The Cl--channel TMEM16A is involved in the generation of cochlear Ca2+ waves and promotes the refinement of auditory brainstem networks in mice.

Before hearing onset (postnatal day 12 in mice), inner hair cells (IHCs) spontaneously fire action potentials, thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISCs) of Kölliker's organ through the activity of the Ca2+-activated Cl--channel TMEM16A (ANO1). Here, we show that conditional deletion of Ano1 (Tmem16a) in mice disrupts Ca2+ waves within Kölliker's organ, reduces the burst-firing activity and the frequency selectivity of auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB), and also impairs the functional refinement of MNTB projections to the lateral superior olive. These results reveal the importance of the activity of Kölliker's organ for the refinement of central auditory connectivity. In addition, our study suggests the involvement of TMEM16A in the propagation of Ca2+ waves, which may also apply to other tissues expressing TMEM16A.

Functional Development of Principal Neurons in the Anteroventral Cochlear Nucleus Extends Beyond Hearing Onset.

Sound information is transduced into graded receptor potential by cochlear hair cells and encoded as discrete action potentials of auditory nerve fibers. In the cochlear nucleus, auditory nerve fibers convey this information through morphologically distinct synaptic terminals onto bushy cells (BCs) and stellate cells (SCs) for processing of different sound features. With expanding use of transgenic mouse models, it is increasingly important to understand the in vivo functional development of these neurons in mice. We characterized the maturation of spontaneous and acoustically evoked activity in BCs and SCs by acquiring single-unit juxtacellular recordings between hearing onset (P12) and young adulthood (P30) of anesthetized CBA/J mice. In both cell types, hearing sensitivity and characteristic frequency (CF) range are mostly adult-like by P14, consistent with rapid maturation of the auditory periphery. In BCs, however, some physiological features like maximal firing rate, dynamic range, temporal response properties, recovery from post-stimulus depression, first spike latency (FSL) and encoding of sinusoid amplitude modulation undergo further maturation up to P18. In SCs, the development of excitatory responses is even more prolonged, indicated by a gradual increase in spontaneous and maximum firing rates up to P30. In the same cell type, broadly tuned acoustically evoked inhibition is immediately effective at hearing onset, covering the low- and high-frequency flanks of the excitatory response area. Together, these data suggest that maturation of auditory processing in the parallel ascending BC and SC streams engages distinct mechanisms at the first central synapses that may differently depend on the early auditory experience.

Sound frequency affects the auditory motion-onset response in humans.

The current study examines the modulation of the motion-onset response based on the frequency-range of sound stimuli. Delayed motion-onset and stationary stimuli were presented in a free-field by sequentially activating loudspeakers on an azimuthal plane keeping the natural percept of externalized sound presentation. The sounds were presented in low- or high-frequency ranges and had different motion direction within each hemifield. Difference waves were calculated by contrasting the moving and stationary sounds to isolate the motion-onset responses. Analyses carried out at the peak amplitudes and latencies on the difference waves showed that the early part of the motion response (cN1) was modulated by the frequency range of the sounds with stronger amplitudes elicited by stimuli with high frequency range. Subsequent post hoc analysis of the normalized amplitude of the motion response confirmed the previous finding by excluding the possibility that the frequency range had an overall effect on the waveform, and showing that this effect was instead limited to the motion response. These results support the idea of a modular organization of the motion-onset response with the processing of primary sound motion characteristics being reflected in the early part of the response. Also, the article highlights the importance of specificity in auditory stimulus design.

Neural Progenitors in the Developing Neocortex of the Northern Tree Shrew (Tupaia belangeri) Show a Closer Relationship to Gyrencephalic Primates Than to Lissencephalic Rodents.

The neocortex is the most complex part of the mammalian brain and as such it has undergone tremendous expansion during evolution, especially in primates. The majority of neocortical neurons originate from distinct neural stem and progenitor cells (NPCs) located in the ventricular and subventricular zone (SVZ). Previous studies revealed that the SVZ thickness as well as the abundance and distribution of NPCs, especially that of basal radial glia (bRG), differ markedly between the lissencephalic rodent and gyrencephalic primate neocortex. The northern tree shrew (Tupaia belangeri) is a rat-sized mammal with a high brain to body mass ratio, which stands phylogenetically mid-way between rodents and primates. Our study provides - for the first time - detailed data on the presence, abundance and distribution of bRG and other distinct NPCs in the developing neocortex of the northern tree shrew (Tupaia belangeri). We show that the developing tree shrew neocortex is characterized by an expanded SVZ, a high abundance of Pax6+ NPCs in the SVZ, and a relatively high percentage of bRG at peak of upper-layer neurogenesis. We further demonstrate that key features of tree shrew neocortex development, e.g., the presence, abundance and distribution of distinct NPCs, are closer related to those of gyrencephalic primates than to those of ferret and lissencephalic rodents. Together, our study provides novel insight into the evolution of bRG and other distinct NPCs in the neocortex development of Euarchontoglires and introduces the tree shrew as a potential novel model organism in the area of human brain development and developmental disorders.

Signal integration at spherical bushy cells enhances representation of temporal structure but limits its range.

Neuronal inhibition is crucial for temporally precise and reproducible signaling in the auditory brainstem. Previously we showed that for various synthetic stimuli, spherical bushy cell (SBC) activity in the Mongolian gerbil is rendered sparser and more reliable by subtractive inhibition (Keine et al., 2016). Here, employing environmental stimuli, we demonstrate that the inhibitory gain control becomes even more effective, keeping stimulated response rates equal to spontaneous ones. However, what are the costs of this modulation? We performed dynamic stimulus reconstructions based on neural population responses for auditory nerve (ANF) input and SBC output to assess the influence of inhibition on acoustic signal representation. Compared to ANFs, reconstructions of natural stimuli based on SBC responses were temporally more precise, but the match between acoustic and represented signal decreased. Hence, for natural sounds, inhibition at SBCs plays an even stronger role in achieving sparse and reproducible neuronal activity, while compromising general signal representation.

Developmental Shift of Inhibitory Transmitter Content at a Central Auditory Synapse.

Synaptic inhibition in the CNS is mostly mediated by GABA or glycine. Generally, the use of the two transmitters is spatially segregated, but there are central synapses employing both, which allows for spatial and temporal variability of inhibitory mechanisms. Spherical bushy cells (SBCs) in the mammalian cochlear nucleus receive primary excitatory inputs through auditory nerve fibers arising from the organ of Corti and non-primary inhibition mediated by a dual glycine-GABA transmission. Slow kinetics IPSCs enable activity dependent tonic-like conductance build up, functioning as a gain control by filtering out small or temporally imprecise EPSPs. However, it remained elusive whether GABA and glycine are released as content of the same vesicle or from distinct presynaptic terminals. The developmental profile of quantal release was investigated with whole cell recordings of miniature inhibitory postsynaptic currents (mIPSCs) from P1-P25 SBCs of Mongolian gerbils. GABA is the initial transmitter eliciting slow-rising and -decaying events of relatively small amplitudes, occurring only during early postnatal life. Around and after hearing onset, the inhibitory quanta are predominantly containing glycine that-with maturity-triggers progressively larger and longer mIPSC. In addition, GABA corelease with glycine evokes mIPSCs of particularly large amplitudes consistently occurring across all ages, but with low probability. Together, these results suggest that GABA, as the primary transmitter released from immature inhibitory terminals, initially plays a developmental role. In maturity, GABA is contained in synaptic vesicles only in addition to glycine to increase the inhibitory potency, thereby fulfilling solely a modulatory function.

Tonotopic action potential tuning of maturing auditory neurons through endogenous ATP.

KEY POINTS: Following the genetically controlled formation of neuronal circuits, early firing activity guides the development of sensory maps in the auditory, visual and somatosensory system. However, it is not clear whether the activity of central auditory neurons is specifically regulated depending on the position within the sensory map. In the ventral cochlear nucleus, the first central station along the auditory pathway, we describe a mechanism through which paracrine ATP signalling enhances firing in a cell-specific and tonotopically-determined manner. Developmental down-regulation of P2X2/3R currents along the tonotopic axis occurs simultaneously with an increase in AMPA receptor currents, suggesting a high-to-low frequency maturation pattern. Facilitated action potential (AP) generation, measured as higher firing rate, shorter EPSP-AP delay in vivo and shorter AP latency in slice experiments, is consistent with increased synaptic efficacy caused by ATP. The long lasting change in intrinsic neuronal excitability is mediated by the heteromeric P2X2/3 receptors. ABSTRACT: Synaptic refinement and strengthening are activity-dependent processes that establish orderly arranged cochleotopic maps throughout the central auditory system. The maturation of auditory brainstem circuits is guided by action potentials (APs) arising from the inner hair cells in the developing cochlea. The AP firing of developing central auditory neurons can be modulated by paracrine ATP signalling, as shown for the cochlear nucleus bushy cells and principal neurons in the medial nucleus of the trapezoid body. However, it is not clear whether neuronal activity may be specifically regulated with respect to the nuclear tonotopic position (i.e. sound frequency selectivity). Using slice recordings before hearing onset and in vivo recordings with iontophoretic drug applications after hearing onset, we show that cell-specific purinergic modulation follows a precise tonotopic pattern in the ventral cochlear nucleus of developing gerbils. In high-frequency regions, ATP responsiveness diminished before hearing onset. In low-to-mid frequency regions, ATP modulation persisted after hearing onset in a subset of low-frequency bushy cells (characteristic frequency< 10 kHz). Down-regulation of P2X2/3R currents along the tonotopic axis occurs simultaneously with an increase in AMPA receptor currents, thus suggesting a high-to-low frequency maturation pattern. Facilitated AP generation, measured as higher firing frequency, shorter EPSP-AP delay in vivo, and shorter AP latency in slice experiments, is consistent with increased synaptic efficacy caused by ATP. Finally, by combining recordings and pharmacology in vivo, in slices, and in human embryonic kidney 293 cells, it was shown that the long lasting change in intrinsic neuronal excitability is mediated by the P2X2/3R.

Inhibition in the auditory brainstem enhances signal representation and regulates gain in complex acoustic environments.

Inhibition plays a crucial role in neural signal processing, shaping and limiting responses. In the auditory system, inhibition already modulates second order neurons in the cochlear nucleus, e.g. spherical bushy cells (SBCs). While the physiological basis of inhibition and excitation is well described, their functional interaction in signal processing remains elusive. Using a combination of in vivo loose-patch recordings, iontophoretic drug application, and detailed signal analysis in the Mongolian Gerbil, we demonstrate that inhibition is widely co-tuned with excitation, and leads only to minor sharpening of the spectral response properties. Combinations of complex stimuli and neuronal input-output analysis based on spectrotemporal receptive fields revealed inhibition to render the neuronal output temporally sparser and more reproducible than the input. Overall, inhibition plays a central role in improving the temporal response fidelity of SBCs across a wide range of input intensities and thereby provides the basis for high-fidelity signal processing.

Slow Cholinergic Modulation of Spike Probability in Ultra-Fast Time-Coding Sensory Neurons.

Sensory processing in the lower auditory pathway is generally considered to be rigid and thus less subject to modulation than central processing. However, in addition to the powerful bottom-up excitation by auditory nerve fibers, the ventral cochlear nucleus also receives efferent cholinergic innervation from both auditory and nonauditory top-down sources. We thus tested the influence of cholinergic modulation on highly precise time-coding neurons in the cochlear nucleus of the Mongolian gerbil. By combining electrophysiological recordings with pharmacological application in vitro and in vivo, we found 55-72% of spherical bushy cells (SBCs) to be depolarized by carbachol on two time scales, ranging from hundreds of milliseconds to minutes. These effects were mediated by nicotinic and muscarinic acetylcholine receptors, respectively. Pharmacological block of muscarinic receptors hyperpolarized the resting membrane potential, suggesting a novel mechanism of setting the resting membrane potential for SBC. The cholinergic depolarization led to an increase of spike probability in SBCs without compromising the temporal precision of the SBC output in vitro. In vivo, iontophoretic application of carbachol resulted in an increase in spontaneous SBC activity. The inclusion of cholinergic modulation in an SBC model predicted an expansion of the dynamic range of sound responses and increased temporal acuity. Our results thus suggest of a top-down modulatory system mediated by acetylcholine which influences temporally precise information processing in the lower auditory pathway.

Subdivision of Broca's region based on individual-level functional connectivity.

Broca's region is composed of two adjacent cytoarchitectonic areas, 44 and 45, which have distinct connectivity to superior temporal and inferior parietal regions in both macaque monkeys and humans. The current study aimed to make use of prior knowledge of sulcal anatomy and resting-state functional connectivity, together with a novel visualization technique, to manually parcellate areas 44 and 45 in individual brains in vivo. One hundred and one resting-state functional magnetic resonance imaging datasets from the Human Connectome Project were used. Left-hemisphere surface-based correlation matrices were computed and visualized in brainGL. By observation of differences in the connectivity patterns of neighbouring nodes, areas 44 and 45 were manually parcellated in individual brains, and then compared at the group-level. Additionally, the manual labelling approach was compared with parcellation results based on several data-driven clustering techniques. Areas 44 and 45 could be clearly distinguished from each other in all individuals, and the manual segmentation method showed high test-retest reliability. Group-level probability maps of areas 44 and 45 showed spatial consistency across individuals, and corresponded well to cytoarchitectonic probability maps. Group-level connectivity maps were consistent with previous studies showing distinct connectivity patterns of areas 44 and 45. Data-driven parcellation techniques produced clusters with varying degrees of spatial overlap with the manual labels, indicating the need for further investigation and validation of machine learning cortical segmentation approaches. The current study provides a reliable method for individual-level cortical parcellation that could be applied to regions distinguishable by even the most subtle differences in patterns of functional connectivity.

The extracellular matrix molecule brevican is an integral component of the machinery mediating fast synaptic transmission at the calyx of Held.

KEY POINTS: The proteoglycan brevican is a major component of the extracellular matrix of perineuronal nets and is highly enriched in the perisynaptic space suggesting a role for synaptic transmission. We have introduced the calyx of Held in the auditory brainstem as a model system to study the impact of brevican on dynamics and reliability of synaptic transmission. In vivo extracellular single-unit recordings at the calyx of Held in brevican-deficient mice yielded a significant increase in the action potential (AP) transmission delay and a prolongation of pre- and postsynaptic APs. The changes in dynamics of signal transmission were accompanied by the reduction of presynaptic vGlut1 and ultrastructural changes in the perisynaptic space. These data show that brevican is an important mediator of fast synaptic transmission at the calyx of Held. ABSTRACT: The extracellular matrix is an integral part of the neural tissue. Its most conspicuous manifestation in the brain are the perineuronal nets (PNs) which surround somata and proximal dendrites of distinct neuron types. The chondroitin sulfate proteoglycan brevican is a major component of PNs. In contrast to other PN-comprising proteoglycans (e.g. aggrecan and neurocan), brevican is mainly expressed in the perisynaptic space closely associated with both the pre- and postsynaptic membrane. This specific localization prompted the hypothesis that brevican might play a role in synaptic transmission. In the present study we specifically investigated the role of brevican in synaptic transmission at a central synapse, the calyx of Held in the medial nucleus of the trapezoid body, by the use of in vivo electrophysiology, immunohistochemistry, biochemistry and electron microscopy. In vivo extracellular single-unit recordings were acquired in brevican-deficient mice and the dynamics and reliability of synaptic transmission were compared to wild-type littermates. In knockout mice, the speed of pre-to-postsynaptic action potential (AP) transmission was reduced and the duration of the respective pre- and postsynaptic APs increased. The reliability of signal transmission, however, was not affected by the lack of brevican. The changes in dynamics of signal transmission were accompanied by the reduction of (i) presynaptic vGlut1 and (ii) the size of subsynaptic cavities. The present results suggest an essential role of brevican for the functionality of high-speed synaptic transmission at the calyx of Held.

Inhibition shapes acoustic responsiveness in spherical bushy cells.

Signal processing in the auditory brainstem is based on an interaction of neuronal excitation and inhibition. To date, we have incomplete knowledge of how the dynamic interplay of both contributes to the processing power and temporal characteristics of signal coding. The spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive their primary excitatory input through auditory nerve fibers via large, axosomatic synaptic terminals called the endbulbs of Held and by additional, acoustically driven inhibitory inputs. SBCs provide the input to downstream nuclei of the brainstem sound source localization circuitry, such as the medial and lateral superior olive, which rely on temporal precise inputs. In this study, we used juxtacellular recordings in anesthetized Mongolian gerbils to assess the effect of acoustically evoked inhibition on the SBCs input-output function and on temporal precision of SBC spiking. Acoustically evoked inhibition proved to be strong enough to suppress action potentials (APs) of SBCs in a stimulus-dependent manner. Inhibition shows slow onset and offset dynamics and increasing strength at higher sound intensities. In addition, inhibition decreases the rising slope of the EPSP and prolongs the EPSP-to-AP transition time. Both effects can be mimicked by iontophoretic application of glycine. Inhibition also improves phase locking of SBC APs to low-frequency tones by acting as a gain control to suppress poorly timed EPSPs from generating postsynaptic APs to maintain precise SBC spiking across sound intensities. The present data suggest that inhibition substantially contributes to the processing power of second-order neurons in the ascending auditory system.

Age-related changes in sound localisation ability.

Auditory spatial processing is an important ability in everyday life and allows the processing of omnidirectional information. In this review, we report and compare data from psychoacoustic and electrophysiological experiments on sound localisation accuracy and auditory spatial discrimination in infants, children, and young and older adults. The ability to process auditory spatial information changes over lifetime: the perception of the acoustic space develops from an initially imprecise representation in infants and young children to a concise representation of spatial positions in young adults and the respective performance declines again in older adults. Localisation accuracy shows a strong deterioration in older adults, presumably due to declined processing of binaural temporal and monaural spectro-temporal cues. When compared to young adults, the thresholds for spatial discrimination were strongly elevated both in young children and older adults. Despite the consistency of the measured values the underlying causes for the impaired performance might be different: (1) the effect is due to reduced cognitive processing ability and is thus task-related; (2) the effect is due to reduced information about the auditory space and caused by declined processing in auditory brain stem circuits; and (3) the auditory space processing regime in young children is still undergoing developmental changes and the interrelation with spatial visual processing is not yet established. In conclusion, we argue that for studying auditory space processing over the life course, it is beneficial to investigate spatial discrimination ability instead of localisation accuracy because it more reliably indicates changes in the processing ability.

Inhibitory properties underlying non-monotonic input-output relationship in low-frequency spherical bushy neurons of the gerbil.

Spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive input from large excitatory auditory nerve (AN) terminals, the endbulbs of Held, and mixed glycinergic/GABAergic inhibitory inputs. The latter have sufficient potency to block action potential firing in vivo and in slice recordings. However, it is not clear how well the data from slice recordings match the inhibition in the intact brain and how it contributes to complex phenomena such as non-monotonic rate-level functions (RLF). Therefore, we determined the input-output relationship of a model SBC with simulated endbulb inputs and a dynamic inhibitory conductance constrained by recordings in brain slice preparations of hearing gerbils. Event arrival times from in vivo single-unit recordings in gerbils, where 70% of SBC showed non-monotonic RLF, were used as input for the model. Model output RLFs systematically changed from monotonic to non-monotonic shape with increasing strength of tonic inhibition. A limited range of inhibitory synaptic properties consistent with the slice data generated a good match between the model and recorded RLF. Moreover, tonic inhibition elevated the action potentials (AP) threshold and improved the temporal precision of output functions in a SBC model with phase-dependent input conductance. We conclude that activity-dependent, summating inhibition contributes to high temporal precision of SBC spiking by filtering out weak and poorly timed EPSP. Moreover, inhibitory parameters determined in slice recordings provide a good estimate of inhibitory mechanisms apparently active in vivo.

Perineuronal nets in the auditory system.

Perineuronal nets (PNs) are a unique and complex meshwork of specific extracellular matrix molecules that ensheath a subset of neurons in many regions of the central nervous system (CNS). PNs appear late in development and are supposed to restrict synaptic plasticity and to stabilize functional neuronal connections. PNs were further hypothesized to create a charged milieu around the neurons and thus, might directly modulate synaptic activity. Although PNs were first described more than 120 years ago, their exact functions still remain elusive. The purpose of the present review is to propose the nuclei of the auditory system, which are highly enriched in PN-wearing neurons, as particularly suitable structures to study the functional significance of PNs. We provide a detailed description of the distribution of PNs from the cochlear nucleus to the auditory cortex considering distinct markers for detection of PNs. We further point to the suitability of specific auditory neurons to serve as promising model systems to study in detail the contribution of PNs to synaptic physiology and also more generally to the functionality of the brain.

Dynamic fidelity control to the central auditory system: synergistic glycine/GABAergic inhibition in the cochlear nucleus.

GABA and glycine are the major inhibitory transmitters that attune neuronal activity in the CNS of mammals. The respective transmitters are mostly spatially separated, that is, synaptic inhibition in the forebrain areas is mediated by GABA, whereas glycine is predominantly used in the brainstem. Accordingly, inhibition in auditory brainstem circuits is largely mediated by glycine, but there are few auditory synapses using both transmitters in maturity. Little is known about physiological advantages of such a two-transmitter inhibitory mechanism. We explored the benefit of engaging both glycine and GABA with inhibition at the endbulb of Held-spherical bushy cell synapse in the auditory brainstem of juvenile Mongolian gerbils. This model synapse enables selective in vivo activation of excitatory and inhibitory neuronal inputs through systemic sound stimulation and precise analysis of the input (endbulb of Held) output (spherical bushy cell) function. The combination of in vivo and slice electrophysiology revealed that the dynamic AP inhibition in spherical bushy cells closely matches the inhibitory conductance profile determined by the glycine-R and GABAA-R. The slow and potent glycinergic component dominates the inhibitory conductance, thereby primarily accounting for its high-pass filter properties. GABAergic transmission enhances the inhibitory strength and shapes its duration in an activity-dependent manner, thus increasing the inhibitory potency to suppress the excitation through the endbulb of Held. Finally, in silico modeling provides a strong link between in vivo and slice data by simulating the interactions between the endbulb- and the synergistic glycine-GABA-conductances during in vivo-like spontaneous and sound evoked activities.

Pre-attentive cortical processing of behaviorally perceptible spatial changes in older adults-a mismatch negativity study.

From behavioral studies it is known that auditory spatial resolution of azimuthal space declines over age. To date, it is not clear how age affects the respective sensory auditory processing at the pre-attentive level. Here we tested the hypothesis that pre-attentive processing of behaviorally perceptible spatial changes is preserved in older adults. An EEG-study was performed in older adults (65-82 years of age) and a mismatch negativity (MMN) paradigm employed. Sequences of frequent standard stimuli of defined azimuthal positions were presented together with rarely occurring deviants shifted by 10° or 20° to the left or to the right of the standard. Standard positions were at +5° (central condition) from the midsagittal plane and at 65° in both lateral hemifields (±65°; lateral condition). The results suggest an effect of laterality on the pre-attentive change processing of spatial deviations in older adults: While for the central conditions deviants close to MAA threshold (i.e., 10°) yielded discernable MMNs, for lateral positions the respective MMN responses were only elicited by spatial deviations of 20° toward the midline (i.e., ±45°). Furthermore, MMN amplitudes were found to be insensitive to the magnitude of deviation (10°, 20°), which is contrary to recent studies with young adults (Bennemann et al., 2013) and hints to a deteriorated pre-attentive encoding of sound sources in older adults. The discrepancy between behavioral MAA data and present results are discussed with respect to the possibility that under the condition of active stimulus processing older adults might benefit from recruiting additional attentional top-down processes to detect small magnitudes of spatial deviations even within the lateral acoustic field.

Position of acoustic stimulus modulates visual α activity.

It has been repeatedly shown that a unimodal stimulus can modulate oscillatory activity of multiple cortical areas already at early stages of sensory processing. In this way, an influence can be exerted on the response to a subsequent sensory input. Even though this fact is now well established, it is still not clear whether cortical sensory areas are informed about spatial positions of objects of modality other than their preferred one. Here, we test the hypothesis of whether oscillatory activity of the human visual cortex depends on the position of a unimodal auditory object. We recorded electroencephalogram while presenting sounds in an acoustic free-field either at the center of the visual field or at lateral positions. Using independent component analysis, we identified three cortical sources located in the visual cortex, showing stimulus position-specific oscillatory responses. The most pronounced effect was an immediate α (8-12 Hz) power decrease over the entire occipital lobe when the stimulus originated from the center of the binocular visual field. Following a lateral stimulation, the amplitude of α activity decreased slightly over contralateral visual areas, while at the same time a weak α synchronization was observed in corresponding ipsilateral areas. Thus, even in the absence of visual stimuli, the visual cortex is differentially activated depending on the position of an acoustic sound source. Our results show that the visual cortex receives information about the position of auditory stimuli within the visual field.

The precise temporal pattern of prehearing spontaneous activity is necessary for tonotopic map refinement.

Patterned spontaneous activity is a hallmark of developing sensory systems. In the auditory system, rhythmic bursts of spontaneous activity are generated in cochlear hair cells and propagated along central auditory pathways. The role of these activity patterns in the development of central auditory circuits has remained speculative. Here we demonstrate that blocking efferent cholinergic neurotransmission to developing hair cells in mice that lack the α9 subunit of nicotinic acetylcholine receptors (α9 KO mice) altered the temporal fine structure of spontaneous activity without changing activity levels. KO mice showed a severe impairment in the functional and structural sharpening of an inhibitory tonotopic map, as evidenced by deficits in synaptic strengthening and silencing of connections and an absence in axonal pruning. These results provide evidence that the precise temporal pattern of spontaneous activity before hearing onset is crucial for the establishment of precise tonotopy, the major organizing principle of central auditory pathways.

Auditory processing disorders with and without central auditory discrimination deficits.

Auditory processing disorder (APD) is defined as a processing deficit in the auditory modality and spans multiple processes. To date, APD diagnosis is mostly based on the utilization of speech material. Adequate nonspeech tests that allow differentiation between an actual central hearing disorder and related disorders such as specific language impairments are still not adequately available. In the present study, 84 children between 6 and 17 years of age (clinical group), referred to three audiological centers for APD diagnosis, were evaluated with standard audiological tests and additional auditory discrimination tests. Latter tests assessed the processing of basic acoustic features at two different stages of the ascending central auditory system: (1) auditory brainstem processing was evaluated by quantifying interaural frequency, level, and signal duration discrimination (interaural tests). (2) Diencephalic/telencephalic processing was assessed by varying the same acoustic parameters (plus signals with sinusoidal amplitude modulation), but presenting the test signals in conjunction with noise pulses to the contralateral ear (dichotic(signal/noise) tests). Data of children in the clinical group were referenced to normative data obtained from more than 300 normally developing healthy school children. The results in the audiological and the discrimination tests diverged widely. Of the 39 children that were diagnosed with APD in the audiological clinic, 30 had deficits in auditory performance. Even more alarming was the fact that of the 45 children with a negative APD diagnosis, 32 showed clear signs of a central hearing deficit. Based on these results, we suggest revising current diagnostic procedure to evaluate APD in order to more clearly differentiate between central auditory processing deficits and higher-order (cognitive and/or language) processing deficits.