Age-related hearing loss: GABA, nicotinic acetylcholine and NMDA receptor expression changes in spiral ganglion neurons of the mouse.

Age-related hearing loss - presbycusis - is the number one communication disorder and most prevalent neurodegenerative condition of our aged population. Although speech understanding in background noise is quite difficult for those with presbycusis, there are currently no biomedical treatments to prevent, delay or reverse this condition. A better understanding of the cochlear mechanisms underlying presbycusis will help lead to future treatments. Objectives of the present study were to investigate GABAA receptor subunit α1, nicotinic acetylcholine (nACh) receptor subunit ß2, and N-methyl-d-aspartate (NMDA) receptor subunit NR1 mRNA and protein expression changes in spiral ganglion neurons (SGN) of the CBA/CaJ mouse cochlea, that occur in age-related hearing loss, utilizing quantitative immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) techniques. We found that auditory brainstem response (ABR) thresholds shifted over 40dB from 3 to 48kHz in old mice compared to young adults. DPOAE thresholds also shifted over 40dB from 6 to 49kHz in old mice, and their amplitudes were significantly decreased or absent in the same frequency range. SGN density decreased with age in basal, middle and apical turns, and SGN density of the basal turn declined the most. A positive correlation was observed between SGN density and ABR wave 1amplitude. mRNA and protein expression of GABAAR α1 and AChR ß2 decreased with age in SGNs in the old mouse cochlea. mRNA and protein expression of NMDAR NR1 increased with age in SGNs of the old mice. These findings demonstrate that there are functionally-relevant age-related changes of GABAAR, nAChR, NMDAR expression in CBA mouse SGNs reflecting their degeneration, which may be related to functional changes in cochlear synaptic transmission with age, suggesting biological mechanisms for peripheral age-related hearing loss.

Inputs to a physiologically characterized region of the inferior colliculus of the young adult CBA mouse.

Presbycusis is a sensory perceptual disorder involving loss of high-pitch hearing and reduced ability to process biologically relevant acoustic signals in noisy environments. The present investigation is part of an ongoing series of studies aimed at discerning the neural bases of presbycusis. The purpose of the present experiment was to delineate the inputs to a functionally characterized region of the dorsomedial inferior colliculus (IC, auditory midbrain) in young, adult CBA mice. Focal, iontophoretic injections of horseradish peroxidase were made in the 18-24 kHz region of dorsomedial IC of the CBA strain following physiological mapping experiments. Serial sections were reacted with diaminobenzidine or tetramethylbenzidine, counterstained and examined for retrogradely labeled cell bodies. Input projections were observed contralaterally from: all three divisions of cochlear nucleus; intermediate and dorsal nuclei of the lateral lemniscus (LL); and the central nucleus, external nucleus and dorsal cortex of the IC. Input projections were observed ipsilaterally from: the medial and lateral superior olivary nuclei; the superior paraolivary nucleus; the dorsolateral and anterolateral periolivary nuclei; the dorsal and ventral divisions of the ventral nucleus of LL; the dorsal and intermediate nuclei of LL; the central nucleus, external nucleus and dorsal cortex of the IC outside the injection site; and small projections from central gray and the medial geniculate body. These findings in young, adult mice with normal hearing can now serve as a baseline for similar experiments being conducted in mice of older ages and with varying degrees of hearing loss to discover neural changes that may cause age-related hearing disorders.

Age-related changes in calbindin D-28k and calretinin immunoreactivity in the inferior colliculus of CBA/CaJ and C57Bl/6 mice.

This study examines calbindin D-28k and calretinin immunoreactivity in the inferior colliculus (IC) of young and old mice of two strains. The CBA/CaJ mouse maintains good hearing until very late in life, whereas the C57Bl/6 strain exhibits severe sensorineural hearing loss at an early age. Young and old mice of both strains were selected with matching auditory brainstem response audiograms and gap detection thresholds. Brain sections were reacted with anti-calbindin D-28k (CB) and anti-calretinin (CR). Staining patterns were characterized and cell counts performed. CB immunoreactivity was high only in the nucleus of the commissure (NCO); counts revealed a 22.3% decrease in the number of CB+ cells in old CBA mice and a 25.1% decrease in old C57 mice. Calretinin immunoreactivity was high in the pericentral regions of the IC, but the central nucleus was devoid of CR+ cells. The dorsal cortex, lateral nucleus, and NCO showed increases of 42.3, 49.0, and 61%, respectively, in the number of CR+ cells, but only in the old CBA mice. No significant change was observed in the old C57 mice. Whereas decreases in CB immunoreactivity are common with age, this study is the first to report an age-related increase in CR immunoreactivity in the auditory system. The increase in CR+ cells is a possible compensatory adaptation to the decrease in CB+ cells. That the number of CR+ cells remains constant with age in C57 mice suggests this compensation may depend upon stimulus-driven activity, but this requires further study.

Neural correlates of behavioral gap detection in the inferior colliculus of the young CBA mouse.

The gap detection paradigm is frequently used in psychoacoustics to characterize the temporal acuity of the auditory system. Neural responses to silent gaps embedded in white-noise carriers, were obtained from mouse inferior colliculus (IC) neurons and the results compared to behavioral estimates of gap detection. Neural correlates of gap detection were obtained from 78 single neurons located in the central nucleus of the IC. Minimal gap thresholds (MGTs) were computed from single-unit gap functions and were found to be comparable, 1-2 ms, to the behavioral gap threshold (2 ms). There was no difference in MGTs for units in which both carrier intensities were collected. Single unit responses were classified based on temporal discharge patterns to steady-state noise bursts. Onset and primary-like units had the shortest mean MGTs (2.0 ms), followed by sustained units (4.0 ms) and phasic-off units (4.2 ms). The longest MGTs were obtained for inhibitory neurons (x = 14 ms). Finally, the time-course of behavioral and neurophysiological gap functions were found to be in good agreement. The results of the present study indicate the neural code necessary for behavioral gap detection is present in the temporal discharge patterns of the majority of IC neurons.

Sensorineural hearing loss alters recovery from short-term adaptation in the C57BL/6 mouse.

Several strains of laboratory mouse (Mus musculus) have a pattern of hearing loss which resembles that found in humans. The C57BL/6 strain of mouse has a genetic defect that results in degeneration of the organ of Corti, originating in the basal, high-frequency region and then proceeding apically over time. The end result is a severe-to-profound sensorineural hearing loss (SNHL) by 14 months of age. In contrast, auditory function of the CBA strain remains normal through its early life span then slowly declines later in life, much like that typified by human presbycusis. The purpose of the present study was to compare ABR (peak 5) forward masking recovery functions in young, normal-hearing CBA and C57BL/6 mice to hearing-impaired C57BL/6 mice. ABR audiograms were obtained prior to collecting the tone-on-tone forward masking data. Masking was defined as a 50% reduction in the P5 component of the ABR, elicited and masked by 12 kHz tone bursts, using masker/probe time delays from 0 to 100 ms. Time constants were computed from an exponential model fit to the recovery functions (masker level vs. time delay). In hearing-impaired animals there was a significant increase in recovery from short-term adaptation as measured by the time constants, as well as a significant latency shift in the P5 component. The effects of SNHL on the recovery of the P5 component from short-term adaptation was comparable to that reported behaviorally for human hearing-impaired listeners and physiologically from the inferior colliculus (IC) of chinchillas suffering permanent threshold shifts.

Neural processing of musical timbre by musicians, nonmusicians, and musicians possessing absolute pitch.

Cognitive event-related potentials (ERPs) were measured during a timbre discrimination task from three subject groups varying in musical experience. The P3 component of the ERP was recorded from musicians with absolute pitch, musicians without absolute pitch, and nonmusicians during a task comprising timbres of varying difficulty. The three-timbre series, all of which consisted of the same pitch, were (1) string instruments in the same family (cello and viola), (2) flutes made of different materials (silver and wood), and (3) instruments of slightly different size (B-flat versus F tubas). The amplitude and latency of the P3 component varied systematically as a function of musical experience and type of timbre discrimination. The difficult timbre task resulted in mean P3 amplitudes which were larger for musicians relative to nonmusicians, however P3 amplitudes were similar for the two additional timbre series. The mean P3 latencies for musicians were shorter when compared to nonmusicians across all three series. In comparison, the AP subjects displayed the shortest mean P3 latencies, but had smaller P3 amplitudes relative to both musicians and nonmusicians. The implications of these findings suggest that perceptual tasks involving one of the fundamental building blocks of music, namely timbre, does elicit differential brain activity from memory or information processing systems from subjects with varying degrees of musical training.

Encoding of amplitude modulation in the gerbil cochlear nucleus: I. A hierarchy of enhancement.

The main goal of the present study was to investigate the encoding of a biologically-relevant acoustic feature--amplitude modulation (AM)--in single neurons of the auditory nerve and ventral cochlear nucleus (VCN). In the anesthetized gerbil auditory-nerve fibers and VCN units show strong synchronous responses to low-intensity, low-frequency AM. As frequency increases, the strength of the synchronous response decreases. In the auditory nerve the strength of the synchronous response is substantially less at high intensities than at low intensities and does not change significantly with AM frequency at high intensities. In contrast to the auditory nerve, VCN units show strong responses at high intensities. They have a particular AM frequency to which they are maximally responsive, and this frequency varies from unit to unit. Therefore, VCN units transform their ascending inputs by enhancing the synchronous response to AM. A correlation exists between a unit's ability to encode AM and its responses to simple sounds. Specifically, onset units show the strongest synchronous responses, followed in order by chopper, primarylike-with-notch and primarylike units. This enhancement is greatest at high intensities and can occur up to 90 dB above a unit's threshold. Thus, a hierarchy of enhancement for AM processing exists in the most peripheral nucleus of the central auditory system.

Functional organization of mustached bat inferior colliculus: I. Representation of FM frequency bands important for target ranging revealed by 14C-2-deoxyglucose autoradiography and single unit mapping.

The representation in the inferior colliculus of the frequency modulated (FM) components of the first (25-30 kHz) and second (50-60 kHz) harmonic of the sonar signal of the mustached bat, which may be important for target range processing, was investigated by using the 2-deoxyglucose (2-DG) technique and single-unit mapping. In the 2-DG experiments, bats presented with second harmonic FM stimuli alone showed uptake of label in specific regions of the central nucleus and dorsal cortex of the inferior colliculus, and the nucleus of the brachium. In the central nucleus, a dorsoventrally and mediolaterally elongated slab at the caudal border of the anterolateral division was observed. Labeling in the dorsal cortex was contiguous with this band. Bats stimulated with pairs of first and second harmonic FM stimuli separated by short time delays showed similar patterns of labeling, with the addition of another dorsoventrally elongated region of uptake in the more rostral part of the anterolateral division, associated with label in the dorsal cortex. By comparison to control cases exposed to delayed pairs of first and third harmonic signals, or to a second harmonic constant-frequency tone burst at the bat's reference frequency (ca. 60 kHz), we deduced that this additional region of uptake was attributable to the first harmonic FM component. To elucidate further the details of the tonotopic organization and to correlate the frequency representation with anatomical features of the IC, fine-grained maps of single-unit best frequencies were obtained in the central nucleus. Isofrequency contours were reconstructed by computer from five bats after focal, iontophoretic injection of horseradish peroxidase to locate the penetrations and trace connections of the FM2 area. We found that the tissue volume representing FM2 frequencies (50-60 kHz) showed approximately a sixfold overrepresentation for this frequency band. This region occupied most of the caudal portion of the anterolateral division of the central nucleus. Only a single tonotopic representation was found in the central nucleus, consistent with the pattern seen in other mammals. However, isofrequency contours in the anterolateral division were oriented dorsoventrally, approximately parallel to the coronal plane. The small band of frequencies (ca. 60-62 kHz) associated with the dominant constant-frequency component of the biosonar signal was even more dramatically overrepresented (40x) and was confined to the dorsoposterior division, as previously reported by Zook et al. (1985, 530-456).(ABSTRACT TRUNCATED AT 400 WORDS)