The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Increased spontaneous firing rates in auditory midbrain following noise exposure are specifically abolished by a Kv3 channel modulator.

Noise exposure has been shown to produce long-lasting increases in spontaneous activity in central auditory structures in animal models, and similar pathologies are thought to contribute to clinical phenomena such as hyperacusis or tinnitus in humans. Here we demonstrate that multi-unit spontaneous neuronal activity in the inferior colliculus (IC) of mice is significantly elevated four weeks following noise exposure at recording sites with frequency tuning within or near the noise exposure band, and this selective central auditory pathology can be normalised through administration of a novel compound that modulates activity of Kv3 voltage-gated ion channels. The compound had no statistically significant effect on IC spontaneous activity without noise exposure, nor on thresholds or frequency tuning of tone-evoked responses either with or without noise exposure. Administration of the compound produced some reduction in the magnitude of evoked responses to a broadband noise, but unlike effects on spontaneous rates, these effects on evoked responses were not specific to recording sites with frequency tuning within the noise exposure band. Thus, the results suggest that modulators of Kv3 channels can selectively counteract increases in spontaneous activity in the auditory midbrain associated with noise exposure.

Mind the Gap: Two Dissociable Mechanisms of Temporal Processing in the Auditory System.

High temporal acuity of auditory processing underlies perception of speech and other rapidly varying sounds. A common measure of auditory temporal acuity in humans is the threshold for detection of brief gaps in noise. Gap-detection deficits, observed in developmental disorders, are considered evidence for "sluggish" auditory processing. Here we show, in a mouse model of gap-detection deficits, that auditory brain sensitivity to brief gaps in noise can be impaired even without a general loss of central auditory temporal acuity. Extracellular recordings in three different subdivisions of the auditory thalamus in anesthetized mice revealed a stimulus-specific, subdivision-specific deficit in thalamic sensitivity to brief gaps in noise in experimental animals relative to controls. Neural responses to brief gaps in noise were reduced, but responses to other rapidly changing stimuli unaffected, in lemniscal and nonlemniscal (but not polysensory) subdivisions of the medial geniculate body. Through experiments and modeling, we demonstrate that the observed deficits in thalamic sensitivity to brief gaps in noise arise from reduced neural population activity following noise offsets, but not onsets. These results reveal dissociable sound-onset-sensitive and sound-offset-sensitive channels underlying auditory temporal processing, and suggest that gap-detection deficits can arise from specific impairment of the sound-offset-sensitive channel. SIGNIFICANCE STATEMENT: The experimental and modeling results reported here suggest a new hypothesis regarding the mechanisms of temporal processing in the auditory system. Using a mouse model of auditory temporal processing deficits, we demonstrate the existence of specific abnormalities in auditory thalamic activity following sound offsets, but not sound onsets. These results reveal dissociable sound-onset-sensitive and sound-offset-sensitive mechanisms underlying auditory processing of temporally varying sounds. Furthermore, the findings suggest that auditory temporal processing deficits, such as impairments in gap-in-noise detection, could arise from reduced brain sensitivity to sound offsets alone.

The cortical modulation of stimulus-specific adaptation in the auditory midbrain and thalamus: a potential neuronal correlate for predictive coding.

To follow an ever-changing auditory scene, the auditory brain is continuously creating a representation of the past to form expectations about the future. Unexpected events will produce an error in the predictions that should "trigger" the network's response. Indeed, neurons in the auditory midbrain, thalamus and cortex, respond to rarely occurring sounds while adapting to frequently repeated ones, i.e., they exhibit stimulus specific adaptation (SSA). SSA cannot be explained solely by intrinsic membrane properties, but likely involves the participation of the network. Thus, SSA is envisaged as a high order form of adaptation that requires the influence of cortical areas. However, present research supports the hypothesis that SSA, at least in its simplest form (i.e., to frequency deviants), can be transmitted in a bottom-up manner through the auditory pathway. Here, we briefly review the underlying neuroanatomy of the corticofugal projections before discussing state of the art studies which demonstrate that SSA present in the medial geniculate body (MGB) and inferior colliculus (IC) is not inherited from the cortex but can be modulated by the cortex via the corticofugal pathways. By modulating the gain of neurons in the thalamus and midbrain, the auditory cortex (AC) would refine SSA subcortically, preventing irrelevant information from reaching the cortex.

Representation of individual elements of a complex call sequence in primary auditory cortex.

Conspecific communication calls can be rhythmic or contain extended, discontinuous series of either constant or frequency modulated harmonic tones and noise bursts separated by brief periods of silence. In the guinea pig, rhythmic calls can produce isomorphic responses within the primary auditory cortex (AI) where single units respond to every call element. Other calls such as the chutter comprise a series of short irregular syllables that vary in their spectral content and are more like human speech. These calls can also evoke isomorphic responses, but may only do so in fields in the auditory belt and not in AI. Here we present evidence that cells in AI treat the individual elements within a syllable as separate auditory objects and respond selectively to one or a subset of them. We used a single chutter exemplar to compare single/multi-unit responses in the low-frequency portion of AI-AI(LF) and the low-frequency part of the thalamic medial geniculate body-MGB(LF) in urethane anaesthetized guinea pigs. Both thalamic and cortical cells responded with brief increases in firing rate to one, or more, of the 8 main elements present in the chutter call. Almost none of the units responded to all 8 elements. While there were many different combinations of responses to between one and five of the elements, MBG(LF) and AI(LF) neurons exhibited the same specific types of response combinations. Nearby units in the upper layers of the cortex tended to respond to similar combinations of elements while the deep layers were less responsive. Thus, the responses from a number of AI units would need to be combined in order to represent the entire chutter call. Our results don't rule out the possibility of constructive convergence but there was no evidence that a convergence of inputs within AI led to a complete representation of all eight elements.

Physiological differences between histologically defined subdivisions in the mouse auditory thalamus.

The auditory thalamic area includes the medial geniculate body (MGB) and the lateral part of the posterior thalamic nucleus (Pol). The MGB can be subdivided into a ventral subdivision, forming part of the lemniscal (primary) auditory pathway, and medial and dorsal subdivisions, traditionally considered (alongside the Pol) part of the non-lemniscal (secondary) pathway. However, physiological studies of the auditory thalamus have suggested that the Pol may be more appropriately characterised as part of the lemniscal pathway, while the medial MGB may be part of a third (polysensory) pathway, with characteristics of lemniscal and non-lemniscal areas. We document physiological properties of neurons in histologically identified areas of the MGB and Pol in the anaesthetised mouse, and present evidence in favour of a distinctive role for medial MGB in central auditory processing. In particular, medial MGB contains a greater proportion of neurons with short first-spike latencies and high response probabilities than either the ventral or dorsal MGB, despite having low spontaneous rates. Therefore, medial MGB neurons appear to fire more reliably in response to auditory input than neurons in even the lemniscal, ventral subdivision. Additionally, responses in the Pol are more similar to those in the ventral MGB than the dorsal MGB.

Stimulus-specific adaptation occurs in the auditory thalamus.

Neurons in the primary auditory cortex respond less strongly to a commonly occurring "standard" tone than to the same tone when it is rare or "deviant." This phenomenon, called "stimulus-specific adaptation" (SSA), has been proposed as a possible single-neuron correlate of the mismatch negativity, a cortical evoked potential associated with stimulus novelty. Previous studies in cat did not observe SSA in single neurons in the auditory thalamus. However, these reports did not differentiate between the auditory thalamic subdivisions and did not examine the effects of changing the stimulus presentation rate. To explore the possibility of thalamic SSA more completely, we recorded extracellularly from 30 single units and 22 multiunit clusters in the ventral, medial, and dorsal subdivisions of the mouse medial geniculate body (MGB), while presenting the anesthetized animals with sequences of standard and deviant tones at interstimulus intervals of 400, 500 and 800 ms. We found SSA in the auditory thalamus at all three stimulus presentation rates, primarily in the medial subdivision but to a lesser degree also in the ventral MGB. Thalamic SSA was evident from the earliest onset of tone-evoked activity, although the latencies of responses to standard and deviant tones were not significantly different. Together with related findings of SSA in neurons of the "belt" regions of the inferior colliculus, these results demonstrate that SSA is present at subcortical levels, primarily in but not restricted to the nonlemniscal auditory pathway.

A monosynaptic pathway from dorsal cochlear nucleus to auditory cortex in rat.

Of the three major subdivisions of the auditory thalamus, the medial subdivision is the only one that receives a direct projection from the dorsal cochlear nucleus. Those cells in the medial auditory thalamus that receive the projection from the dorsal cochlear nucleus continue to the auditory cortex. A combination of anterograde and retrograde anatomical tracer injections made in the dorsal cochlear nucleus and the auditory cortex respectively, revealed terminal boutons which were directly apposed onto the dendrites and cell bodies of neurons in the medial auditory thalamus. The presence of a monosynaptic pathway, which transfers information from the first relay in the auditory system to the last, suggests that this pathway may rapidly convey very basic information to the auditory cortex.

Phase-locked responses to pure tones in the auditory thalamus.

Accurate temporal coding of low-frequency tones by spikes that are locked to a particular phase of the sine wave (phase-locking), occurs among certain groups of neurons at various processing levels in the brain. Phase-locked responses have previously been studied in the inferior colliculus and neocortex of the guinea pig and we now describe the responses in the auditory thalamus. Recordings were made from 241 single units, 32 (13%) of which showed phase-locked responses. Units with phase-locked responses were mainly (82%) located in the ventral division of the medial geniculate body (MGB), and also the medial division (18%), but were not found in the dorsal or shell divisions. The upper limiting frequency of phase-locking varied greatly between units (60-1,100 Hz) and between anatomical divisions. The upper limit in the ventral division was 520 Hz and in the medial was 1,100 Hz. The range of steady-state delays calculated from phase plots also varied: ventral division, 8.6-14 ms (mean 11.1 ms; SD 1.56); medial division, 7.5-11 ms (mean 9.3 ms; SD 1.5). Taken together, these measurements are consistent with the medial division receiving a phase-locked input directly from the brain stem, without an obligatory relay in the inferior colliculus. Cells in both the ventral and medial divisions of the MGB showed a response that phase-locked to the fundamental frequency of a guinea pig purr and may be involved in analyzing communication calls.

Representation of the purr call in the guinea pig primary auditory cortex.

Guinea pigs produce the low-frequency purr or rumble call as an alerting signal. A digitised example of the call was presented to anaesthetised guinea pigs via a closed sound system while recording from the primary auditory cortex. The exemplar used in this study had 9 regular phrases each spaced with their centres about 80 ms apart. Low-frequency (1.1 kHz) units responded best to the call but within this population there were four separate groups: (1) cells that responded vigorously to many or all of the 9 phrases; (2) cells that gave an onset response; (3) cells that only responded to a click embedded in the call; (4) cells that did not respond. Particular response types were often grouped together. Thus when orthogonal electrode tracks were used most units gave a similar response. There was no correlation between the type of response and the cortical depth. A similar range of response types was also found in the thalamus and there was no evidence of a distinct response in the cortex that was due to intracortical processing. Cells in the cortex were able to represent the temporal structure of the purr with the same fidelity as cells in the thalamus.

The effect of chewing bicarbonate-containing gum on salivary flow rate and pH in humans.

OBJECTIVE: Gum chewing increases salivary flow rate and pH. The aim of this study was to compare the effects of chewing standard sugar-free gum with those of a gum containing sodium bicarbonate. DESIGN: Whole mouth saliva was collected from 20 volunteers who met inclusion criteria and gave informed consent. After unstimulated saliva was collected, stimulated saliva was collected at intervals during 30 min of chewing either a standard, mint-flavoured gum or bicarbonate-containing, mint-flavoured gum. The salivary flow and pH were measured for each sample. RESULTS: With the standard gum, the mean peak salivary flow rate was 3.1+/-1.27 ml/min and the peak salivary pH was 7.39+/-0.14. With the bicarbonate gum, the peak flow rate was 2.79+/-1.38 ml/min and the peak salivary pH was 8.06+/-0.18. The salivary flow rates with the two gums were not significantly different; however, the increase in salivary pH was significantly greater for the bicarbonate gum. CONCLUSION: The increased salivary pH with bicarbonate gum may have implications for oral health and prevention of dental caries.