Biomedical subjects

Robert D Frisina

Publications and source records attributed to Robert D Frisina.

16 recordsLinked to original sources

PubMed2006

Glutamate-related gene expression changes with age in the mouse auditory midbrain.

Glutamate is the main excitatory neurotransmitter in both the peripheral and central auditory systems. Changes of glutamate and glutamate-related genes with age may be an important factor in the pathogenesis of age-related hearing loss-presbycusis. In this study, changes in glutamate-related mRNA gene expression in the CBA mouse inferior colliculus with age and hearing loss were examined and correlations were sought between these changes and functional hearing measures, such as the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs). Gene expression of 68 glutamate-related genes was investigated using both genechip microarray and real-time PCR (qPCR) molecular techniques for four different age/hearing loss CBA mouse subject groups. Two genes showed consistent differences between groups for both the genechip and qPCR. Pyrroline-5-carboxylate synthetase enzyme (Pycs) showed down-regulation with age and a high-affinity glutamate transporter (Slc1a3) showed up-regulation with age and hearing loss. Since Pycs plays a role in converting glutamate to proline, its deficiency in old age may lead to both glutamate increases and proline deficiencies in the auditory midbrain, playing a role in the subsequent inducement of glutamate toxicity and loss of proline neuroprotective effects. The up-regulation of Slc1a3 gene expression may reflect a cellular compensatory mechanism to protect against age-related glutamate or calcium excitoxicity.

Aging↗

PubMed2006

Progestin negatively affects hearing in aged women.

Female hormone influences on auditory system aging are not completely understood. Because of widespread clinical use of hormone replacement therapy (HRT), it is critical to understand HRT effects on sensory systems. The present study retrospectively analyzed and compared hearing abilities among 124 postmenopausal women taking HRT, treated with estrogen and progestin (E+P; n = 32), estrogen alone (E; n = 30), and a third [non-hormone replacement therapy (NHRT; n = 62)] control group. Subjects were 60-86 years old and were matched for age and health status. All had relatively healthy medical histories and no significant noise exposure, middle-ear problems, or major surgeries. Hearing tests included pure-tone audiometry, tympanometry, distortion-product otoacoustic emissions (DPOAEs), transient otoacoustic emissions, and the hearing-in-noise test (HINT). The HINT tests for speech perception in background noise, the major complaint of hearing-impaired persons. Pure-tone thresholds in both ears were elevated (poorer) for the E+P relative to the E and control groups. For DPOAEs, the E+P group presented with lower (worse) levels than the E and control groups, with significant differences for both ears. For the HINT results, the E+P group had poorer speech perception than the E and control groups across all background noise speaker locations and in quiet. These findings suggest that the presence of P as a component of HRT results in poorer hearing abilities in aged women taking HRT, affecting both the peripheral (ear) and central (brain) auditory systems, and it interferes with the perception of speech in background noise.

Aged↗

PubMed2006

Serotonin 2B receptor: upregulated with age and hearing loss in mouse auditory system.

Serotonin (5-HT) is a monoamine neurotransmitter. Serotonin may modulate afferent fiber discharges in the cochlea, inferior colliculus (IC) and auditory cortex. Specific functions of serotonin are exerted upon its interaction with specific receptors; one of those receptors is the serotonin 2B receptor. The aim of this study was to investigate the differences in gene expression of serotonin 2B receptors with age in cochlea and IC, and the possible correlation between gene expression and functional hearing measurements in CBA/CaJ mice. Immunohistochemical examinations of protein expression of IC in mice of different age groups were also performed. Gene expression results showed that serotonin 2B receptor gene was upregulated with age in both cochlea and IC. A significant correlation between gene expression and functional hearing results was established. Immunohistochemical protein expression studies of IC showed more serotonin 2B receptor cells in old mice relative to young adult mice, particularly in the external nucleus. We conclude that serotonin 2B receptors may play a role in the pathogenesis of age-related hearing loss.

Acoustic Stimulation↗

PubMed2006

Age-related structural and functional changes in the cochlear nucleus.

Presbycusis - age-related hearing loss - is a key communication disorder and chronic medical condition of our aged population. The cochlear nucleus is the major site of projections from the auditory portion of the inner ear. Relative to other levels of the peripheral and central auditory systems, relatively few studies have been conducted examining age-related changes in the cochlear nucleus. The neurophysiological investigations suggest declines in glycine-mediated inhibition, reflected in increased firing rates in cochlear nucleus neurons from old animals relative to young adults. Biochemical investigations of glycine inhibition in the cochlear nucleus are consistent with the functional aging declines of this inhibitory neurotransmitter system that affect complex sound processing. Anatomical reductions in neurons of the cochlear nucleus and their output pathways can occur due to aging changes in the brain, as well as due to age-dependent plasticity of the cochlear nucleus in response to the age-related loss of inputs from the cochlea, particularly from the basal, high-frequency regions. Novel preventative and curative biomedical interventions in the future aimed at alleviating the hearing loss that comes with age, will likely emanate from increasing our knowledge and understanding of its neural and molecular bases. To the extent that this sensory deficit resides in the central auditory system, including the cochlear nucleus, future neural therapies will be able to improve hearing in the elderly.

Age Factors↗

PubMed2006

Estrogen blockade reduces auditory feedback in CBA mice.

OBJECTIVE: To examine the effects of estrogen suppression on age-related changes in distortion product otoacoustic emissions (DPOAEs) and contralateral suppression (CS) of DPOAEs in CBA mice. STUDY DESIGN AND SETTING: Young CBA mice received a slow-release shoulder implantation of either tamoxifen or placebo. Serial DPOAEs and CS of DPOAEs were obtained at 3-week intervals over a period of 9 weeks. RESULTS: Although DPOAEs were maintained over the study interval, CS of DPOAEs decreased significantly with age in the experimental group. No such declines were observed in either the control animals or the untreated male mice. CONCLUSIONS: Estrogen suppression negatively affects the MOC efferent feedback system. SIGNIFICANCE: Our results support the hypothesis that estrogen plays an important role in the maintenance of auditory integrity. Additionally, our findings raise intriguing questions about auditory effects of hormonal shifts in humans resulting from menopause, hormone supplements such as oral contraceptives, and hormone replacement therapy as well as antiestrogens.

Aging↗

PubMed2005

Characterization of hearing loss in aged type II diabetics.

Presbycusis - age-related hearing loss - is the number one communicative disorder and a significant chronic medical condition of the aged. Little is known about how type II diabetes, another prevalent age-related medical condition, and presbycusis interact. The present investigation aimed to comprehensively characterize the nature of hearing impairment in aged type II diabetics. Hearing tests measuring both peripheral (cochlea) and central (brainstem and cortex) auditory processing were utilized. The majority of differences between the hearing abilities of the aged diabetics and their age-matched controls were found in measures of inner ear function. For example, large differences were found in pure-tone audiograms, wideband noise and speech reception thresholds, and otoacoustic emissions. The greatest deficits tended to be at low frequencies. In addition, there was a strong tendency for diabetes to affect the right ear more than the left. One possible interpretation is that as one develops presbycusis, the right ear advantage is lost, and this decline is accelerated by diabetes. In contrast, auditory processing tests that measure both peripheral and central processing showed fewer declines between the elderly diabetics and the control group. Consequences of elevated blood sugar levels as possible underlying physiological mechanisms for the hearing loss are discussed.

Aged↗

PubMed2005

Age-related declines in distortion product otoacoustic emissions utilizing pure tone contralateral stimulation in CBA/CaJ mice.

One role of the medial olivocochlear (MOC) auditory efferent system is to suppress cochlear outer hair cell (OHC) responses when presented with a contralateral sound. Using distortion product otoacoustic emissions (DPOAEs), the effects of active changes in OHC responses due to the MOC as a function of age can be observed when contralateral stimulation with a pure tone is applied. Previous studies have shown that there are age-related declines of the MOC when broad band noise is presented to the contralateral ear. In this study, we measured age-related changes in CBA/CaJ mice by comparing DPOAE generation with and without a contralateral pure tone at three different frequencies (12, 22, and 37 kHz). Young (n = 16), middle (n = 10) and old-aged (n = 10) CBA mice were tested. DPOAE-grams were obtained using L1 = 65 and L2 = 50 dB SPL, F1/F2 = 1.25, using eight points per octave covering a frequency range from 5.6-44.8 kHz. The pure tone was presented contralaterally at 55 dB SPL. DPOAE-grams and ABR levels indicated age-related hearing loss in the old mice. In addition, there was an overall change in DPOAEs in the middle-aged and old groups relative to the young. Pure tone stimulation was not as effective as a suppressor compared to broadband noise. An increase in pure tone frequency from 12 to 22 kHz induced greater suppression of DPOAEs, but the 37 kHz was least effective. These results indicate that as the mouse ages, there are significant changes in the efficiency of the suppression mechanism as elicited by contralateral narrowband stimuli. These findings reinforce the idea that age-related changes in the MOC or the operating points of OHCs play a role in the progression of presbycusis - age-related hearing loss in mammals.

Acoustic Stimulation↗

PubMed2005

Higher serum aldosterone correlates with lower hearing thresholds: a possible protective hormone against presbycusis.

Aldosterone hormone is a mineralocorticoid secreted by adrenal gland cortex and controls serum sodium (Na(+)) and potassium (K(+)) levels. Aldosterone has a stimulatory effect on expression of sodium-potassium ATPase (Na, K-ATPase) and sodium-potassium-chloride cotransporter (NKCC) in cell membranes. In the present investigation, the relation between serum aldosterone levels and age-related hearing loss (presbycusis) and the correlation between these levels versus the degree of presbycusis in humans were examined. Serum aldosterone concentrations were compared between normal hearing and presbycusic groups. Pure-tone audiometry, transient evoked otoacoustic emissions (TEOAE), hearing in noise test (HINT) and gap detection were tested for each subject and compared to the serum aldosterone levels. A highly significant difference between groups in serum aldosterone concentrations was found (p = 0.0003, t = 3.95, df = 45). Highly significant correlations between pure-tone thresholds in both right and left ears, and HINT scores versus serum aldosterone levels were also discovered. On the contrary, no significant correlations were seen in the case of TEOAEs and gap detection. We conclude that aldosterone hormone may have a protective effect on hearing in old age. This effect is more peripheral than central, appearing to affect inner hair cells more than outer hair cells.

Aged↗

PubMed2004

Sex differences in distortion product otoacoustic emissions as a function of age in CBA mice.

Age-related hearing loss--presbycusis--is the number one communication problem of the aged. A major contributor to presbycusis is the progressive degeneration of cochlear outer hair cells (OHCs). Distortion product otoacoustic emissions (DPOAEs) are effective in vivo, physiological measures of hearing, assessing the health and functioning of the OHCs in mammals. We and others have previously demonstrated that DPOAE amplitudes decline with age in humans and mice. The present study's objective was to measure age-related declines in the OHCs in CBA mice (slow, progressive age-related hearing loss) by comparing DPOAEs and auditory brainstem responses (ABRs) generated from females and males. Young adult (2.1-2.9 months) and middle-aged CBA (14.0-16.4 months) mice were tested, as well as old CBAs (24.3-29.0 months). DPOAE-grams were obtained with L1 = 65 and L2 = 50 dB SPL, f1/f2 = 1.25, using eight points per octave covering a frequency range from 5.6 to 44.8 kHz (geometric mean frequency). ABRs ranged from 3 to 48 kHz. Analyses revealed that DPOAE levels decreased with age for middle-aged and old male CBAs, but for female CBAs, declines did not occur until old age - after menopause. In contrast, ABR amplitudes for female and male young adult and middle-aged CBAs were the same. Female ABR thresholds were lower than males for old CBAs. In conclusion, we discovered that pre-menopausal CBA female mice have healthier OHCs relative to middle-aged males, but much of this relative advantage is lost post-menopause. Understanding sex differences in age-related sensory disorders will be quite helpful for the goals of preventing, slowing or curing sensory problems in old age for both women and men.

Aging↗

PubMed2004

Age reduces response latency of mouse inferior colliculus neurons to AM sounds.

Age and stimulus rise time (RT) effects on response latency were investigated for inferior colliculus (IC) neurons in young-adult and old CBA mice. Single-unit responses were recorded to unmodulated and sinusoidal amplitude modulated (SAM) broadband noise carriers, presented at 35 to 80 dB SPL. Data from 63 young-adult and 76 old phasic units were analyzed to identify the time interval between stimulus onset and driven-response onset (latency). When controlling for stimulus sound level and AM frequency, significant age-related changes in latency were identified. Absolute latency decreased with age at all stimulus AM frequencies, significantly so for equivalent rise times (RT) < or = 12.5 ms. The linear correlation of latency with AM stimulus RT was significant for both young-adult and old units, and increased significantly with age. It is likely that both the decrease in absolute latency and the increase in latency/RT correlation with age are consistent with a reduction of inhibitory drive with age in the IC. These latency changes will result in age-related timing variations in brainstem responses to stimulus onsets, and therefore affect the encoding of complex sounds.

Aging↗

PubMed2003

The effects of early bilateral deafening on calretinin expression in the dorsal cochlear nucleus of aged CBA/CaJ mice.

The aim of this study was to test the hypothesis that calretinin (CR) levels in the aged mouse auditory brainstem depend upon hearing ability. Old animals with good hearing, and thus higher sound-evoked activity levels, were predicted to have higher levels of CR immunoreactivity than old animals with hearing loss. CR immunoreactivity was analyzed in the deep layer (layer III) of the dorsal cochlear nucleus (DCN) in CBA/CaJ mice that were bilaterally deafened at 3 months of age with kanamycin, and then aged until 24 months. This manipulation partially mimics the lack of sound-evoked auditory activity experienced by old C57BL/6J mice, who are deaf at 24 months of age (but show residual hearing at 15 months) and have lower levels of CR immunoreactivity than old CBA mice with normal hearing [Hear. Res. 158 (2001) 131]. Cell counts revealed that the density of CR+ cells in DCN layer III of the deafened CBA mice was statistically different from old intact CBA mice raised under identical conditions. Old deafened CBAs showed a decline of 47% in the mean density of CR+ cells compared to old hearing CBAs, thus supporting the hypothesis. Interestingly, while there tended to be fewer CR+ cells in the old deaf C57s as compared to young C57s and young and old CBAs with normal hearing, the difference was not statistically significant. It is possible that the residual hearing of C57 mice at 15 months may provide sufficient auditory input to maintain CR at levels higher than CBA mice that are deafened completely at 3 months of age, and are profoundly deaf for a much longer time (21 months).

Aging↗

PubMed2003

Contralateral suppression of distortion-product otoacoustic emissions declines with age: a comparison of findings in CBA mice with human listeners.

OBJECTIVES/HYPOTHESIS: The auditory efferent system plays presumed roles in enhancing signals in noise, maintaining the cochlea for optimal acoustic signal processing, and may have a protective role in preserving auditory function in the face of ototoxic events. The objective of the study was to measure age-related changes of the medial olivocochlear efferent system in mice by comparing distortion-product otoacoustic emissions generated with and without contralateral white noise stimulation. Consistent with prior work, distortion-product otoacoustic emissions were typically reduced in magnitude when white noise was presented to the contralateral ear. This contralateral suppression is attributed to activation of the medial olivocochlear efferent system, which has an inhibitory effect on the cochlear hair cell system. By studying contralateral suppression on cochlear output in subjects of different ages, it is possible to describe aging effects on the medial olivocochlear system. STUDY DESIGN: CBA mice were divided into three age groups: young adult, middle-aged, and old-aged animals (21, 13, and 22 animals per group, respectively), and auditory brainstem responses were obtained before distortion-product otoacoustic emission testing to assess overall hearing abilities. METHODS: 2f1-f2 distortion-product otoacoustic emission recordings were obtained from individual subjects (anesthetized with ketamine/xylazine) in each age group under two conditions: 1) in quiet and 2) in the presence of a contralaterally applied wideband noise. RESULTS: Principal findings were that distortion-product otoacoustic emission levels decreased with age for mice in a way similar to humans, when correcting for the absolute difference in life spans. In addition, contralateral suppression declined in middle-aged and old-aged groups relative to the young adults for mice in a manner similar to humans. The contralateral suppression decline at low frequencies preceded that of the decline in distortion-product otoacoustic emissions with age. CONCLUSION: Functional decline of the medial olivocochlear efferent system with age precedes outer hair cell degeneration. Loss of medial olivocochlear suppressive function may play a role in the development of presbycusis in both clinical cases and animal models.

Age Factors↗

PubMed2002

Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea.

Ototoxicity is a major dose-limiting side effect of cisplatin chemotherapy for cancer patients. We previously demonstrated in vitro that herpes simplex type 1 (HSV-1) amplicon-mediated delivery of a neurotrophin-3 (NT-3)/myc chimera protects spiral ganglion neurons (SGNs) in murine cochlear cultures from cisplatin-induced ototoxicity. To extend these findings, a newly constructed amplicon vector (HSVnt-3myc/SV40lac) that expresses the NT-3myc chimera and the Escherichia coli beta-galactosidase (lacZ) reporter gene under separate transcriptional control was initially tested in vitro and then was delivered to the cochlea of aged mice that were subsequently treated with cisplatin. Successful transduction with the new amplicon was observed in vitro as determined by its capacity to infect SGNs and to express NT-3myc mRNA and protein. To determine whether amplicon-directed NT-3myc overexpression could abrogate the ototoxicity in vivo, two groups of aged mice (CBA) were inoculated with HSVnt-3myc/SV40lac or control vector, HSVSV40lac, preceding administration of cisplatin. Cochleas inoculated with HSVnt-3myc/SV40lac harbored significantly greater numbers of surviving SGNs and showed lower incidence of cisplatin-induced apoptosis or necrosis than those injected with the control virus. These data demonstrate that HSV amplicon-mediated NT-3 delivery can attenuate the ototoxic actions of cisplatin in the peripheral auditory system of the aged mouse. The potency of NT-3 in SGN neuroprotection suggests that in vivo neurotrophin-based gene therapy is a promising preventative treatment for chemical-induced hearing disorders, and potentially for hearing degeneration due to normal aging.

Animals↗

PubMed2002

Age-related alterations in the neural coding of envelope periodicities.

This research was guided by the working hypothesis that the aging auditory system progressively loses its ability to process rapid acoustic transients efficiently, and in elderly listeners, this results in difficulties in speech perception. Neural correlates of age-related deficits in temporal processing were investigated by recording from inferior colliculus (IC) neurons from young adult and old CBA mice. Single-unit responses were recorded to sinusoidally amplitude-modulated (SAM) noise carriers, presented at 65-80 dB SPL, having modulation frequencies (MFs) that ranged from 10 to 800 Hz. Because phasic-type temporal response patterns dominate responses to tone and noise in mammalian IC, we limited our analyses to only phasic units. Modulation transfer functions (MTF) for both rate (rMTF) and synchronization (sMTF) measures were used to derive respective best modulation frequencies (rBMF and sBMF). The main age-related finding was that there was an overall increase in response rate to SAM noise carriers and a decrease in the median upper cutoff frequency in units from old mice. At rBMF, the median spike count from units from old animals was 1.63 times greater, and at the sBMF, the median spike count was 2.29 times greater than the young adult sample. We explored whether the increase in driven activity was due to a change in the transient (first cycle response) or periodic (remaining response) component of the response to SAM noise. Median spike counts of the transient component decreased with increasing MF for both young adult and old units, with median counts consistently greater in the old sample as compared with young. Median spike counts for the periodic response remained relatively constant as a function of MF; however, there was a significantly greater (3 times) response for older units in a restricted range of MFs. The greater median spike counts found for the transient and periodic response was also evident when we analyzed the cycle-by-cycle response. The magnitude of the differences between the young adult and the old spike median responses was greatest at low MFs and then declined as MF increased. Finally, the young adult distribution of rBMFs extends to higher MFs than the old, with 36.0% of units having rBMFs >100 Hz as compared with only 12.5% of the old unit sample. We postulate that this age-related difference in rate coding of SAM noise carriers is consistent with a loss, or imbalance, of excitatory and inhibitory neural mechanisms known to shape encoding of envelope periodicities in the IC.

Acoustic Stimulation↗

PubMedDate not supplied

Effects of age on contralateral suppression of distortion product otoacoustic emissions in human listeners with normal hearing.

The auditory efferent system presumably plays a role in enhancing signals in noise and, in particular, speech perception in background noise. This study measured the age-related changes of the medial olivocochlear (MOC) system by comparing distortion product otoacoustic emissions (DPOAEs) with and without contralateral white noise stimulation. Otoacoustic emissions were typically reduced in level (magnitude) when white noise was presented to the contralateral ear. This contralateral suppression (CS) is attributed to activation of the MOC system, which has an inhibitory effect on the outer hair cell (OHC) system. By studying CS on cochlear output in human listeners of different ages, it is possible to describe aging effects on the MOC system. Human subjects were young adult, middle aged and old (n = 10/group). All subjects had normal hearing and middle-ear function based upon standard audiometric criteria. The present study recorded 2f(1)-f(2) DPOAE-grams in response to moderate primary tones (L1 = 75, L2 = 65 dB SPL), from 1 to 6.3 kHz. The principal findings were that DPOAE levels were smaller in the old compared to the young group and that CS declined with age for the middle-aged and old groups. In addition, CS in the 1- to 2-kHz range was greater than in the 4- to 6-kHz range for all ages, but especially for the old group. These findings suggest that a functional decline of the MOC system with age precedes OHC degeneration. Moreover, the MOC system maintains better function in the 1- to 2-kHz range than in the 4- to 6-kHz range as a function of age.

Acoustic Stimulation↗

PubMedDate not supplied

Loss of peripheral right-ear advantage in age-related hearing loss.

In young adults with normal hearing, the right ear is more sensitive than the left to simple sounds (peripheral right-ear advantage) and to processing complex sounds such as speech (central right-ear advantage). In the present investigation, the effects of hearing loss and aging on this auditory asymmetry were examined at both peripheral and central levels. Audiograms and transient evoked otoacoustic emission (TEOAE) and distortion product otoacoustic emission amplitudes were used to assess cochlear function. The contralateral suppression of TEOAEs was measured to assess the medial olivocochlear efferent system. The Hearing in Noise Test (HINT; binaural speech) was conducted to assess higher central auditory function. A group of aged subjects with normal hearing (flat audiograms) were compared to a group of aged subjects with sloping audiograms (presbycusis). At the cochlear (peripheral) level, the normal hearing group showed significantly higher otoacoustic emission amplitudes for the right ear compared to the left ear, which is consistent with the right-ear dominance normally seen in young adults. However, this finding was reversed in the presbycusic group that showed higher left-ear emission amplitudes. At the brainstem level, the amplitudes of TEOAE contralateral suppression were small and no significant difference was found between the right and left ears in both groups. On the contrary, HINT results showed a continuous dominance of the right ear (left hemisphere) in both groups, which was consistent with previous reports showing that the right hemisphere is more affected by age than the left hemisphere.

Acoustic Impedance Tests↗