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Effects of reaction time performance on single-unit activity in the central auditory pathway of the rhesus macaque.

The activity of single units at various locations in the central auditory pathway of rhesus macaques was recorded during the monkeys' performance and nonperformance in an auditory reaction time task. Evoked unit responses during performance were compared with those observed during passive delivery of identical stimuli. Single units were recorded from the cochlear nucleus, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate nucleus, and auditory cortex. Significant effects of task performance on unit discharge patterns were observed at all levels of the central auditory pathway: Spontaneous discharge rates in the more peripheral auditory nuclei tended to be higher during performance. Evoked discharge that occurred relatively late during a stimulus presentation (greater than 75 msec after stimulus onset) was increased during performance, compared with the nonperformance condition, in nuclei above the cochlear nucleus. The initial latency of evoked discharge was increased during performance for subcortical nuclei but was decreased for units in auditory cortex. These results suggest that the effects of performance may be mediated by a tonic increase in the excitability of auditory units which operates primarily at peripheral auditory stations, and a descending, stimulus-evoked increase in excitability which primarily influences the cells of higher auditory nuclei. At the cortical level, these changes lead to increased signal-to-noise ratio of the evoked response during performance in the auditory task.

Acoustic Stimulation↗

Effect of transient neonatal hypothyroidism on the free aspartic acid, glutamic acid, and GABA content of different central auditory regions in the rat.

The aspartic acid, glutamic acid, and gamma-aminobutyric acid (GABA) contents were determined in four central auditory system regions in rats with transient neonatal hypothyroidism compared with control ones: the ventral and dorsal parts of the cochlear nucleus, the central nucleus of the inferior colliculus, the auditory cortex, and in an extra-auditory structure, the substantia nigra pars reticulata. The animals were sacrificed at 50 days of age, brain tissue samples were taken out by microdissection, and the free amino acids were extracted. The amino acid content was assessed by double-isotope labelling following two-dimensional thin-layer chromatography separation. GABA content was significantly decreased in both cochlear nucleus regions and glutamic acid was elevated in the inferior colliculus. Neonatal hypothyroidism had no significant effect on the aspartic acid levels in the regions studied. The results suggest an effect of neonatal hypothyroidism on regional contents of free amino acids known as candidate neurotransmitters in the auditory system.

Animals↗

Neurophysiological correlates of auditory maturation.

At the time of its birth, the auditory system of the cat is not completely developed. Anatomic maturity of the peripheral auditory system, ie, the cochlea, auditory nerve and cochlear nucleus, is attained at about two or three weeks of age. Physiological response properties of neural elements of the peripheral auditory system change radically during the first few weeks of life, with most measures of responsiveness to acoustic stimuli reaching adult status by the end of the third of fourth postnatal week. The physiological maturation of neural responses correlates well with the anatomic maturation of the auditory structures. At least one physiological response property, namely the ability of cochlear nucleus neurons to time their discharges in response to low-frequency tones, is not fully achieved until the sixth postnatal week or later. Although considerably less is known about the development of the central auditory system, it appears that it is in part dependent upon the maturation of more peripheral elements. Auditory evoked responses, for example, follow roughly the same developmental time course as do the majority of response properties of peripheral neurons. This implies that the central system is ready to function at birth, but that it must await the maturation of more peripheral elements before it can function properly. In contrast to that of the cat and other mammals, the auditory system of the human is relatively well advanced at birth. Certain aspects of brain development, such as dendritic aborization and axonal myelination, undergo considerable change postnatally. How these factors influence hearing is not known.

Animals↗

Elevated expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in cerebellar unipolar brush cells of a Down syndrome mouse model.

1. Down syndrome (DS) arises from the presence of three copies of chromosome (Chr.) 21. Fine motor learning deficits found in DS from childhood to adulthood result from expression of extra genes on Chr. 21, however, it remains unclear which if any of these genes are the specific causes of the cognitive and motor dysfunction. DS cerebellum displays morphological abnormalities that likely contribute to the DS motor phenotype. 2. The G-protein-activated inwardly rectifying potassium channel subunit 2 (GIRK2) is expressed in cerebellum and can shunt dendritic conductance and attenuate postsynaptic potentials. We have used an interbreeding approach to cross a genetic mouse model of DS (Ts65Dn) with Girk2 knockout mice and examined its relative expression level by quantitative real-time RT-PCR, Western blotting and immunohistochemistry. 3. We report here for the first time that GIRK2 is expressed in unipolar brush cells, which are excitatory interneurons of the vestibulocerebellum and dorsal cochlear nucleus. Analysis of disomic-Ts65Dn/Girk2((+/+/-)) and heterozygous-Diploid/Girk2((+/-)) mice shows that GIRK2 expression in Ts65Dn lobule X follows gene dosage. The lobule X of Ts65Dn mice contain greater numbers of unipolar brush cells co-expressing GIRK2 and calretinin than the control mouse groups. 4. These results demonstrate that gene triplication can impact specific cell types in the cerebellum. We hypothesize that GIRK2 overexpression will adversely affect cerebellar circuitry in Ts65Dn vestibulocerebellum and dorsal cochlear nucleus due to GIRK2 shunting properties and its effects on resting membrane potential.

Animals↗

Evoked potentials recorded from brain-stem nuclei in awake cat: interaction of tone bursts and continuous tone.

Previous work indicated that components of the auditory thalamocortical potential evoked by a brief binaural tone burst could be enhanced by certain stimulus combinations, e.g., a brief tone burst in the presence of a continuous tone. The principal questions of the present study were whether enhanced components could be obtained caudal to thalamocortex and whether monaural stimuli would be effective in producing enhancement. Eight cats received permanent electrodes in cochlear nucleus and the nucleus of the inferior colliculus. Custom earmolds were made for each ear of each animal. The median attenuation produced by the earmolds was 35 dB and the use of a single earmold approximated monaural stimulation. Auditory evoked potentials were recorded from the electrodes while the animals were unanesthetized but comfortably restrained. Brief 6.25 kHz tone bursts were presented against a background of silence or of a 4.96 kHz continuous tone. In the presence of the continuous tone, enhanced components were obtained from a majority of the electrodes in inferior colliculus but from none of the electrodes in cochlear nucleus. The late negative component in the colliculus potential was increased in amplitude while other components were reduced in amplitude by the continuous tone. The latencies of all components from all electrodes were increased by the presence of the continuous tone. It was concluded that enhancement effects could be obtained at the level of inferior colliculus, and that binaural stimulation does not appear to be necessary to produce enhanced components.

Acoustic Stimulation↗

Directing gene expression to cerebellar granule cells using gamma-aminobutyric acid type A receptor alpha6 subunit transgenes.

Expression of the gamma-aminobutyric acid type A receptor alpha6 subunit gene is restricted to differentiated granule cells of the cerebellum and cochlear nucleus. The mechanisms underlying this limited expression are unknown. Here we have characterized the expression of a series of alpha6-based transgenes in adult mouse brain. A DNA fragment containing a 1-kb portion upstream of the start site(s), together with exons 1-8, can direct high-level cerebellar granule cell-specific reporter gene expression. Thus powerful granule cell-specific determinants reside within the 5' half of the alpha6 subunit gene body. This intron-containing transgene appears to lack the cochlear nucleus regulatory elements. It therefore provides a cassette to deliver gene products solely to adult cerebellar granule cells.

Animals↗

Distribution of corticotropin-releasing factor mRNA and immunoreactivity in the central auditory system of the rat.

Hybridization histochemical and immunohistochemical methods were used to characterize the distribution of corticotropin-releasing factor (CRF) messenger RNA (mRNA) and peptide, respectively, in the central auditory system of the rat. Cell bodies expressing CRF mRNA and/or immunoreactivity (IR) were detected at each level of the system, including sparse or equivocal localizations in the dorsal cochlear nucleus, the medial nucleus of the trapezoid body, and the lateral superior olive. More prominent groups of cells expressing CRF mRNA and CRF-IR were found in the nuclei of the lateral lemniscus, the shell of the inferior colliculus, the medial division of the medial geniculate body and in primary auditory cortices. The latter showed the greatest density of CRF-expressing interneurons, distributed primarily in layers II, III and V, of any neocortical area. Results obtained using the two staining methods were in good agreement, except in the cochlear and superior olivary nuclei, where cells displaying CRF-IR were apparent in far greater abundance than those expressing CRF mRNA. CRF-IR fibers and terminals were detected in regions generally consistent with the cellular localizations described above. These results provide evidence for a surprisingly widespread expression of CRF in the auditory system of the rat. This includes generally low levels of expression in components of the primary auditory path (cochlear nucleus, trapezoid body, superior olive, lemniscal nuclei). CRF appears to be more prominently expressed in so-called non-primary components of the auditory system, including aspects of the medial geniculate body that constitute an interface between the auditory system and stress-related limbic system circuitry.

Animals↗

Expression of mKirre, a mammalian homolog of Drosophila kirre, in the developing and adult mouse brain.

mKirre, a mammalian homolog of the Drosophila kirre, is expressed in bone marrow stromal cells and the brain. Although mKirre has been shown to support the hematopoietic stem cells, little is known about the function of mKirre in the brain. In the present study, to gain insights into the function of mKirre, we investigated the expression pattern of mKirre gene in the developing and adult mouse brain using in situ hybridization. In the adult brain, mKirre mRNA was highly expressed in the olfactory bulb, the piriform cortex, the cochlear nucleus, and the cerebellum. At embryonic day (E) 11.5, we could observe mKirre mRNA in the differentiating zones of various regions, such as the caudate-putamen, the geniculate body, the thalamus, the amygdala, and the brainstem. Its gene expression in these regions at E11.5 also persisted to the adult, in which its expression levels were much less prominent. After birth, we could first observe high expression of mKirre mRNA in the glomerular and mitral layers of the olfactory bulb, the cortical plate of the neocortex, the cochlear nucleus, and the molecular and granule cell layers of the cerebellum. In the hippocampus, its gene expression was first observed in the dentate gyrus at postnatal day 7. The spatiotemporal expression pattern of mKirre mRNA suggests important roles of mKirre in later developmental processes, especially the synapse formation.

Age Factors↗

Inputs to combination-sensitive neurons of the inferior colliculus.

In the mustached bat, combination-sensitive neurons display integrative responses to combinations of acoustic elements in biosonar or social vocalizations. One type of combination-sensitive neuron responds to multiple harmonics of the frequency-modulated (FM) components in the sonar pulse and echo of the bat. These neurons, termed FM-FM neurons, are sensitive to the pulse-echo delay and may encode the distance of sonar targets. FM-FM neurons are common in high-frequency regions of the central nucleus of the inferior colliculus (ICC) and may be created there. If so, they must receive low-frequency inputs in addition to the expected high-frequency inputs. We placed single deposits of a tracer at FM-FM recording sites in the ICC and then analyzed retrograde labeling in the brainstem and midbrain. We were particularly interested in labeling patterns suggestive of low-frequency input to these FM-FM neurons. In most nuclei containing labeled cells, there was a single focus of labeling in regions thought to be responsive to high-frequency sounds. More complex labeling patterns were observed in three nuclei. In the anteroventral cochlear nucleus, labeling in the anterior and marginal cell divisions occurred in regions thought to respond to low-frequency sounds. This labeling comprised 6% of total brainstem labeled cells. Labeling in the intermediate nucleus of the lateral lemniscus and the magnocellular part of the ventral nucleus of the lateral lemniscus together comprised nearly 40% of all labeled cells. In both nuclei, multiple foci of labeling occurred. These different foci may represent groups of cells tuned to different frequency bands. Thus, one or more of these three nuclei may provide low-frequency input to high-frequency-sensitive cells in the ICC, creating FM-FM responses. We also examined whether ICC neurons responsive to lower frequencies project to high-frequency-sensitive ICC regions; only 0.15% of labeling originated from these lower frequency representations. If the spectral integration of FM-FM neurons is created at the level of the ICC, these results suggest that neurons of the anteroventral cochlear nucleus or monaural nuclei of the lateral lemniscus may provide the essential low-frequency input. In contrast, there is little evidence that the low-frequency representation of the ICC contributes to these integrative responses.

Acoustic Stimulation↗

[Mitochondrial DNA4977 deletions associated with human presbycusis].

OBJECTIVE: To determine whether or not the mtDNA4977 deletions contribute to human aging and involve in the development of presbycusis. METHODS: 67 sides of archival temporal bone sections, 20 temporal brains, 21 cochlear nucleus, 20 hearts and 22 livers were harvested and the total DNA was extracted. The presence of mtDNA4977 deletions was examined using nest polymerase chain reaction(PCR). RESULTS: Our results showed: (1) the highly conserved mitochondrially-encoded tRNA and ND1 segments were amplified from all tissues, as well as mtDNA4977 deletions related to aging. (2) The incidence of carrying mtDNA4977 deletions in all tissues in aged group was significant higher than that of young control group (P < 0.05). (3) The incidence of carrying mtDNA4977 deletions in temporal bone sections and cochlear nucleus with presbycusis patients was significant higher than that of aged normal hearing control group (P < 0.05). However, the incidence of carrying mtDNA4977 deletions in heart and liver were no significant difference between presbycusis patients and the control group. CONCLUSION: These findings indicated that mtDNA4977 deletions in human contribute to presbycusis, as well as aging.

Adult↗

Neural delay in the ascending auditory pathway.

Evoked responses from the cochlea and cochlear nucleus in the rat were studied using two types of stimuli: (1) bursts of tones or noise, and (2) continuous tones or noise that were amplitude modulated with pseudorandom noise. While the responses to the first type of stimuli were averaged only in the conventional way, the responses to the continuous and amplitude modulated sounds were averaged over one period of the pseudorandom noise. This average was then cross correlated with one period of the noise. The morphology of these cross correlation functions was in many ways similar to the response to transient sounds. Recordings from the round window of the cochlea and the cochlear nucleus showed that the latencies of these peaks in the responses to tone bursts and those of the cross correlation functions obtained from the continuous tones modulated with pseudorandom noise were similar. However, the latencies of the peaks in the cross correlation functions were slightly shorter and showed less dependency on the stimulus intensity than did the peaks in the responses to tone bursts. When the responses to noise bursts and the responses to noise that was amplitude modulated were compared, it was found that the latencies of the peaks in the cross correlation functions were nearly independent of the stimulus intensity. However, the peaks in the averaged responses to noise bursts showed a decrease in latency with increasing sound intensity.

Animals↗

Rehabilitation of hearing and communication functions in patients with NF2.

Most patients with neurofibromatosis type 2 (NF2) lose hearing either spontaneously or after removal of their neurofibromas. The patient may benefit from conventional hearing aids if, due to modern microsurgery and intraoperative monitoring the integrity of the cochlea and the 8th nerve is preserved. With lost auditory function but preserved electrical stimulibility of the 8th nerve a cochlear implant may be appropriate. But if the patients have no remaining 8th nerve to stimulate, there is no benefit from cochlear implants. Until some years ago, vibrotactile aids, lip-reading, and sign language have been the only communication modes available to these patients. With auditory brain stem implants it is now possible to bypass both the cochlea and the 8th nerve and to stimulate the cochlear nucleus directly. Stimulation of the devices produces useful auditory sensations in almost all patients. Testing of perceptual performance indicated significant benefit from the device for communication purposes, including sound-only sentence recognition scores and the ability to converse on the telephone. Also lip-reading is significantly improved with brain stem implants. The successful work of an auditory brainstem program center depends very much on the close interdisciplinary collaboration between the Departments of Neurosurgery and ENT-surgery. In the future new developments like speech processing strategies and new designed electrodes accessing the complex tonotopic organization of the cochlear nucleus may further improve rehabilitation in these patients who would have been deaf some years ago.

Auditory Pathways↗

Central projections of auditory nerve fibers of differing spontaneous rate, II: Posteroventral and dorsal cochlear nuclei.

Response properties of auditory nerve fibers (ANFs), including threshold sensitivity, vary systematically with spontaneous discharge rate (SR) (Liberman, M.C.: J. Acoust. Soc Amer. 63:442-455, 1978). Thus, an understanding of the mechanisms underlying signal transformation in the cochlear nucleus (CN) must include a description of any SR-based difference in ANF projections. This study is the second of a pair describing the CN projections of intracellularly labeled ANFs of known SR, the first of which summarized projection to the anteroventral CN (Liberman, M.C.: J. Comp. Neurol. 313:240-258, 1991). For each swelling from each labeled fiber, the position (within CN subdivisions), the size, and the type of cell contacted (if determinable) was noted: roughly one in four labeled swellings appeared in intimate contact with the soma or proximal dendrites of a CN cell. In all such cases, cell size and swelling size were measured. As reported for auteroventral cochlear nucleus, the ANF innervation of the small-cell regions of posteroventral CN (PVCN) was almost exclusively by low- and medium-SR fibers. Other significant SR-based trends in ANF projections included 1) a tendency for high-SR fibers to contact larger cells in PVCN, 2) a meager projection of low- and medium-SR fibers to octopus cells, and 3) a tendency in the dorsal CN (DCN) for low-SR terminals to end closer to the fusiform cell layer than high-SR terminals. There were no significant SR-based difference in ANF swelling sizes in any subdivision. A consideration of the average cell sizes, ANF swelling sizes and estimated numbers of ANFs of different CF and SR converging on each CN cell help explain some of the differences in response transformation associated with different cell types in the CN.

Acoustic Stimulation↗

Temporal coding of periodicity pitch in the auditory system: an overview.

This paper outlines a taxonomy of neural pulse codes and reviews neurophysiological evidence for interspike interval-based representations for pitch and timbre in the auditory nerve and cochlear nucleus. Neural pulse codes can be divided into channel-based codes, temporal-pattern codes, and time-of-arrival codes. Timings of discharges in auditory nerve fibers reflect the time structure of acoustic waveforms, such that the interspike intervals that are produced precisely convey information concerning stimulus periodicities. Population-wide inter-spike interval distributions are constructed by summing together intervals from the observed responses of many single Type I auditory nerve fibers. Features in such distributions correspond closely with pitches that are heard by human listeners. The most common all-order interval present in the auditory nerve array almost invariably corresponds to the pitch frequency, whereas the relative fraction of pitch-related intervals amongst all others qualitatively corresponds to the strength of the pitch. Consequently, many diverse aspects of pitch perception are explained in terms of such temporal representations. Similar stimulus-driven temporal discharge patterns are observed in major neuronal populations of the cochlear nucleus. Population-interval distributions constitute an alternative time-domain strategy for representing sensory information that complements spatially organized sensory maps. Similar autocorrelation-like representations are possible in other sensory systems, in which neural discharges are time-locked to stimulus waveforms.

Acoustic Stimulation↗

Coding of sound envelopes by inhibitory rebound in neurons of the superior olivary complex in the unanesthetized rabbit.

Most natural sounds (e.g., speech) are complex and have amplitude envelopes that fluctuate rapidly. A number of studies have examined the neural coding of envelopes, but little attention has been paid to the superior olivary complex (SOC), a constellation of nuclei that receive information from the cochlear nucleus. We studied two classes of predominantly monaural neurons: those that displayed a sustained response to tone bursts and those that gave only a response to the tone offset. Our results demonstrate that the off neurons in the SOC can encode the pattern of amplitude-modulated sounds with high synchrony that is superior to sustained neurons. The upper cutoff frequency and highest modulation frequency at which significant synchrony was present were, on average, slightly higher for off neurons compared with sustained neurons. Finally, most sustained and off neurons encoded the level of pure tones over a wider range of intensities than those reported for auditory nerve fibers and cochlear nucleus neurons. A traditional view of inhibition is that it attenuates or terminates neural activity. Although this holds true for off neurons, the robust discharge when inhibition is released adds a new dimension. For simple sounds (i.e., pure tones), the off response can code a wide range of sound levels. For complex sounds, the off response becomes entrained to each modulation, resulting in a precise temporal coding of the envelope.

Acoustic Stimulation↗

A statistically based method to generate response maps objectively.

One scheme to classify the physiological response properties of single units in the cochlear nucleus is based on the average discharge rate of the unit and is reflected in the distribution of excitatory and inhibitory regions in a frequency-level map (response map) that spans the unit's receptive area (e.g., Evans and Nelson, 1973; Young and Brownell, 1976; Young and Voigt, 1982; Shofner and Young, 1985, Spirou and Young, 1991). Typically, discharge rate versus level curves are acquired at many frequencies and the investigator determines that a unit is excited or inhibited at a given level if the driven rate is above or below a spontaneous rate estimate by a specified criterion (for example, 20%). The investigator then encloses regions of excitation and inhibition where responses over adjacent frequencies and levels are consistent. In the present report, we describe an objective 3-step computer-based method to generate response maps: raw driven and spontaneous rate estimates are smoothed with a low-pass spatial filter; a unit is said to be excited or inhibited at a given level if the filtered driven rate is above or below the mean filtered spontaneous rate for that frequency by a specified criterion (percentage or statistical); and resultant response maps are median spatial filtered to eliminate spurious regions. The results shown here demonstrate that use of a statistical criterion provides a more reliable detection of excitation and inhibition than a 20% criterion, particularly when the variance of the rate estimates is high. Further, the statistically based method permits unit classification based on response map data that are more rapidly acquired with shorter duration stimuli (32 vs. 200 ms). Although this method is applied to units recorded in the dorsal cochlear nucleus, the technique may be applicable to studies of receptive fields and their plasticity in other systems.

Acoustic Stimulation↗

Systematic errors in indirect estimates of basilar membrane travel times.

There exist in the literature three attempts to derive basilar membrane travel times from the phase versus frequency characteristics of responses to tones in the auditory nerve [Anderson et al., J. Acoust. Soc. Am. 4., 1131-1139 (1971)], cochlear nucleus [Gibson et al., in Psychophysics and Physiology of Hearing, edited by Evans and Wilson (Academic, New York, 1977), pp. 57-68], and basilar membrane [Robles et al., J. Acoust. Soc. Am. 59, 926-939 (1976)]. It is argued in this paper that these derivations probably have overestimated the actual mechanical travel times. Travel time was originally defined by von Békésy as the latency between the onset of a click stimulus and the onset of basilar membrane vibration. For a linear bandpass system, the frequency-domain equivalent of this latency is the high-frequency asymptotoic slope of the phase lag versus frequency characteristic, which is not generally a linear function. In the neural studies (auditory nerve and cochlear nucleus) it was assumed that the phase versus frequency characteristic was a straight line. Slopes derived under a linear assumption are probably closer to the weighted average group delay (i.e., the center of gravity of the click response) than they are to travel time. In the Mössbauer study of basilar membrane mechanics the latency of the response to clicks was compared with the low-frequency slope of the phase characteristic. The comparison should have been made with the high-frequency slope.

Basilar Membrane↗

Acoustic chiasm. III: Nature, distribution, and sources of afferents to the lateral superior olive in the cat.

The outcomes of seven experiments are reported, each directed to the nature and sources of the excitation and inhibition impinging on the lateral superior olive (LSO) in cats. In the first experiment, we used conventional 14C 2-DG methods to determine the specificity, precision, and extent of symmetry in the stimulation reaching LSO from the ipsilateral and contralateral ears. In Experiment 2, we sought the presence of GABA and glycine receptors in LSO using conventional, in vitro receptor-binding methods. On the basis of these results, we used in vitro high-affinity uptake methods in Experiment 3 to seek evidence that some of the terminals as well as the receptors in LSO are glycinergic. In Experiment 4, we used immunocytochemical methods to show that the somata known to supply the contralateral projections to LSO, and their terminals in LSO, are each immunoreactive with an antibody directed to a glycine-protein conjugate. In Experiment 5, we made use of a glycinergic neuron's avidity for transporting glycine retrogradely to label the likely sources of the glycinergic terminals in LSO. In Experiment 6, we used immunocytochemical methods to show that the spherical and globular cells of the ventral cochlear nucleus and terminals in LSO and in MTB are glutamatergic and/or aspartergic. In Experiment 7, we used receptor binding methods to determine whether the glutamate/aspartate receptors in LSO are probably of the kainate or of the quisqualate type. The results of the several experiments suggest that probably glutamate-quisqualate synapses mediate LSO's ipsilaterally driven excitatory responses and glycinergic synapses mediate its contralaterally driven inhibitory responses. The two types of input appear to be well matched in LSO's medial and middle limbs with glycinergic terminals mostly perisomatic and glutamatergic terminals mostly peridendritic. However, LSO's low frequency lateral limb appears to be somewhat different; it receives less stimulation from the contralateral ear. Instead, LSO's lateral limb may receive some of its glycinergic input directly from the ipsilateral ventral cochlear nucleus and/or indirectly via the juxtaposed lateral nucleus of the trapezoid body.

Afferent Pathways↗