Candidate Key Proteins in Tinnitus-A Bioinformatic Study of Synaptic Transmission in the Cochlear Nucleus.

The aim of this study was to identify key proteins of synaptic transmission in the cochlear nucleus (CN) that are involved in normal hearing, acoustic stimulation, and tinnitus. A gene list was compiled from the GeneCards database using the keywords "synaptic transmission" AND "tinnitus" AND "cochlear nucleus" (Tin). For comparison, two gene lists with the keywords "auditory perception" (AP) AND "acoustic stimulation" (AcouStim) were built. The STRING protein-protein interaction (PPI) network and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and their high-score interaction proteins (HSIPs), together referred to as key proteins. The top1 key proteins of the Tin-process were BDNF, NTRK1, NTRK3, and NTF3; the top2 key proteins are FOS, JUN, CREB1, EGR1, MAPK1, and MAPK3. Highly significant GO terms in CN in tinnitus were "RNA polymerase II transcription factor complex", "late endosome", cellular response to cadmium ion", "cellular response to reactive oxygen species", and "nerve growth factor signaling pathway", indicating changes in vesicle and cell homeostasis. In contrast to the spiral ganglion, where important changes in tinnitus are characterized by processes at the level of cells, important biological changes in the CN take place at the level of synapses and transcription.

Medial superior olive in the rat: Anatomy, sources of input and axonal projections.

Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential aspect of binaural hearing: the ability of animals to localize the sources of low-frequency sounds by detecting the interaural time difference (ITD), that is the difference in the time at which the sound arrives at each ear. In mammals, ITDs are mostly encoded in the medial superior olive (MSO), one of the main nuclei of the superior olivary complex (SOC). Because of their small heads and high frequency hearing range, rats and mice are often considered unable to use ITDs for sound localization. Moreover, their MSO is frequently viewed as too small or insignificant compared to that of mammals that use ITDs to localize sounds, including cats and gerbils. However, recent research has demonstrated remarkable similarities between most morphological and physiological features of mouse MSO neurons and those of MSO neurons of mammals that use ITDs. In this context, we have analyzed the structure and neural afferent and efferent connections of the rat MSO, which had never been studied by injecting neuroanatomical tracers into the nucleus. The rat MSO spans the SOC longitudinally. It is relatively small caudally, but grows rostrally into a well-developed column of stacked bipolar neurons. By placing small, precise injections of the bidirectional tracer biotinylated dextran amine (BDA) into the MSO, we show that this nucleus is innervated mainly by the most ventral and rostral spherical bushy cells of the anteroventral cochlear nucleus of both sides, and by the most ventrolateral principal neurons of the ipsilateral medial nucleus of the trapezoid body. The same experiments reveal that the MSO densely innervates the most dorsolateral region of the central nucleus of the inferior colliculus, the central region of the dorsal nucleus of the lateral lemniscus, and the most lateral region of the intermediate nucleus of the lateral lemniscus of its own side. Therefore, the MSO is selectively innervated by, and sends projections to, neurons that process low-frequency sounds. The structural and hodological features of the rat MSO are notably similar to those of the MSO of cats and gerbils. While these similarities raise the question of what functions other than ITD coding the MSO performs, they also suggest that the rat MSO is an appropriate model for future MSO-centered research.

Fast inhibition slows and desynchronizes mouse auditory efferent neuron activity.

The encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem are well-suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that restrict MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation ('wedge-slice'). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The 'in vivo-like' timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivo-like timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hyper-suppression of cochlear activity.

Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain.

Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.

Cochlear Nucleus Transcriptome of a Fragile X Mouse Model Reveals Candidate Genes for Hyperacusis.

OBJECTIVE: Fragile X Syndrome (FXS) is a hereditary form of autism spectrum disorder. It is caused by a trinucleotide repeat expansion in the Fmr1 gene, leading to a loss of Fragile X Protein (FMRP) expression. The loss of FMRP causes auditory hypersensitivity: FXS patients display hyperacusis and the Fmr1- knock-out (KO) mouse model for FXS exhibits auditory seizures. FMRP is strongly expressed in the cochlear nucleus and other auditory brainstem nuclei. We hypothesize that the Fmr1-KO mouse has altered gene expression in the cochlear nucleus that may contribute to auditory hypersensitivity. METHODS: RNA was isolated from cochlear nuclei of Fmr1-KO and WT mice. Using next-generation sequencing (RNA-seq), the transcriptomes of Fmr1-KO mice and WT mice (n = 3 each) were compared and analyzed using gene ontology programs. RESULTS: We identified 270 unique, differentially expressed genes between Fmr1-KO and WT cochlear nuclei. Upregulated genes (67%) are enriched in those encoding secreted molecules. Downregulated genes (33%) are enriched in neuronal function, including synaptic pathways, some of which are ideal candidate genes that may contribute to hyperacusis. CONCLUSION: The loss of FMRP can affect the expression of genes in the cochlear nucleus that are important for neuronal signaling. One of these, Kcnab2, which encodes a subunit of the Shaker voltage-gated potassium channel, is expressed at an abnormally low level in the Fmr1-KO cochlear nucleus. Kcnab2 and other differentially expressed genes may represent pathways for the development of hyperacusis. Future studies will be aimed at investigating the effects of these altered genes on hyperacusis. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:1363-1371, 2024.

Mechanisms of age-related hearing loss at the auditory nerve central synapses and postsynaptic neurons in the cochlear nucleus.

Sound information is transduced from mechanical vibration to electrical signals in the cochlea, conveyed to and further processed in the brain to form auditory perception. During the process, spiral ganglion neurons (SGNs) are the key cells that connect the peripheral and central auditory systems by receiving information from hair cells in the cochlea and transmitting it to neurons of the cochlear nucleus (CN). Decades of research in the cochlea greatly improved our understanding of SGN function under normal and pathological conditions, especially about the roles of different subtypes of SGNs and their peripheral synapses. However, it remains less clear how SGN central terminals or auditory nerve (AN) synapses connect to CN neurons, and ultimately how peripheral pathology links to structural alterations and functional deficits in the central auditory nervous system. This review discusses recent progress about the morphological and physiological properties of different subtypes of AN synapses and associated postsynaptic CN neurons, their changes during aging, and the potential mechanisms underlying age-related hearing loss.

Age-related upregulation of perineuronal nets on inferior collicular cells that project to the cochlear nucleus.

Introduction: Disruptions to the balance of excitation and inhibition in the inferior colliculus (IC) occur during aging and underlie various aspects of hearing loss. Specifically, the age-related alteration to GABAergic neurotransmission in the IC likely contributes to the poorer temporal precision characteristic of presbycusis. Perineuronal nets (PNs), a specialized form of the extracellular matrix, maintain excitatory/inhibitory synaptic environments and reduce structural plasticity. We sought to determine whether PNs increasingly surround cell populations in the aged IC that comprise excitatory descending projections to the cochlear nucleus. Method: We combined Wisteria floribunda agglutinin (WFA) staining for PNs with retrograde tract-tracing in three age groups of Fischer Brown Norway (FBN) rats. Results: The data demonstrate that the percentage of IC-CN cells with a PN doubles from ~10% at young age to ~20% at old age. This was true in both lemniscal and non-lemniscal IC. Discussion: Furthermore, the increase of PNs occurred on IC cells that make both ipsilateral and contralateral descending projections to the CN. These results indicate that reduced structural plasticity in the elderly IC-CN pathway, affecting excitatory/inhibitory balance and, potentially, may lead to reduced temporal precision associated with presbycusis.

mRNA Abundance of Neurogenic Factors Correlates with Hearing Capacity in Auditory Brainstem Nuclei of the Rat.

Neural stem cells (NSCs) have previously been described up to the adult stage in the rat cochlear nucleus (CN). A decreasing neurogenic potential was observed with critical changes around hearing onset. A better understanding of molecular factors affecting NSCs and neurogenesis is of interest as they represent potential targets to treat the cause of neurologically based hearing disorders. The role of genes affecting NSC development and neurogenesis in CN over time on hearing capacity has remained unclear. This study investigated the mRNA abundance of genes influencing NSCs and neurogenesis in rats' CN over time. The CN of rats on postnatal days 6, 12, and 24 were examined. Real-time quantitative polymerase chain reaction arrays were used to compare mRNA levels of 84 genes relevant to NSCs and neurogenesis. Age- and hearing-specific patterns of changes in mRNA abundance of neurogenically relevant genes were detected in the rat CN. Additionally, crucial neurogenic factors with significant and relevant influence on neurogenesis were identified. The results of this work should contribute to a better understanding of the molecular mechanisms underlying the neurogenesis of the auditory pathway.

Comprehensive analysis of cellular specializations that initiate parallel auditory processing pathways in mice.

The cochlear nuclear complex (CN) is the starting point for all central auditory processing and comprises a suite of neuronal cell types that are highly specialized for neural coding of acoustic signals. To examine how their striking functional specializations are determined at the molecular level, we performed single-nucleus RNA sequencing of the mouse CN to molecularly define all constituent cell types and related them to morphologically- and electrophysiologically-defined neurons using Patch-seq. We reveal an expanded set of molecular cell types encompassing all previously described major types and discover new subtypes both in terms of topographic and cell-physiologic properties. Our results define a complete cell-type taxonomy in CN that reconciles anatomical position, morphological, physiological, and molecular criteria. This high-resolution account of cellular heterogeneity and specializations from the molecular to the circuit level illustrates molecular underpinnings of functional specializations and enables genetic dissection of auditory processing and hearing disorders with unprecedented specificity.

Is phase locking crucial to improve hearing thresholds in tinnitus patients?

Temporal processing of auditory data plays a crucial role in our proposed model of tinnitus development through stochastic resonance (SR). The model assumes a physiological mechanism optimizing auditory information transmission (as quantified by autocorrelation [AC] analysis) into the brain by adding the optimal amount of neuronal noise to otherwise subthreshold signals. We hypothesize that this takes place at the second synapse of the auditory pathway in the dorsal cochlear nucleus (DCN). We propose that after hearing loss, this neuronal noise is increased in the affected frequency band to improve hearing thresholds at the cost of upward propagation of this added noise, which finally may be perceived as tinnitus. We already showed the improvement of hearing thresholds in a large population of patients. Until now, we did not investigate the differences in hearing thresholds based on the biological constraints of early auditory temporal processing (phase locking) that is only possible up to frequencies of 5 kHz. In this report, we grouped our patient database (N = 47,986) according to tinnitus pitch (TP) of below (TP<5kHz ) or above (TP>5kHz ) the 5 kHz limit or having no tinnitus (NT) and compared their mean audiograms. We found that TP<5kHz patients showed significantly better hearing thresholds than all other patient groups independent of age. No improvement was seen for TP>5kHz patients who even showed worse thresholds than NT patients for high frequencies. These results are further evidence for our SR model of tinnitus development and the existence of AC analysis at the level of the DCN.

Sensitivity to Pulse Rate and Amplitude Modulation in an Animal Model of the Auditory Brainstem Implant (ABI).

The auditory brainstem implant (ABI) is an auditory neuroprosthesis that provides hearing by electrically stimulating the cochlear nucleus (CN) of the brainstem. Our previous study (McInturff et al., 2022) showed that single-pulse stimulation of the dorsal (D)CN subdivision with low levels of current evokes responses that have early latencies, different than the late response patterns observed from stimulation of the ventral (V)CN. How these differing responses encode more complex stimuli, such as pulse trains and amplitude modulated (AM) pulses, has not been explored. Here, we compare responses to pulse train stimulation of the DCN and VCN, and show that VCN responses, measured in the inferior colliculus (IC), have less adaption, higher synchrony, and higher cross-correlation. However, with high-level DCN stimulation, responses become like those to VCN stimulation, supporting our earlier hypothesis that current spreads from electrodes on the DCN to excite neurons located in the VCN. To AM pulses, stimulation of the VCN elicits responses with larger vector strengths and gain values especially in the high-CF portion of the IC. Additional analysis using neural measures of modulation thresholds indicate that these measures are lowest for VCN. Human ABI users with low modulation thresholds, who score best on comprehension tests, may thus have electrode arrays that stimulate the VCN. Overall, the results show that the VCN has superior response characteristics and suggest that it should be the preferred target for ABI electrode arrays in humans.

Development of electrophysiological properties of fusiform neurons from the dorsal cochlear nucleus of mice before and after hearing onset.

The dorsal cochlear nucleus (DCN) in the auditory brainstem integrates auditory and somatosensory information. Mature DCN fusiform neurons fall into two qualitatively distinct types: quiet, with no spontaneous regular action potential firing, or active, with regular spontaneous action potential firing. However, how these firing states and other electrophysiological properties of fusiform neurons develop during early postnatal days to adulthood is not known. Thus, we recorded fusiform neurons from mice from P4 to P21 and analyzed their electrophysiological properties. In the prehearing phase (P4-P13), we found that most fusiform neurons are quiet, with active neurons emerging after hearing onset at P14. Subthreshold properties underwent significant changes before hearing onset, whereas changes to the action potential waveform occurred mainly after P14, with the depolarization and repolarization phases becoming markedly faster and half-width significantly decreased. The activity threshold in posthearing neurons was more negative than in prehearing cells. Persistent sodium current (INaP) was increased after P14, coinciding with the emergence of spontaneous firing. Thus, we suggest that posthearing expression of INaP leads to hyperpolarization of the activity threshold and the active state of the fusiform neuron. At the same time, other changes refine the passive membrane properties and increase the speed of action potential firing of fusiform neurons.NEW & NOTEWORTHY Auditory brainstem neurons express unique electrophysiological properties adapted for their complex physiological functions that develop before hearing onset. Fusiform neurons of the DCN present two firing states, quiet and active, but the origin of these states is not known. Here, we showed that the quiet and active states develop after hearing onset at P14, along with changes in action potentials, suggesting an influence of auditory input on the refining of fusiform neuron's excitability.

Cochlear synaptopathy impairs suprathreshold tone-in-noise coding in the cochlear nucleus.

Hearing impairment without threshold elevations can occur when there is damage to high-threshold auditory nerve fibre synapses with cochlear inner hair cells. Instead, cochlear synaptopathy produces suprathreshold deficits, especially in older patients, which affect conversational speech. Given that listening in noise at suprathreshold levels presents significant challenges to the ageing population, we examined the effects of synaptopathy on tone-in-noise coding on the central recipients of auditory nerve fibres, i.e. the cochlear nucleus neurons. To induce synaptopathy, guinea pigs received a unilateral sound overexposure to the left ears. A separate group received sham exposures. At 4 weeks post-exposure, thresholds had recovered but reduced auditory brainstem response wave 1 amplitudes and auditory nerve synapse loss remained on the left side. Single-unit responses were recorded from several cell types in the ventral cochlear nucleus to pure-tone and noise stimuli. Receptive fields and rate-level functions in the presence of continuous broadband noise were examined. The synaptopathy-inducing noise exposure did not affect mean unit tone-in-noise thresholds, nor the tone-in-noise thresholds in each animal, demonstrating equivalent tone-in-noise detection thresholds to sham animals. However, synaptopathy reduced single-unit responses to suprathreshold tones in the presence of background noise, particularly in the cochlear nucleus small cells. These data demonstrate that suprathreshold tone-in-noise deficits following cochlear synaptopathy are evident in the first neural station of the auditory brain, the cochlear nucleus neurons, and provide a potential target for assessment and treatment of listening-in-noise deficits in humans. KEY POINTS: Recording from multiple central auditory neurons can determine tone-in-noise deficits in animals with quantified cochlear synapse damage. Using this technique, we found that tone-in-noise thresholds are not altered by cochlear synaptopathy, whereas coding of suprathreshold tones-in-noise is disrupted. Suprathreshold deficits occur in small cells and primary-like neurons of the cochlear nucleus. These data provide important insights into the mechanisms underlying difficulties associated with hearing in noisy environments.

Resveratrol prevents hearing loss and a subregion specific- reduction of serotonin reuptake transporter induced by noise exposure in the central auditory system.

Prolonged or excessive exposure to noise can lead to hearing loss, tinnitus and hypersensitivity to sound. The effects of noise exposure on main excitatory and inhibitory neurotransmitter systems in auditory pathway have been extensively investigated. However, little is known about aberrant changes in neuromodulator systems caused by noise exposure. In the current study, we exposed 2-month-old mice to a narrow band noise at 116 dB SPL for 6 h or sham exposure, assessed auditory brainstem responses as well as examined the expression of serotonin reuptake transporter (SERT) in the cochlear nucleus (CN), inferior colliculus (IC), and primary auditory cortex (Au1) using immunohistochemistry. We found that noise exposure resulted in a significant increase in hearing thresholds at 4, 8, 16, 24, and 32 kHz, as well as led to a significant reduction of SERT in dorsal cochlear nucleus (DCN), dorsal IC (ICd), external IC (ICe), and Au1 layers I-IV. This reduction of SERT in these subregions of central auditory system was partially recovered 15 or 30 days after noise exposure. Furthermore, we examined efficacy of resveratrol (RSV) on hearing loss and loss of SERT induced by noise exposure. The results demonstrated that RSV treatment significantly attenuated threshold shifts of auditory brainstem responses and loss of SERT in DCN, ICd, ICe, and Au1 layers I-IV. These findings show that noise exposure can cause hearing loss and subregion-specific loss of SERT in the central auditory system, and RSV treatment could attenuate noise exposure-induced hearing loss and loss of SERT in central auditory system.

Comparative analysis of four nuclei in the human brainstem: Individual differences, left-right asymmetry, species differences.

Introduction: It is commonly thought that while the organization of the cerebral cortex changes dramatically over evolution, the organization of the brainstem is conserved across species. It is further assumed that, as in other species, brainstem organization is similar from one human to the next. We will review our data on four human brainstem nuclei that suggest that both ideas may need modification. Methods: We have studied the neuroanatomical and neurochemical organization of the nucleus paramedianus dorsalis (PMD), the principal nucleus of the inferior olive (IOpr), the arcuate nucleus of the medulla (Arc) and the dorsal cochlear nucleus (DC). We compared these human brainstem nuclei to nuclei in other mammals including chimpanzees, monkeys, cats and rodents. We studied human cases from the Witelson Normal Brain collection using Nissl and immunostained sections, and examined archival Nissl and immunostained sections from other species. Results: We found significant individual variability in the size and shape of brainstem structures among humans. There is left-right asymmetry in the size and appearance of nuclei, dramatically so in the IOpr and Arc. In humans there are nuclei, e.g., the PMD and the Arc, not seen in several other species. In addition, there are brainstem structures that are conserved across species but show major expansion in humans, e.g., the IOpr. Finally, there are nuclei, e.g. the DC, that show major differences in structure among species. Discussion: Overall, the results suggest several principles of human brainstem organization that distinguish humans from other species. Studying the functional correlates of, and the genetic contributions to, these brainstem characteristics are important future research directions.

Dendritic Degeneration and Altered Synaptic Innervation of a Central Auditory Neuron During Age-related Hearing Loss.

Cellular morphology and synaptic configuration are key determinants of neuronal function and are often modified under pathological conditions. In the first nucleus of the central auditory system, the cochlear nucleus (CN), principal bushy neurons specialize in processing temporal information of sound critical for hearing. These neurons alter their physiological properties during aging that contribute to age-related hearing loss (ARHL). The structural basis of such changes remains unclear, especially age-related modifications in their dendritic morphology and the innervating auditory nerve (AN) synapses. Using young (2-5 months) and aged (28-33 months) CBA/CaJ mice of either sex, we filled individual bushy neurons with fluorescent dye in acute brain slices to characterize their dendritic morphology, followed by immunostaining against vesicular glutamate transporter 1 (VGluT1) and calretinin (CR) to identify innervating AN synapses. We found that dendritic morphology of aged bushy neurons had significantly reduced complexity, suggesting age-dependent dendritic degeneration, especially in neurons with predominantly non-CR-expressing synapses on the soma. These dendrites were innervated by AN bouton synapses, which were predominantly non-CR-expressing in young mice but had increased proportion of CR-expressing synapses in old mice. While somatic AN synapses degenerated substantially with age, as quantified by VGluT1-labeled puncta volume, no significant difference was observed in the total volume of dendritic synapses between young and old mice. Consequently, synaptic density on dendrites was significantly higher in old mice. The findings suggest that dendritic degeneration and altered synaptic innervation in bushy neurons during aging may underlie their changed physiological activity and contribute to the development of ARHL.

Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum.

Mammals have a dorsal cochlear nucleus (DCN), which is thought to be a cerebellum-like structure with similar features in terms of structure and microcircuitry to the cerebellum. Both the DCN and cerebellum perform their functions depending on synaptic and neuronal networks mediated by various glutamate receptors. Kainate receptors (KARs) are one class of the glutamate receptor family and are strongly expressed in the hippocampus, the cerebellum, and cerebellum-like structures. The cellular distribution and the potential role of KARs in the hippocampus have been extensively investigated. However, the cellular distribution and the potential role of KARs in cerebellum-like structures, including the DCN and cerebellum, are poorly understood. In this review, we summarize the similarity between the DCN and cerebellum at the levels of structure, circuitry, and cell type as well as the investigations referring to the expression patterns of KARs in the DCN and cerebellum according to previous studies. Recent studies on the role of KARs have shown that KARs mediate a bidirectional modulatory effect at parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum, implying insights into their roles in cerebellum-like structures, including the DCN, that remain to be explored in the coming years.

Hierarchical differences in the encoding of sound and choice in the subcortical auditory system.

Detection of sounds is a fundamental function of the auditory system. Although studies of auditory cortex have gained substantial insight into detection performance using behaving animals, previous subcortical studies have mostly taken place under anesthesia, in passively listening animals, or have not measured performance at threshold. These limitations preclude direct comparisons between neuronal responses and behavior. To address this, we simultaneously measured auditory detection performance and single-unit activity in the inferior colliculus (IC) and cochlear nucleus (CN) in macaques. The spontaneous activity and response variability of CN neurons were higher than those observed for IC neurons. Signal detection theoretic methods revealed that the magnitude of responses of IC neurons provided more reliable estimates of psychometric threshold and slope compared with the responses of single CN neurons. However, pooling small populations of CN neurons provided reliable estimates of psychometric threshold and slope, suggesting sufficient information in CN population activity. Trial-by-trial correlations between spike count and behavioral response emerged 50-75 ms after sound onset for most IC neurons, but for few neurons in the CN. These results highlight hierarchical differences between neurometric-psychometric correlations in CN and IC and have important implications for how subcortical information could be decoded.NEW & NOTEWORTHY The cerebral cortex is widely recognized to play a role in sensory processing and decision-making. Accounts of the neural basis of auditory perception and its dysfunction are based on this idea. However, significantly less attention has been paid to midbrain and brainstem structures in this regard. Here, we find that subcortical auditory neurons represent stimulus information sufficient for detection and predict behavioral choice on a trial-by-trial basis.

Eph and ephrin signaling in the development of the central auditory system.

Acoustic communication relies crucially on accurate interpretation of information about the intensity, frequency, timing, and location of diverse sound stimuli in the environment. To meet this demand, neurons along different levels of the auditory system form precisely organized neural circuits. The assembly of these precise circuits requires tight regulation and coordination of multiple developmental processes. Several groups of axon guidance molecules have proven critical in controlling these processes. Among them, the family of Eph receptors and their ephrin ligands emerge as one group of key players. They mediate diverse functions at multiple levels of the auditory pathway, including axon guidance and targeting, topographic map formation, as well as cell migration and tissue pattern formation. Here, we review our current knowledge of how Eph and ephrin molecules regulate different processes in the development and maturation of central auditory circuits.

NRG1/ErbB2 axis regulated mitochondrial function and antioxidant enzymes of neural stem cells in the cochlear nucleus partially through PGC-1α.

Neuregulin-1 (NRG1)/erythroblastic leukaemia viral oncogene homologues 2 (ErbB2) pathway had been implicated in promoting differentiation and suppressing apoptosis of neuronal stem cells (NSCs) isolated from cochlear nucleus. In the current study, we aimed at determining the effects of NRG1/ErbB2 on mitochondrial (mt) function of NSCs. As expected, NRG1 increased the expression of mitofusin (Mfn) 1 and Mfn2 and decreased the expression of mitochondrial fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1). However, after ErbB2 knockout, Mfn1 and Mfn2 expression decreased while Fis1 and Drp1 increased. Moreover, the increased mtDNA copy number and intracellular ATP level, elevated ATPase activities as well as decreased lactate production induced by NRG1 were partially reversed by ErbB2 knockout. Additionally, NRG1 treatment increased the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and upregulated the protein expression of catalase, manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and transcription factor A, mitochondrial (TFAM), which were also reversed by ErbB2 knockout. Furthermore, PGC-1α overexpression partially reversed the above effects of ErbB2 knockout. In conclusion, these findings suggest that the promotion of mitochondrial function of NRG1/ErbB2 axis is at least in part mediated by PGC-1α in NSCs from cochlear nucleus.