Günter Ehret

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

Abstract 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.

Impaired Synaptic Plasticity and Motor Learning in Mice with a Point Mutation Implicated in Human Speech Deficits

Summary The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene [1]. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language [2]. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning [3, 4]. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits.

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.

Corticofugal modulation of midbrain sound processing in the house mouse.

An understanding of the neural mechanisms responsible for auditory information processing is incomplete without a careful examination of substantial descending pathways. This study focuses on the functional role of corticofugal projections. Our work with the house mouse reveals that the focal electrical stimulation of the primary auditory cortex leads to profound changes in auditory response properties in the central nucleus of the inferior colliculus of the midbrain. Cortical stimulation does not impact on the collicular best frequencies when the best frequencies of stimulated cortical neurons and recorded collicular neurons are similar. Rather, collicular best frequencies are shifted toward the stimulated cortical best frequencies when cortical and collicular frequencies are different. Such a shift is unrelated to the differences in minimum thresholds between cortical and collicular neurons. In addition to frequency‐specific shifts in collicular best frequencies, cortical stimulation elevates collicular minimum thresholds and reduces both dynamic ranges and response magnitudes if cortical and collicular best frequencies are different. If cortical and collicular best frequencies are similar but minimum thresholds are different, collicular minimum thresholds are shifted toward the stimulated cortical thresholds; dynamic ranges and response magnitudes may either increase or decrease in this scenario. Our results suggest that the corticofugal adjustment has a centre–surround organization with regard to both cortical best frequencies and cortical minimum thresholds. The midbrain processing of sound components in the centre of cortical feedback is largely enhanced while processing in the surround is suppressed.

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.

Categorical perception of mouse-pup ultrasounds in the temporal domain

Abstract Mouse-pup ultrasounds emitted from outside the nest area are releasers of maternal pup searching and retrieving behaviour. House mouse, Mus domesticus , mothers were tested in a situation with two alternative choices for their unconditioned preference of 50 kHz tone bursts of various durations (models of mouse-pup ultrasounds). Categorical perception in the temporal domain was established by labelling and discrimination tests. Two categories occurred: one of non-preferred short-duration tones (25 ms and shorter) and the other of preferred long-duration tones (30 ms and longer) with a sharp boundary between 25 and 30 ms. Stimuli from the two categories were discriminated, however, only if they differed in duration by at least 20–25ms, which may be the threshold of duration discrimination. The discussion concentrates on the biological significance of categorical perception of communication sounds and possible mechanisms of boundary formation.

Ultrasound recognition in house mice: key-stimulus configuration and recognition mechanism

Summary1.We determined the ability of lactating female house mice (Mus musculus, strain NMRI) to recognize natural ultrasonic calls (USC) of their pups or synthesized USC models. Recognition was shown by the mice preferentially responding to these sounds in the presence of an alternative sound signal.2.Preferred USC models had total durations (flat top + rise and fall times) between 30 and 270 ms. Shorter and longer ones were not preferentially responded to. Response to USC models with major frequency components above 40 kHz was the same as that to natural ultrasonic calls of mouse pups.3.The key-stimulus configuration for recognition of mouse pup ultrasound in the frequency domain can be characterized as pulses of sound energy in a narrow frequency band in the ultrasonic range with significantly less energy in adjacent frequency bands. The decisive units for call recognition are frequency bandwidths which are almost identical in width with the critical bands of hearing, a measure of frequency resolution in the auditory system. The critical frequency bands for the recognition of USC models have a bandwidth of 22.5 kHz at a center frequency near 50 kHz (the critical band of hearing is 22 kHz wide), and 15 kHz at a center frequency near 40 kHz (the critical band of hearing is 18 kHz wide). We conclude that the discrimination of ultrasonic mouse pup calls from other mouse calls and their recognition is most probably directly related to the critical band analysis in the auditory system.

Masked auditory thresholds, critical ratios, and scales of the basilar membrane of the housemouse (Mus musculus)

Summary1.Masked auditory thresholds were determined for the housemouse (Mus musculus, outbred strain NMRI) between 1 kHz and 80 kHz and for four noise spectrum levels.2.Critical ratios (K, K1) after Fletcher (1940), which represent bands of summated sound evaluation, were calculated. For frequencies (f) below 15 kHz critical ratios (CR-bands) remain constant (K = 35 dB;K1 = 3162 Hz). Above 15 kHz the relation between CR-bands andf can be expressed by the following functions:K = 13.27·Ig f−19.87;K1 = 0.456·f −2836.3.From these functions the width in kHz and the number of CR-bands in the acoustic system of the mouse could be derived. The ear ofMus musculus is able to form maximally 10 CR-bands between 0.8 kHz and 115.4 kHz.4.The width and number of CR-bands could be used to calculate a function for frequency distribution along the basilar membrane of the mouse, or to estimate fitting factors for Greenwoods (1961) equation respectively. The following function is proposed to be the best approximation:f = 3350·(100.21x−1),x = distance from the helicotrema.5.Equidistant scales for the basilar membrane ofMus musculus are constructed.6.The comparison of data on man, cat, and mouse shows that the CR-bands of these mammals are equal to a width of 0.67 mm on all respective basilar membranes. Thus accuracy of sound evaluation in mammals is directly proportional to the length of the respective basilar membranes.

Frequency response areas of neurons in the mouse inferior colliculus. I. Threshold and tuning characteristics

Abstract. Excitatory and inhibitory frequency response areas of 130 neurons of the central nucleus of the mouse inferior colliculus (ICC) were mapped by extracellular single-unit recordings and quantitatively evaluated with regard to thresholds, steepness of slopes of excitatory tuning, characteristic frequencies of excitation (CFE), inhibition (CFI), and bandwidths of response areas (sharpness of tuning). Two-tone stimuli were used to determine the shapes of inhibitory response areas. Class I neurons (n=54) had asymmetrical (with regard to the CFE) excitatory and inhibitory response areas, with inhibition above CFE having lower thresholds and covering larger areas than inhibition below CFE. Quantitative relationships between CFE and CFI thresholds, and sharpness of tuning showed that the receptive fields of about two-thirds of these neurons had properties similar to auditory nerve fibers. Class II neurons (n=36) had small symmetrical or tilted excitatory areas of rather constant bandwidths and broad inhibitory areas reaching far into and often through the excitatory area, leading to closed excitatory areas in ten neurons. Class III neurons (n=32) had higher excitatory thresholds and the highest proportions of unilateral inhibitory areas compared with neurons of the other classes. Their excitatory area often widened symmetrically with increasing sound level. Their inhibitory areas did not overlap with the excitatory area. Class IV neurons (n=8) had two branches of excitatory areas (two-CFsE) and six of the neurons had a central inhibitory area in addition to the low- and high-frequency inhibitory areas. In most neurons, the shapes of excitatory response areas predicted the shapes of inhibitory areas. Altogether, 15 neurons from all 4 classes had areas of facilitation in addition to inhibitory areas. Facilitation in six class IV neurons occurred between the two branches of the excitatory area. All 130 neurons had large inhibitory areas, 106 of them on both sides of the excitatory area. That is, sound processing in the ICC shows strong inhibitory components. The close relationships between excitatory and inhibitory CFs found here indicate that inhibitory projections to and interactions within the ICC are tonotopically organized comparable to the excitatory ones.

Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders

Proteins of the ProSAP/Shank family act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses. Deletions, mutations or the downregulation of these molecules has been linked to autism spectrum disorders, the related Phelan McDermid Syndrome or Alzheimers disease. ProSAP/Shank proteins are targeted to synapses depending on binding to zinc, which is a prerequisite for the assembly of the ProSAP/Shank scaffold. To gain insight into whether the previously reported assembly of ProSAP/Shank through zinc ions provides a crossing point between genetic forms of autism spectrum disorder and zinc deficiency as an environmental risk factor for autism spectrum disorder, we examined the interplay between zinc and ProSAP/Shank in vitro and in vivo using neurobiological approaches. Our data show that low postsynaptic zinc availability affects the activity dependent increase in ProSAP1/Shank2 and ProSAP2/Shank3 levels at the synapse in vitro and that a loss of synaptic ProSAP1/Shank2 and ProSAP2/Shank3 occurs in a mouse model for acute and prenatal zinc deficiency. Zinc-deficient animals displayed abnormalities in behaviour such as over-responsivity and hyperactivity-like behaviour (acute zinc deficiency) and autism spectrum disorder-related behaviour such as impairments in vocalization and social behaviour (prenatal zinc deficiency). Most importantly, a low zinc status seems to be associated with an increased incidence rate of seizures, hypotonia, and attention and hyperactivity issues in patients with Phelan-McDermid syndrome, which is caused by haploinsufficiency of ProSAP2/Shank3. We suggest that the molecular underpinning of prenatal zinc deficiency as a risk factor for autism spectrum disorder may unfold through the deregulation of zinc-binding ProSAP/Shank family members.