The structure of innate vocalizations in Foxp2-deficient mouse pups.

Heterozygous mutations of the human FOXP2 gene are implicated in a severe speech and language disorder. Aetiological mutations of murine Foxp2 yield abnormal synaptic plasticity and impaired motor-skill learning in mutant mice, while knockdown of the avian orthologue in songbirds interferes with auditory-guided vocal learning. Here, we investigate influences of two distinct Foxp2 point mutations on vocalizations of 4-day-old mouse pups (Mus musculus). The R552H missense mutation is identical to that causing speech and language deficits in a large well-studied human family, while the S321X nonsense mutation represents a null allele that does not produce Foxp2 protein. We ask whether vocalizations, based solely on innate mechanisms of production, are affected by these alternative Foxp2 mutations. Sound recordings were taken in two different situations: isolation and distress, eliciting a range of call types, including broadband vocalizations of varying noise content, ultrasonic whistles and clicks. Sound production rates and several acoustic parameters showed that, despite absence of functional Foxp2, homozygous mutants could vocalize all types of sounds in a normal temporal pattern, but only at comparably low intensities. We suggest that altered vocal output of these homozygotes may be secondary to developmental delays and somatic weakness. Heterozygous mutants did not differ from wild-types in any of the measures that we studied (R552H ) or in only a few (S321X ), which were in the range of differences routinely observed for different mouse strains. Thus, Foxp2 is not essential for the innate production of emotional vocalizations with largely normal acoustic properties by mouse pups.

Corticofugal reorganization of the midbrain tonotopic map in mice.

Previous studies have indicated that frequency maps (tonotopies) in mammalian auditory brain centers are plastic. Here, we examined this plasticity in the mouse auditory midbrain through focal stimulation of the primary auditory cortex. Cortical activation shifted midbrain frequency tunings toward the best frequencies of the stimulated cortical neurons if these were either higher or lower than the cortical ones. Such corticofugal adjustments appear to minimize the difference between cortical and collicular frequency tuning within the critical bandwidths of the auditory system. Consequently, the neural representation is enhanced for the frequencies to which the cortical neurons were tuned. Our data suggest that the auditory cortex reorganizes midbrain tonotopy on the basis of which cortical frequencies are stimulated, mostly probably through corticofugal projections.

Perception and recognition discriminated in the mouse auditory cortex by c-Fos labeling.

The functions of the fields of the mammalian auditory cortex in sound perception and recognition are unknown. We used Fos (a protein of the inducible immediate-early gene c-fos) as a cellular marker of activated brain areas to show in the mouse (Mus domesticus) that sound is processed differentially in auditory cortical fields according to its actual significance in a behavioral context. Recognition, compared with perception of exactly the same sound, produced significantly less but well focused Fos-positive cells in a primary auditory cortical field and significantly more labeling in higher auditory and association fields. Thus, recognition means a state of distinctive spatial distribution of activity in auditory cortical fields with a predominance of activation in higher-order fields.

The auditory cortex of the house mouse: left-right differences, tonotopic organization and quantitative analysis of frequency representation.

Multi-unit electrophysiological mapping was used to establish the area of the left- and right-hemisphere auditory cortex (AC) of the mouse and to characterize various fields within the AC. The AC of the left hemisphere covered a significantly larger (factor of 1.30) area compared to that of the right side. Based on best-frequency (BF) maps and other neuronal response characteristics to tone and noise bursts, five fields (primary auditory field, anterior auditory field, second auditory field, ultrasonic field, dorsoposterior field) and two small non-specified areas could be delimited on both hemispheres. The relative sizes of these fields and areas were similar on both sides. The primary and anterior auditory fields were tonotopically organized with counter running frequency gradients merging in the center of the AC. These fields covered BF ranges up to about 45 kHz. Higher BFs up to about 70 kHz were represented non-tonotopically in the separate ultrasonic field, part of which may be considered as belonging to the primary field. The dorsoposterior and second auditory fields were non-tonotopically organized and neurons had special response properties. These characteristics of the mouse AC were compared with auditory cortical maps of other mammals.

Frequency resolution and spectral integration (critical band analysis) in single units of the cat primary auditory cortex.

Frequency resolution and spectral filtering in the cat primary auditory cortex (AI) were mapped by extracellular recordings of tone responses in white noise of various bandwidths. Single-tone excitatory tuning curves, critical bandwidths, and critical ratios were determined as a function of neuronal characteristic frequency and tone level. Single-tone excitatory tuning curves are inadequate measures of frequency resolution and spectral filtering in the AI, because their shapes (in most neurons) deviated substantially from the shapes of "tuning curves for complex sound analysis", the curves determined by the band limits of the critical bandwidths. Perceptual characteristics of spectral filtering (intensity independence and frequency dependence) were found in average critical bandwidths of neurons from the central and ventral AI. The highest frequency resolution (smallest critical bandwidths) reached by neurons in the central and ventral AI equaled the psychophysical frequency resolution. The dorsal AI is special, since most neurons there had response properties incompatible with psychophysical features of frequency resolution. Perceptual characteristics of critical ratios were not found in the average neuronal responses in any area of the AI. It seems that spectral integration in the way proposed to be the basis for the perception of tones in noise is not present at the level of the AI.

Development of tonotopy in the inferior colliculus II: 2-DG measurements in the kitten.

The development of size and tonotopy in the inferior colliculus of the kitten was studied using the [14C]2-deoxyglucose technique and tone stimulation with 2 and 15 kHz at a maximum 110 dB sound pressure level. At 2 days of age, frequency-specific labelling cannot be detected. Two kilohertz labelling is distinctly visible in the rostral and central inferior colliculus at day 6; 15 kHz labelling occurs first at day 11. In the rostral and central inferior colliculus, 2 kHz labelling starts at a ventral and central position and shifts dorsalwards and to a more lateral location between postnatal days 6 and 21. Such a shift is not seen in the caudal inferior colliculus. There, the focus of 2 kHz labelling remains rather constant; only the extension of the labelling increases in the older animals. In all parts of the inferior colliculus, 15 kHz labelling starts at a ventromedial position and shifts to a more lateral location while extending also more dorsalwards as the age increases. These changes in 15 kHz labelling continue up to 3 months. In addition to the ventromedial-to-dorsolateral shift and expansion of labelling, there is also a rostral-to-caudal gradient of maturation, in that in older animals frequency-specific labelling reaches farther caudalwards. The reported changes in frequency representation in the inferior colliculus can be explained on the basis of a shift in frequency input and input sensitivity to the laminae of the inferior colliculus, mainly due to maturational changes within the cochlea and/or as a consequence of the increasing size of the inferior colliculus.

Neuronal activity and tonotopy in the auditory system visualized by c-fos gene expression.

Responsiveness in the cochlear nucleus complex and inferior colliculus of the mouse to tonal stimulation is labelled via immunocytochemically stained Fos protein that is expressed by c-fos gene activation in excited neurons. The locations of Fos-positive neurons closely reproduce the tonotopic maps in the dorsal cochlear nucleus and inferior colliculus. Thus, the c-fos method can demonstrate stimulus-related local neuronal activation on a single-cell level and may be useful to complement other mapping techniques such as electrophysiological recording or 2-deoxyglucose autoradiography.

Development of tonotopy in the inferior colliculus. I. Electrophysiological mapping in house mice.

The development of the size and tonotopy of the mouse inferior colliculus (IC) was studied at postnatal ages of 9-20 days. During that time, the size of the IC remained constant in all 3 planes (rostrocaudal, mediolateral dorsoventral). At day 10, the first low-frequency responses without tonotopy could be recorded from neurons in the rostral and central parts of the central nucleus sparing its caudal part, very medial portions, the medial part (M) of the central nucleus, the dorsal cortex and the lateral nucleus. Then, an extension of the frequency responsiveness occurred towards (1) the caudal pole which was reached by about day 14, (2) the dorsal surface reached between days 12 and 14, (3) the ventral border of the IC reached by about day 15. The high-frequency nucleus of the IC (M part of the central nucleus) remained unresponsive to tones up to day 13. Between days 10 and 20, there was a constant increase of highest characteristic frequencies (CFs) measurable of neurons in the IC. During that time, lowest measurable CFs remained rather constant. Neurons at a given constant collicular depth of more than about 400 microm showed a clear shift of CF from low to high, that is, they were tuned to the higher frequencies the older the animals were. Cochlear and collicular origins of this observed shift of tonotopy are discussed.

Complex sound analysis (frequency resolution, filtering and spectral integration) by single units of the inferior colliculus of the cat.

The central nucleus of the inferior colliculus (ICC) is a center of convergence of brainstem input and is critical for auditory information processing. Here, the analysis of complex sound spectra by single neurons in the ICC is investigated. Several measures of frequency resolution (excitatory/inhibitory tuning curves, effective bandwidths, critical ratio bands, critical bands derived using narrowband masking and two-tone separation paradigms) have been obtained from the responses of these neurons at sound pressure levels (SPL) up to 80 dB above the units' response thresholds (nearly 110 dB SPL). Among our results are the following: (1) Narrowband masking measures of critical bands from ICC neurons closely parallel behavioral measures using the same stimulus paradigm. (2) Frequency resolution power as measured by critical bandwidths varies little as a function of stimulus intensity. (3) Tuning curves of ICC neurons provide no simple basis for predicting the frequency filtering of the same neurons excited by complex sound spectra. (4) There is a frequency dependence of all measures of frequency resolution similar to that found in psychophysical determinations of critical bandwidths. That is, spatial frequency resolution in the cochlea is the origin for the resolution found in the ICC and in behavioral tests. (5) Lateral inhibition at the level of the ICC clearly plays a role in frequency resolution. (6) Frequency resolution is encoded by response rate changes of ICC neurons and is independent of tone response threshold, response latency, spontaneous activity, tone response type, binaural response type. It is concluded that spectral analysis of sound is established by processes, including lateral inhibition, independent of other basic response properties of neurons at the level of the ICC.

Stiffness gradient along the basilar membrane as a basis for spatial frequency analysis within the cochlea.

Stiffness z of the basilar membrane of the house mouse against a displacement by sound was calculated from data on width and thickness of the membrane. Three functions of the kind log10z = ax + b were obtained which equally express the stiffness change in dependence on the locus x on the basilar membrane. These functions were compared with the one for frequency representation. The result is that the spatial distribution of displacement maxima for frequencies and of stiffness follows the same kind of place-dependent functions over a large portion of the basilar membrane. From this it can be concluded empirically that the frequency and stiffness (calculated from width and thickness of the basilar membrane) scales along the cochlea are generally proportional to each other and that stiffness is a dominant factor for the determination of the locus of the displacement maximum for a given frequency.

Development of absolute auditory thresholds in the house mouse (Mus musculus).

The development of hearing in the house mouse (Mus musculus) was behaviorally tested from the first postnatally measurable thresholds to those of young adults. An unconditioned stop reaction on tones was used in 9- to 11-day-old mice, then an unconditioned pinna reflex that can be elicited at low intensities and is not equal to the Preyer reflex. In addition, thresholds from 17- to 19-day-old and adult mice were obtained by a conditioned eyelid reflex. Frequencies between 1 and 80 kHz were tested. First reactions on tones were found at day 10 after birth in the frequency range of greatest sensitivity in the adults (10-20 kHz). The sensitivity optimum at 15 kHz becomes evident at day 14. Up to day 15 a sensitivity increase is noticeable for frequencies below the optimum, whereas high frequency sensitivity increases up to day 18. A second maximum of sensitivity at 50 kHz is measurable in 2- to 3-month-old mice, the threshold curve of which is defined as the standard for Mus musculus. The present behavioral data can well be correlated with existing electrophysiological results in mice and rats.