AMFR
E3 ubiquitin-protein ligase AMFR (EC 2.3.2.27) (Autocrine motility factor receptor) (AMF receptor) (RING finger protein 45) (gp78) [RNF45]
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A mutation in the Cdh23 gene is implicated in both syndromic and nonsyndromic hearing loss in humans and age-related hearing loss in C57BL/6 mice. It is generally assumed that human patients (as well as mouse models) only have a hearing loss phenotype if the mutation is homozygous. However, a major complaint for patients with a hearing disability is a reduced speech intelligibility that may be related to temporal processing deficits rather than just elevated thresholds. In this study, we used the amplitude modulation following response (AMFR) to test whether mice heterozygous for Cdh23 have an auditory phenotype that includes temporal processing deficits. The hearing of mice heterozygous for the Cdh23 mutation was compared with age-matched mice homozygous for either the mutation or the wild type in 3 cohorts of mice of both sexes at 2-3, 6, and 12 months of age. The AMFR technique was used to generate objective hearing thresholds for all mice across their range of hearing and to test their temporal processing. We found a genotype-dependent hearing loss in mice homozygous for the mutation starting at 5-11 weeks of age, an age when mice on the C57BL/6 background are often presumed to have normal hearing. The heterozygous animals retained normal hearing thresholds up to one year of age. Nevertheless, the heterozygous animals showed a decline in temporal processing abilities at one year of age that was independent of their hearing thresholds. These results suggest that mice heterozygous for the Cdh23 mutation do not have truly normal hearing.
MeSH Terms
- Animals
- Auditory Cortex
- Auditory Perception
- Auditory Threshold
- Cadherins
- Cross-Sectional Studies
- Disease Models, Animal
- Female
- Hearing
- Hearing Loss
- Heterozygote
- Male
- Mice, Inbred C57BL
- Mutation
- Presbycusis
Keywords
- Aging
- Amplitude modulation following response
- Cadherin 23
- Hearing loss
- Hearing test
- Temporal precision
The autocrine motility factor receptor (AMFR) is a multifunctional protein involved in cellular adhesion, proliferation, motility and apoptosis. Our study showed that increased AMFR protein expression in the hippocampus of KM mice correlated with enhanced capacity for learning and memory following the shuttle-box test and was significantly elevated in the highest score group. Also, AMF and AMFR mRNA expression positively correlates with the mRNA expression of the synapse marker synaptophysin (Syp). Aging studies in the senescence-accelerated mouse strain (SAM) prone/8 (SAMP8), an animal model of Alzheimer's disease (AD), revealed significantly decreased mRNA and protein expression of AMF and AMFR in the hippocampus. This is especially true for AMFR and AMF protein expression compared with age-matched SAM resistant/1 (SAMR1) mouse strain as the control. Additionally, the low mRNA expression of AMFR could be up-regulated by the four nootropic traditional Chinese medicinal prescriptions (TCMPs): Ba-Wei-Di-Huang decoction (BW), Huang-Lian-Jie-Du decoction (HL), Dang-Gui-Shao-Yao-San (DSS) and Tiao-Xin-Fang decoction (TXF). AMFR protein expression could be up-regulated by two TCMPs, Liu-Wei-Di-Huang decoction (LW) and BW. This indicated that AMFR is involved in the process of learning and memory in the central nervous system. These results may provide useful clues for understanding the etiology of AD.
MeSH Terms
- Aging
- Alzheimer Disease
- Animals
- Animals, Outbred Strains
- Avoidance Learning
- Disease Models, Animal
- Drugs, Chinese Herbal
- Gene Expression Regulation
- Glucose-6-Phosphate Isomerase
- Hippocampus
- Learning
- Male
- Memory
- Mice
- Motor Activity
- Nootropic Agents
- Receptors, Autocrine Motility Factor
- Synaptophysin
Older human listeners demonstrate perceptual deficits in temporal processing even when audibility has been controlled. These age-related auditory deficits in temporal processing are thought to originate in the central auditory pathway. Precise temporal processing is necessary to detect and discriminate auditory cues such as modulation frequency, modulation depth and envelope shape which are critical for perception of speech and environmental sounds. This study aims to further understanding of temporal processing in aging using non-invasive electrophysiological measurements. Amplitude modulation following responses (AMFRs) and frequency modulation following responses (FMFRs) were recorded from aged (92-95-weeks old) and young (9-12-weeks old) Fischer-344 (F-344) rats for sinusoidally amplitude modulated (sAM) tones, sinusoidally frequency modulated (sFM) tones and ramped and damped amplitude modulation (AM) stimuli which differ in their envelope shapes. The modulation depth for the sAM and sFM stimuli and envelope shape for the ramped and damped stimuli were systematically varied. There was a monotonic decrease in AMFR and FMFR amplitudes with decreases in modulation depth across age for sAM and sFM stimuli. There was no significant difference between the response amplitudes of the young and aged animals for the largest modulation depths. However, a reduction in modulation depth resulted in a significant decrease in the response amplitudes and higher modulation detection thresholds for sAM and sFM stimuli with age. The aged animals showed significantly lower response amplitudes for ramped stimuli but not for damped stimuli. Cross correlating the responses with the ramped, symmetric, or damped stimulus envelopes revealed a decreased fidelity in encoding envelope shapes with age. These results indicate that age related temporal processing deficits become apparent only with reduced modulation depths or when discriminating envelope shapes. This has implications for psychophysical or diagnostic testing as well as for constraining potential cellular and network mechanisms responsible for these deficits.
MeSH Terms
- Acoustic Stimulation
- Aging
- Animals
- Auditory Perception
- Evoked Potentials, Auditory, Brain Stem
- Male
- Rats
- Rats, Inbred F344
Our knowledge of age-related changes in auditory processing in the central auditory system is limited, unlike the changes in the peripheral hearing organs which are more extensively studied. This study aims to further understanding of temporal processing in aging using non-invasive electrophysiological measurements in a rat model system. Amplitude modulation following responses (AMFRs) were assessed using sinusoidally amplitude modulated (SAM) tones presented to aged (92- to 95-weeks old) and young (9- to 12-weeks old) Fischer-344 rats. The modulation frequency and sound level were systematically varied, and the SAM stimuli were also presented simultaneously with wideband background noise at various levels. The overall shapes and cutoff frequencies of the AMFR temporal modulation transfer functions (tMTFs) were similar between young and aged animals. The fast Fourier transform (FFT) amplitudes of the aged animals were similar to the young in the 181-512 Hz modulation frequency range, but were significantly lower at most modulation frequencies above and below. There were no significant age-related differences in the nature of growth or FFT amplitudes with change in sound level at 256 and 1024 Hz modulation frequencies. The AMFR amplitudes were also not correlated with the ABR wave I or wave III amplitudes elicited for broadband click stimuli presented at the same sound level suggesting that sustained AMFR provide complementary information to phasic ABR responses. The FFT amplitudes varied significantly between young and aged animals for SAM stimuli in the presence of background noise, depending on the modulation frequency used and signal to noise ratio. The results show that the representation of temporally modulated stimuli is similar between young and aged animals in quiet listening conditions, but diverges substantially with the addition of background noise. This is consistent with a decrease in inhibition causing altered temporal processing with age.
Keywords
- Fischer-344
- aging
- amplitude modulation
- auditory
- colliculus
- evoked potential
- following response
Liuwei Dihuang decoction (LW), a traditional Chinese medicinal prescription, enhances the cognitive function of CNS by significant modulating effects on some of the gene expressions. Expressions of genes, such as DUSP12, NSF, STUB1, CaMKIIalpha, AMFR, UQCRFS1 and other 11 novel genes without any functional clues changed significantly. These genes are involved in the protein-tyrosine phosphatase family, the AAA (ATPases associated with diverse cellular activities) gene family, the serine/threonine protein kinases family, ubiquitin ligase, mitochondrial function and so on.
MeSH Terms
- Aging
- Alkaloids
- Alzheimer Disease
- Animals
- Cholinesterase Inhibitors
- DNA, Complementary
- Drugs, Chinese Herbal
- Gene Expression Regulation
- Hippocampus
- Male
- Mice
- Mice, Inbred Strains
- Phytotherapy
- Plant Extracts
- Polymerase Chain Reaction
- Protein Tyrosine Phosphatases
- Sesquiterpenes
The amplitude-modulation following response (AMFR) is a steady-state auditory response which may be an objective measure of intensity discrimination. Aged subjects with normal hearing have poorer intensity discrimination for low-frequency tones measured behaviorally, which would predict poorer AMFRs for low-frequency carriers. Experiment 1 was designed to assess age-related differences in AMFR characteristics. Response amplitudes were not significantly different among the young and aged groups for either carrier frequency (520 or 4000 Hz) or modulation depth (0--100%). Response phase did not vary systematically among groups. These results suggest that the AMFR may not be directly comparable to behavioral measures of intensity discrimination in aged subjects with normal hearing. To assess the contribution of high-frequency hearing loss on the AMFR in aged subjects, Experiment 2 compared AMFR amplitudes in aged subjects and in young subjects under the condition of high-pass masking. The amplitude of the AMFR was reduced at 520 Hz for both aged subjects and masked young subjects compared to unmasked young subjects, suggesting that reduced amplitudes in aged subjects with high-frequency hearing loss were associated with threshold elevations. Furthermore, the results suggest that the base of the cochlea contributes to the AMFR for low carrier frequencies.
MeSH Terms
- Acoustic Stimulation
- Adult
- Aged
- Aged, 80 and over
- Aging
- Auditory Threshold
- Cochlea
- Hearing
- Hearing Loss, High-Frequency
- Humans
- Middle Aged
- Pitch Discrimination
- Presbycusis
In young children, there appears to be no advantage to recording steady-state response (SSR) at a stimulus rate of 40 Hz. To determine the optimal modulation frequency in auditory SSR evoked by sinusoidally amplitude-modulated (SAM) tones (amplitude-modulation following response: AMFR) in children during sleep and compare response patterns of AMFR at different modulation frequencies while awake with those during sleep, AMFR was examined in 10 adults with normal hearing while awake and during sleep and in 10 young children with normal hearing during sleep. The stimulus was a 1000 Hz, 50 dBnHL SAM tone with a modulation depth of 95%. Modulation frequency was varied from 20 to 200 Hz in 20 Hz steps. Response was determined by phase spectral analysis and the S/N ratio calculated by spectral amplitude at the modulation frequency and noise level around the modulation frequency using fast Fourier transform. Although AMFR was clearly evoked only by a modulation frequency of 40 Hz in adults while awake, AMFRs at modulation frequencies of 80 and 100 Hz were detected during sleep, in addition to 40 Hz AMFR. In children, 40 Hz AMFR was difficult to detect, but response could be clearly detected at higher modulation rates, especially at modulation frequencies of 80 and 100 Hz, compared with response in adults during sleep. Modulation frequencies from 80 to 100 Hz would thus appear optimal for detecting AMFR during sleep in children.
MeSH Terms
- Adult
- Aging
- Auditory Threshold
- Child, Preschool
- Data Interpretation, Statistical
- Electroencephalography
- Evoked Potentials, Auditory
- Female
- Humans
- Male
- Middle Aged
- Sleep
Scalp responses to continuous amplitude-modulated (AM) tones were recorded from adults and 1-month-old infants. The amplitude-modulation following (or envelope) response (AMFR) was quantified using magnitude-squared coherence. This measurement indicates the strength of the frequency-following response relative to background neural noise. The optimal modulation rate for generating the AMFR was determined by studying the effects of stimulus modulation rate on the response. Stimulus AM rate was varied between 10 and 80 Hz for continuous tonal stimuli of 500 Hz, and between 20 and 80 Hz for continuous tonal stimuli of 2000 Hz. Optimal modulation rate was defined as the AM rate that provided the highest coherence estimate. Adult AMFR coherence increased between 10 and 40 Hz (20-40 Hz for 2000 Hz), and decreased between 40 and 80 Hz in both carrier frequency conditions. Infant AMFR coherence, in contrast, monotonically increased between 10 and 80 H (20-80 Hz for 2000 Hz). Thus, within the frequency range examined, 40 Hz is optimal for generating the AMFR in adults, whereas 80 Hz is optimal in infants. Adults were tested while awake and infants were tested during periods of sleep. Given the observed age difference in effective modulation rate, we examined modulation rate effects in a group of adults in both awake and sedated states. As in sleeping infants, 80 Hz was optimal for generating AMFRs in the sedated adults.
MeSH Terms
- Acoustic Stimulation
- Adolescent
- Adult
- Aging
- Analysis of Variance
- Auditory Perception
- Evoked Potentials, Auditory, Brain Stem
- Humans
- Infant
- Infant, Newborn
- Sleep
Phase spectral analysis as developed by Fridman (1982) was used to detect amplitude-modulation following response (AMFR). The threshold of AMFR was determined with greater sensitivity and accuracy by phase spectral analysis than by visual analysis. Using this method, a modulation frequency (MF) of 80 Hz was found optimal for detecting AMFR in young children (ranging in age from 2 to 4 years) during sleep, for whom there is no advantage in recording 40-Hz steady-state responses. To determine the optimal MF for detecting AMFR during sleep in children less than 2 years of age and age limitation for using 80-Hz MAFR in objective audiometry, AMFR as a function of MF was investigated during sleep in 25 children with normal hearing ranging from 4 months to 15 years of age, and 10 normal hearing adults. The stimulus was a 1000 Hz, 50 dBnHL sinusoidally amplitude modulated tone with a modulation depth of 95%. MF was varied from 20 to 200 Hz in 20 Hz steps. Response was determined by phase spectral analysis and the S/N ratio calculated by spectral amplitude at the modulation frequency and noise level around the modulation frequency using fast Fourier transform. Phase spectral analysis showed AMFR at MF of 80 Hz to be the most stable and reliable in all children during sleep among MFs from 20 to 200 Hz. Spectral amplitude analysis demonstrated 80-Hz AMFR to have a high S/N ratio in all children.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Acoustic Stimulation
- Adolescent
- Adult
- Aging
- Audiometry, Evoked Response
- Audiometry, Pure-Tone
- Auditory Threshold
- Child
- Child, Preschool
- Electroencephalography
- Evoked Potentials, Auditory
- Evoked Potentials, Auditory, Brain Stem
- Female
- Fourier Analysis
- Hearing
- Humans
- Infant
- Male
- Reaction Time
- Signal Processing, Computer-Assisted
- Sleep