is achieved by (i) a tightly controlled spatial and temporal expression of ligands, (ii) different Trk receptors playing distinct roles within the same neuronal subpopulation, or (iii) selective receptor expression in sensory neuron subpopulations.

Animals↗

PubMed2002

Activation of tyrosine hydroxylase in the lateral efferent terminals by sound conditioning.

Preconditioning to sound is a well-documented strategy to provide protections against a subsequent acoustic trauma. In the present study, preconditioning (1.0 kHz tone at 81 dB sound pressure level (SPL) for 24 h) protected ABR thresholds by 17-28 dB from an acoustic trauma (2.7 kHz, 103 dB SPL, 30 min) that resulted in a temporary threshold shift. The protection afforded by sound conditioning was shown to be blocked by the administration of 6-hydroxydopamine which disrupts tyrosine hydroxylase in the nerve terminals of the lateral efferent fibers. Furthermore, tyrosine hydroxylase immunoreactivity was up-regulated both by sound conditioning alone, and by the combined treatment of sound conditioning and acoustic trauma. In contrast, acoustic trauma alone resulted in a reduction in tyrosine hydroxylase immunoreactivity compared to unexposed controls. These findings are the first demonstration that tyrosine hydroxylase in the lateral efferents are up-regulated during sound conditioning and suggests a role for the lateral efferent system in protecting against acoustic trauma by sound conditioning.

Adrenergic Agents↗

PubMed2002

Protective mechanisms of sound conditioning.

Evidence continues to accumulate demonstrating the importance of reducing the deleterious effects of noise trauma by sound conditioning. Sound conditioning is an active process induced by low-level, nondamaging noise exposure that creates long-term protective effects to subsequent detrimental forms of noise trauma. This phenomenon is now shown to occur in a variety of mammals, including gerbils, chinchillas, guinea pigs, rabbits, rats, mice and human subjects. Different sound-conditioning paradigms have been proven successful in preventing pathological changes to the auditory system. These studies are reviewed in the present chapter and the possible biological mechanisms underlying this phenomenon are discussed.

Acoustic Stimulation↗

PubMed1998

Pharmacological strategies for preventing cochlear damage induced by noise trauma.

Hearing loss induced by noise, as well as in combination with other environmental factors, is a significant health problem throughout the world. Although most structures in the inner ear can be harmed by excessive sound exposure, the sensory cells are the most vulnerable. Damage to the stereocilia bundle is often the first structural alteration noted. Once a large number of hair cells are lost, the nerve fibres to that region also degenerate resulting in an irreversible hearing loss. At present, the underlying mechanism for cochlear damage induced by noise is not fully understood. The failure of the adult peripheral auditory system to regenerate after injury is a major clinical problem. However, a number of experimental applications have recently become available and are effective in reducing the damaging effects of noise. Current experimental designs include strategies for protecting against injury and are primarily based on the fact that the metabolic state of the cochlea can determine the overall degree of hearing loss induced by noise. The purpose of the present article is to review the current literature dealing with strategies for protecting against noise trauma.

Journal Article↗

PubMed1991

The Identification and Localization of the Guanine Nucleotide Binding Protein G0 in the Auditory System.

The identification of guanine nucleotide binding proteins (G proteins) in guinea-pig tissues was assessed by the adenosine diphosphate-ribosylation of the alpha subunit by Bordetella pertussis toxin using [alpha32P]nicotinamide adenine dinucleotide as the substrate followed by sodium dodecyl sulphate - polyacrylamide gel electrophoresis and autoradiography. Three tissues (inferior colliculus, neuroblastoma cells, and the organ of Corti) contained G0alpha (39 kD), as well as Gi2alpha (40 kD) and Gi1alpha and/or Gi3alpha (41 kD). The stria vascularis and the VIIIth nerve contained mainly Gi2alpha, Gi1alpha and/or Gi3alpha, but G0alpha was barely detectable. A purified preparation of outer hair cells from the organ of Corti contained all three pertussis toxin substrates including G0alpha, with the Gi2alpha (40 kD) subunit being the most prominent. The immunocytochemical localization of the G0alpha subunit was determined by light microscopy after incubating isolated outer hair cells, Hensen cells and the stria vascularis with affinity-purified anti-G0alpha antibodies. In hair cells a positive reaction was observed along the plasma membrane and around the perimeter of the cuticular plate (zona adherens). Positive reaction was also observed within the infracuticular network extending from the cuticular plate towards the nucleus in outer hair cells. Finally, the base of the outer hair cells also contained G0alpha. However, it is likely that the G0alpha that is present in this cell region is not within the hair cell itself, but rather in nerve terminals which remained attached during dissection.

Journal Article↗