Slc4a11 gene disruption in mice: cellular targets of sensorineuronal abnormalities.

NaBC1 (the SLC4A11 gene) belongs to the SLC4 family of sodium-coupled bicarbonate (carbonate) transporter proteins and functions as an electrogenic sodium borate cotransporter. Mutations in SLC4A11 cause either corneal abnormalities (corneal hereditary dystrophy type 2) or a combined auditory and visual impairment (Harboyan syndrome). The role of NaBC1 in sensory systems is poorly understood, given the difficulty of studying patients with NaBC1 mutations. We report our findings in Slc4a11(-/-) mice generated to investigate the role of NaBC1 in sensorineural systems. In wild-type mice, specific NaBC1 immunoreactivity was detected in fibrocytes of the spiral ligament, from the basal to the apical portion of the cochlea. NaBC1 immunoreactivity was present in the vestibular labyrinth, in stromal cells underneath the non-immunoreactive sensory epithelia of the macula utricle, sacule, and crista ampullaris, and the membranous vestibular labyrinth was collapsed. Both auditory brain response and vestibular evoked potential waveforms were significantly abnormal in Slc4a11(-/-) mice. In the cornea, NaBC1 was highly expressed in the endothelial cell layer with less staining in epithelial cells. However, unlike humans, the corneal phenotype was mild with a normal slit lamp evaluation. Corneal endothelial cells were morphologically normal; however, both the absolute height of the corneal basal epithelial cells and the relative basal epithelial cell/total corneal thickness were significantly increased in Slc4a11(-/-) mice. Our results demonstrate for the first time the importance of NaBC1 in the audio-vestibular system and provide support for the hypothesis that SLC4A11 should be considered a potential candidate gene in patients with isolated sensorineural vestibular hearing abnormalities.

Binaural unmasking of frequency-following responses in rat amygdala.

Survival in natural environments for small animals such as rats often depends on precise neural coding of life-threatening acoustic signals, and binaural unmasking of species-specific pain calls is especially critical. This study investigated how species-specific tail-pain chatter is represented in the rat amygdala, which receives afferents from both auditory thalamus and auditory association cortex, and whether the amygdaloid representation of the chatter can be binaurally unmasked. The results show that chatter with a fundamental frequency (F0) of 2.1 kHz was able to elicit salient phase-locked frequency-following responses (FFRs) in the lateral amygdala nucleus in anesthetized rats. FFRs to the F0 of binaurally presented chatter were sensitive to the interaural time difference (ITD), with the preference of ipsilateral-ear leading, as well as showing features of binaural inhibition. When interaurally correlated masking noises were added and ipsilateral chatter led contralateral chatter, introducing an ITD disparity between the chatter and masker significantly enhanced (unmasked) the FFRs. This binaural unmasking was further enhanced by chemically blocking excitatory glutamate receptors in the auditory association cortex. When the chatter was replaced by a harmonic tone complex with an F0 of 0.7 kHz, both the binaural-inhibition feature and the binaural unmasking were preserved only for the harmonic of 2.1 kHz but not the tone F0. These results suggest that both frequency-dependent ascending binaural modulations and cortical descending modulations of the precise auditory coding of the chatter in the amygdala are critical for processing life-threatening acoustic signals in noisy and even reverberant environments.

Auditory frequency-following responses in rat ipsilateral inferior colliculus.

Auditory frequency-following responses (FFRs) are sustained potentials based on phase-locked neural activity preserving low-frequency information. Some neurons in rat inferior colliculus are excited by stimuli at either ear. This study shows that FFRs in inferior colliculus can be elicited by presenting pure tone bursts with frequencies from 225 to 4025 Hz at the ipsilateral ear in anesthetized rats. Moreover, chemical block of glutamate transmissions in the contralateral inferior colliculus markedly reduced the ipsilaterally driven FFRs, which, however, were significantly enhanced by blocking the contralateral dorsal nucleus of the lateral lemniscus. Thus, FFRs in inferior colliculus to ipsilateral stimulation were facilitated by excitatory projections from the contralateral inferior colliculus but suppressed by inhibitory projections from the contralateral dorsal nucleus of the lateral lemniscus.

Neural crest cell deficiency of c-myc causes skull and hearing defects.

The proto-oncogene c-myc has a central role in multiple processes important for embryonic development, including cell proliferation, growth, apoptosis, and differentiation. We have investigated the role of c-myc in neural crest by using Wnt1-Cre-mediated deletion of a conditional mutation of the c-myc gene. c-myc deficiency in neural crest resulted in viable adult mice that have defects in coat color, skull frontal bone, and middle ear ossicle development. Physiological hearing studies demonstrated a significant hearing deficit in the mutant mice. In this report, we focus on the craniofacial and hearing defects. To further examine neural crest cells affected by c-myc deficiency, we fate mapped Wnt1-Cre expressing neural crest cells using the ROSA26 Cre reporter transgene. The phenotype obtained demonstrates the critical role that c-myc has in neural crest during craniofacial development as well as in providing a model for examining human congenital skull defects and deafness.

Correlated brain stem and cortical evoked responses to auditory tone change.

Numerous human studies have separately observed the effects of auditory stimuli at brain stem and cortical levels, but little research has focused on possible functional coupling between these diverse brain areas. The present study recorded the cortical C-process [5] evoked by a pitch change between two successive tones, as well as the brain stem frequency-following response (FFR) evoked by each tone. The results replicated expected C-process component waveforms, including a late, negative (N2) component. FFR spectral intensity differences between the two tones were significantly correlated with N2 amplitude. These results suggest that signal processing reflected in long-latency auditory evoked response components is not exclusively a cortical phenomenon, but also depends upon patterns of neural processing occurring in brain stem pathways.

Brain stem evoked response to forward and reversed speech in humans.

Speech stimuli played in reverse are perceived as unfamiliar and alien-sounding, even though phoneme duration and fundamental voicing frequency are preserved. Although language perception ultimately resides in the neocortex, the brain stem plays a vital role in processing auditory information, including speech. The present study measured brain stem frequency-following responses (FFR) evoked by forward and reverse speech stimuli recorded from electrodes oriented horizontally and vertically to measure signals with putative origins in auditory nerve and rostral brain stem, respectively. The vertical FFR showed increased amplitude due to forward speech. It is concluded that familiar phonological and prosodic properties of forward speech selectively activate central brain stem neurons.

Selective attention affects human brain stem frequency-following response.

Selective attention modifies long-latency cortical event-related potentials. Amplitudes are typically enhanced and/or latencies reduced when evoking stimuli are attended. However, there is controversy concerning the effects of selective attention on short-latency brain stem evoked potentials. The objective of the present study was to assess possible attention effects on the brain stem auditory frequency-following response (FFR) elicited by a periodic tone. Young adult subjects heard a repetitive auditory stimulus while detecting infrequent target stimuli in either an auditory or visual detection task. Five channels of high frequency electroencephalographic (EEG) activity were recorded along the scalp midline with the center electrode positioned at the vertex. The FFR was elicited by the repetitive tone during both tasks. There were significant individual differences in the electrode sites yielding maximum response amplitudes, but overall FFR amplitudes were significantly larger during the auditory attention task. These results suggest that selective attention in humans can modify signal processing in sensory (afferent) pathways at the level of the brain stem. This may reflect top-down perceptual preprocessing mediated by extensive descending (efferent) pathways that originate in the cortex. Overall, the FFR appears to be a robust indicator of early auditory neural processing and shows effects not seen in brain stem auditory evoked response studies employing transient (click) acoustic stimuli.