Superior Olivary Research Articles

In vivo AAV9-Myo7a gene rescue restores hearing and cholinergic efferent innervation in inner hair cells.

In the mammalian cochlea, sensory hair cells are crucial for the transduction of acoustic stimuli into electrical signals, which are then relayed to the central auditory pathway via spiral ganglion neuron (SGN) afferent dendrites. The SGN output is directly modulated by inhibitory cholinergic axodendritic synapses from the efferent fibers originating in the superior olivary complex. When the adult cochlea is subjected to noxious stimuli or aging, the efferent system undergoes major rewiring, such that it reestablishes direct axosomatic contacts with the inner hair cells (IHCs), which occur only transiently during prehearing stages of development. The trigger, origin, and degree of efferent plasticity in the cochlea remains largely unknown. Using functional and morphological approaches, we demonstrate that efferent plasticity in the adult cochlea occurs as a direct consequence of mechanoelectrical transducer current dysfunction. We also show that, different from prehearing stages of development, the lateral olivocochlear - but not the medial olivocochlear - efferent fibers are those that form the axosomatic synapses with the IHCs. The study also demonstrates that in vivo restoration of IHC function using AAV-Myo7a rescue reestablishes the synaptic profile of adult IHCs and improves hearing, highlighting the potential of using gene-replacement therapy for progressive hearing loss.

Electrophysiological correlates of divergent projections in the avian superior olivary nucleus.

The physiological diversity of inhibitory neurons provides ample opportunity to influence a wide range of computational roles through their varied activity patterns, especially via feedback loops. In the avian auditory brain stem, inhibition originates primarily from the superior olivary nucleus (SON), and so it is critical to understand the intrinsic physiological properties and processing capabilities of these neurons. Neurons in the SON receive ascending input via the cochlear nuclei: directly from the intensity-coding cochlear nucleus angularis (NA) and indirectly via the interaural timing nucleus laminaris (NL), which itself receives input from cochlear nucleus magnocellularis (NM). Two distinct populations of SON neurons provide inhibitory feedback either to ipsilateral NA, NL, and the timing cochlear nucleus NM or to the contralateral SON. To determine whether these populations correspond to distinct response types, we investigated their electrophysiology in brain stem slices, using patch-clamp electrophysiology. We identified three phenotypes: single-spiking, chattering tonic, and regular tonic neurons. The two tonic phenotypes displayed distinct firing patterns and different membrane properties. Fluctuating "noisy" currents used to probe the capability of SON neurons to encode temporal features showed that each phenotype differed in sensitivity to temporally modulated input. By using cell fills and anatomical reconstructions, we could correlate the firing phenotypes with their axonal projection patterns. We found that SON axons exited via three fiber tracts, with each tract composed of specific phenotypes. These results provide a basis for understanding the role of specific inhibitory cell types in auditory function and elucidate the organization of the SON outputs.NEW & NOTEWORTHY Inhibitory inputs for the avian brain stem originate primarily from the superior olivary nucleus (SON). We describe three intrinsic phenotypes of SON neurons and show how they differ in their temporal processing and projection patterns. We propose that the two types of tonic firing neurons (including one novel type) and the single-spiking neurons in SON comprise separate feedback circuits that may differentially influence the auditory information flowing via the cochlear nuclei and nucleus laminaris.

Obliteration of a glycinergic projection to the medial geniculate in an animal model of autism.

Auditory dysfunction affects the vast majority of people with autism spectrum disorder (ASD) and can range from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid (VPA) is associated with significant risk of an ASD diagnosis in humans and timed in utero exposure to VPA is utilized as an animal model of ASD. VPA-exposed rats have significantly fewer neurons in their auditory brainstem, thalamus and cortex, reduced ascending projections to the midbrain and thalamus and reduced descending projections from the cortex to the auditory midbrain. Consistent with these anatomical changes, VPA-exposed animals also have abnormal auditory brainstem responses. We have recently described a significant ascending projection from calbindin-positive neurons in the medial nucleus of the trapezoid body (MNTB) to the ventral division of the medial geniculate (vMG) in rats that bypasses the central nucleus of the inferior colliculus (CNIC). Since we found that axonal projections to the vMG in VPA-exposed rats are reduced beyond what is predicted from neuron loss alone, we hypothesize that VPA exposure would result in a significant reduction in the MNTB projection to the vMG. We examined this hypothesis by quantifying the proportion of retrogradely-labeled neurons in the MNTB of control and VPA-exposed animals after injections of retrograde tracers in the CNIC and vMG in control and VPA-exposed animals. Our results indicate that in control animals, the MNTB forms the largest projection from the superior olivary complex to the MG and that this projection is nearly abolished by in utero VPA exposure.

Age-dependent deficits of auditory brainstem responses in juvenile Neurexin1α knockout rats.

Abnormal sensory processing is core to neuropsychiatric and neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders. Developing efficient therapies requires understanding the basic sensory pathways and identifying circuit abnormalities during early development. Auditory brainstem responses (ABRs) are well-established biomarkers for auditory processing on the brainstem level. Beyond their advantage of being easily applicable in clinics (given their non-invasive nature), ABRs have high reproducibility in rodents and translate well to humans (e.g. wave identity), despite species differences (e.g. wave features). We hypothesized that ABRs would reveal sensory abnormalities in neurodevelopmental models with construct validity, such as Neurexin1α knockout (Nrxn1α KO) rats during their development. In a previous study, adult Nrxn1α KO rats showed altered cortical auditory-evoked potentials and impaired prediction error to auditory stimuli (Janz in Transl Psychiat, 12:455, 2022 ). This study used ABR measurements to assess brainstem physiology during auditory processing in Nrxn1α KO rats and their wild-type littermates. Therefore, we followed the development trajectories of ABRs from the age of 3weeks to 12weeks longitudinally. We found that juvenile Nrxn1α KO rats (3weeks of age) show altered ABRs, which normalized during further development. This alteration was confined to increased latency in waves II, III, and IV of the ABRs, suggesting impaired auditory processing on the level of the superior olivary complex and inferior colliculus. In conclusion, our results suggest that early but transient deficits in the processing of auditory information on the level of the brainstem are present in Nrxn1α KO rats, which may contribute to later cortical auditory processing deficits observed in adulthood. Our study emphasizes the value of ABRs as a functional readout of auditory brainstem circuit function with potential value as a translational biomarker.

Ototoxicity-related changes in GABA immunolabeling within the rat inferior colliculus

Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat. The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation.There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al., 1995; Mossop et al., 2000; Salvi et al., 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78 % in axodendritic and 82 % in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.

Sapphire-Based Optrode for Low Noise Neural Recording and Optogenetic Manipulation.

Electrophysiological recordings of neurons in deep brain regions using optogenetic stimulation are essential to understanding and regulating the role of complex neural activity in biological behavior and cognitive function. Optogenetic techniques have significantly advanced neuroscience research by enabling the optical manipulation of neural activities. Because of the significance of the technique, constant advancements in implantable optrodes that integrate optical stimulation with low-noise, large-scale electrophysiological recording are in demand to improve the spatiotemporal resolution for various experimental designs and future clinical applications. However, robust and easy-to-use neural optrodes that integrate neural recording arrays with high-intensity light emitting diodes (LEDs) are still lacking. Here, we propose a neural optrode based on Gallium Nitride (GaN) on sapphire technology, which integrates a high-intensity blue LED with a 5x2 recording array monolithically for simultaneous neural recording and optogenetic manipulation. To reduce the noise interference between the recording electrodes and the LED, which is in close physical proximity, three metal grounding interlayers were incorporated within the optrode, and their ability to reduce LED-induced artifacts during neural recording was confirmed through both electromagnetic simulations and experimental demonstrations. The capability of the sapphire optrode to record action potentials has been demonstrated by recording the firing of mitral/tuft cells in the olfactory bulbs of mice in vivo. Additionally, the elevation of action potential firing due to optogenetic stimulation observed using the sapphire probe in medial superior olive (MSO) neurons of the gerbil auditory brainstem confirms the capability of this sapphire optrode to precisely access neural activities in deep brain regions under complex experimental designs.

Bidirectional remodeling of the central auditory system caused by unilateral auditory deprivation.

Unilateral auditory deprivation (UAD) results in cross-modal reorganization of the auditory cortex (AC), which can impair auditory and cognitive functions and diminish the recovery effect of cochlear implantation. Moreover, the subcortical areas provide extensive ascending projections to the AC. To date, a thorough systematic study of subcortical auditory neural plasticity has not been undertaken. Therefore, this review aims to summarize the current evidence on the bidirectional remodeling of the central auditory system caused by UAD, particularly the changes in subcortical neural plasticity. Lateral changes occur in the cochlear nucleus, lateral superior olive, medial nucleus of the trapezoid body, inferior colliculus, and AC of individuals with UAD. Moreover, asymmetric neural activity becomes less prominent in the higher auditory nuclei, which may be due to cross-projection regulation of the bilateral pathway. As a result, subcortical auditory neural plasticity caused by UAD may contribute to the outcomes of cochlear implantation in patients with single-sided deafness (SSD), and the development of intervention strategies for patients with SSD is crucial. Considering that previous studies have focused predominantly on the neural plasticity of the AC, we believe that bidirectional remodeling of subcortical areas after UAD is also crucial for investigating the mechanisms of interventions.

Anatomy of superior olivary complex and lateral lemniscus in Etruscan shrew

Based on the auditory periphery and the small head size, Etruscan shrews (Suncus etruscus) approximate ancestral mammalian conditions. The auditory brainstem in this insectivore has not been investigated. Using labelling techniques, we assessed the structures of their superior olivary complex (SOC) and the nuclei of the lateral lemniscus (NLL). There, we identified the position of the major nuclei, their input pattern, transmitter content, expression of calcium binding proteins (CaBPs) and two voltage-gated ion channels. The most prominent SOC structures were the medial nucleus of the trapezoid body (MNTB), the lateral nucleus of the trapezoid body (LNTB), the lateral superior olive (LSO) and the superior paraolivary nucleus (SPN). In the NLL, the ventral (VNLL), a specific ventrolateral VNLL (VNLLvl) cell population, the intermediate (INLL) and dorsal (DNLL) nucleus, as well as the inferior colliculus’s central aspect were discerned. INLL and VNLL were clearly separated by the differential distribution of various marker proteins. Most labelled proteins showed expression patterns comparable to rodents. However, SPN neurons were glycinergic and not GABAergic and the overall CaBPs expression was low. Next to the characterisation of the Etruscan shrew’s auditory brainstem, our work identifies conserved nuclei and indicates variable structures in a species that approximates ancestral conditions.

Neurexins control the strength and precise timing of glycinergic inhibition in the auditory brainstem.

Neurexins play diverse functions as presynaptic organizers in various glutamatergic and GABAergic synapses. However, it remains unknown whether and how neurexins are involved in shaping functional properties of the glycinergic synapses, which mediate prominent inhibition in the brainstem and spinal cord. To address these issues, we examined the role of neurexins in a model glycinergic synapse between the principal neuron in the medial nucleus of the trapezoid body (MNTB) and the principal neuron in the lateral superior olive (LSO) in the auditory brainstem. Combining RNAscope with stereotactic injection of AAV-Cre in the MNTB of neurexin1/2/3 conditional triple knockout mice, we showed that MNTB neurons highly express all isoforms of neurexins although their expression levels vary remarkably. Selective ablation of all neurexins in MNTB neurons not only reduced the amplitude but also altered the kinetics of the glycinergic synaptic transmission at LSO neurons. The synaptic dysfunctions primarily resulted from an impaired Ca2+ sensitivity of release and a loosened coupling between voltage-gated Ca2+ channels and synaptic vesicles. Together, our current findings demonstrate that neurexins are essential in controlling the strength and temporal precision of the glycinergic synapse, which therefore corroborates the role of neurexins as key presynaptic organizers in all major types of fast chemical synapses.

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.

Molecular and functional profiling of cell diversity and identity in the lateral superior olive, an auditory brainstem center with ascending and descending projections

The lateral superior olive (LSO), a prominent integration center in the auditory brainstem, contains a remarkably heterogeneous population of neurons. Ascending neurons, predominantly principal neurons (pLSOs), process interaural level differences for sound localization. Descending neurons (lateral olivocochlear neurons, LOCs) provide feedback into the cochlea and are thought to protect against acoustic overload. The molecular determinants of the neuronal diversity in the LSO are largely unknown. Here, we used patch-seq analysis in mice at postnatal days P10-12 to classify developing LSO neurons according to their functional and molecular profiles. Across the entire sample (n = 86 neurons), genes involved in ATP synthesis were particularly highly expressed, confirming the energy expenditure of auditory neurons. Two clusters were identified, pLSOs and LOCs. They were distinguished by 353 differentially expressed genes (DEGs), most of which were novel for the LSO. Electrophysiological analysis confirmed the transcriptomic clustering. We focused on genes affecting neuronal input–output properties and validated some of them by immunohistochemistry, electrophysiology, and pharmacology. These genes encode proteins such as osteopontin, Kv11.3, and Kvβ3 (pLSO-specific), calcitonin-gene-related peptide (LOC-specific), or Kv7.2 and Kv7.3 (no DEGs). We identified 12 “Super DEGs” and 12 genes showing “Cluster similarity.” Collectively, we provide fundamental and comprehensive insights into the molecular composition of individual ascending and descending neurons in the juvenile auditory brainstem and how this may relate to their specific functions, including developmental aspects.

Developmental fine-tuning of medial superior olive neurons mitigates their predisposition to contralateral sound sources.

Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.

Comparison of the connectivity of the posterior intralaminar thalamic nucleus and peripeduncular nucleus in rats and mice.

The posterior intralaminar thalamic nucleus (PIL) and peripeduncular nucleus (PP) are two adjoining structures located medioventral to the medial geniculate nucleus. The PIL-PP region plays important roles in auditory fear conditioning and in social, maternal and sexual behaviors. Previous studies often lumped the PIL and PP into single entity, and therefore it is not known if they have common and/or different brain-wide connections. In this study, we investigate brain-wide efferent and afferent projections of the PIL and PP using reliable anterograde and retrograde tracing methods. Both PIL and PP project strongly to lateral, medial and anterior basomedial amygdaloid nuclei, posteroventral striatum (putamen and external globus pallidus), amygdalostriatal transition area, zona incerta, superior and inferior colliculi, and the ectorhinal cortex. However, the PP rather than the PIL send stronger projections to the hypothalamic regions such as preoptic area/nucleus, anterior hypothalamic nucleus, and ventromedial nucleus of hypothalamus. As for the afferent projections, both PIL and PP receive multimodal information from auditory (inferior colliculus, superior olivary nucleus, nucleus of lateral lemniscus, and association auditory cortex), visual (superior colliculus and ectorhinal cortex), somatosensory (gracile and cuneate nuclei), motor (external globus pallidus), and limbic (central amygdaloid nucleus, hypothalamus, and insular cortex) structures. However, the PP rather than PIL receives strong projections from the visual related structures parabigeminal nucleus and ventral lateral geniculate nucleus. Additional results from Cre-dependent viral tracing in mice have also confirmed the main results in rats. Together, the findings in this study would provide new insights into the neural circuits and functional correlation of the PIL and PP.

483 Radiographic Changes in the Auditory Pathway to Predict Outcomes of Children with Hearing Loss

OBJECTIVES/GOALS: Early diagnosis of congenital sensorineural hearing loss (SNHL) is of paramount importance in preventing speech and language impairment.Diffusion tensor imaging (DTI) MRI can identify brain microstructural changes that may potentially contribute towards prognosticating rehabilitation. METHODS/STUDY POPULATION: We retrospectively reviewed pediatric patients with SNHL who obtained DTI MRI between 2011 and 2019, identifying 16 pediatric patients (age <18 years) with at least moderate asymmetric/bilateral SNHL., and gender-matched controlswithout neurological, developmental, or MRI-based brain macrostructural abnormalities. The following brainstem regions and tracts of the auditory pathway were assessed: superior olivary nucleus (SON), inferior colliculus (IC), ipsilateral tracts between the inferior colliculus and superior olivary nucleus (IC-SON). Diffusion values for bilateral regions and tracts were generated, then averaged to calculate a mean value for fractional anisotropy (FA) and mean diffusivity (MD) for each subject. RESULTS/ANTICIPATED RESULTS: Significant differences were identified in FA values of the SON between the SNHL cohort and controls (0.377±0.056 vs 0.422±0.052; p=0.009). No other FA or MD values were significantly different. In children £5 years, MD was significantly decreased in the SNHL cohort compared to controls in the IC (0.918±0.051 vs 1.120±0.142; p<0.001). In children >5 years, there were no significant differences in MD (1.124±0.198 vs 0.997±0.103; p = 0.119). There were no significant differences in MD or FA in the white matter fibers of the IC-SON tract [applewebdata%3A//720AAF0C-C4CF-459C-A42A-6BAA56C4E4CA#_msocom_2]. DISCUSSION/SIGNIFICANCE: This is the first study to assess microstructural changes in brainstem auditory pathway regions among children with SNHL. Longitudinal studies are warranted to assess the predictive value of DTI imaging for long-term outcomes and prognosticating intervention.

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.

Microstructural Changes in the Brainstem Auditory Pathway in Children With Hearing Loss.

To assess the utility of diffusion tensor imaging of the auditory pathway in children with sensorineural hearing loss (SNHL). Retrospective cohort study. A single academic tertiary children's hospital. Sixteen pediatric patients with bilateral SNHL of at least moderate severity in the poorer ear (eight male; mean age, 5.3 ± 4.9 yrs). Controls consisted of age- and sex-matched children with normal hearing who were imaged for nonotologic, non-neurologic medical concerns and found to have normal magnetic resonance imaging (MRI). Three Tesla MRI scanners were used for diffusion tensor imaging. Quantitative diffusion tensor metrics were extracted from the superior olivary nucleus (SON), inferior colliculus (IC), and ipsilateral fiber tracts between the SON and IC delineated by tractography. We identified differences in fractional anisotropy of the SON between the SNHL cohort and controls (0.377 ± 0.056 vs. 0.422 ± 0.052; p = 0.009), but not in the IC. There were no differences in the mean diffusivity (MD) values in the IC and SON. Among younger children (≤5 yrs), MD was decreased in the SNHL cohort compared with controls in the IC (0.918 ± 0.051 vs. 1.120 ± 0.142; p < 0.001). However, among older children (>5 yrs), there were no differences in MD (1.124 ± 0.198 vs. 0.997 ± 0.103; p = 0.119). There were no differences in MD or fractional anisotropy in the white matter fibers of the IC-SON tract. Our results suggest abnormal neural tracts along the central auditory pathway among children with SNHL. Longitudinal studies should assess the prognostic value of these MRI-based findings for assessing long-term outcomes and determining intervention efficacy.

Development of myelination and axon diameter for fast and precise action potential conductance.

Axons of globular bushy cells in the cochlear nucleus convey hyper-accurate signals to the superior olivary complex, the initial site of binaural processing via comparably thick axons and the calyx of the Held synapse. Bushy cell fibers involved in hyper-accurate binaural processing of low-frequency sounds are known to have an unusual internode length-to-axon caliber ratio (L/d) correlating with higher conduction velocity and superior temporal precision of action potentials. How the L/d-ratio develops and what determines this unusual myelination pattern is unclear. Here we describe a gradual developmental transition from very simple to complex, mature nodes of Ranvier on globular bushy cell axons during a 2-week period starting at postnatal day P6/7. The molecular composition of nodes matured successively along the axons from somata to synaptic terminals with morphologically and molecularly mature nodes appearing almost exclusively after hearing onset. Internodal distances are initially coherent with the canonical L/d-ratio of ~100. Several days after hearing onset, however, an over-proportional increase in axon caliber occurs in cells signaling low-frequency sounds which alters their L/d ratio to ~60. Hence, oligodendrocytes initially myelinating axons according to their transient axon caliber but a subsequent differential axon thickening after hearing onset results in the unusual myelination pattern.

Bilateral and symmetric glycinergic and glutamatergic projections from the LSO to the IC in the CBA/CaH mouse.

Auditory space has been conceptualized as a matrix of systematically arranged combinations of binaural disparity cues that arise in the superior olivary complex (SOC). The computational code for interaural time and intensity differences utilizes excitatory and inhibitory projections that converge in the inferior colliculus (IC). The challenge is to determine the neural circuits underlying this convergence and to model how the binaural cues encode location. It has been shown that midbrain neurons are largely excited by sound from the contralateral ear and inhibited by sound leading at the ipsilateral ear. In this context, ascending projections from the lateral superior olive (LSO) to the IC have been reported to be ipsilaterally glycinergic and contralaterally glutamatergic. This study used CBA/CaH mice (3-6 months old) and applied unilateral retrograde tracing techniques into the IC in conjunction with immunocytochemical methods with glycine and glutamate transporters (GlyT2 and vGLUT2, respectively) to analyze the projection patterns from the LSO to the IC. Glycinergic and glutamatergic neurons were spatially intermixed within the LSO, and both types projected to the IC. For GlyT2 and vGLUT2 neurons, the average percentage of ipsilaterally and contralaterally projecting cells was similar (ANOVA, p = 0.48). A roughly equal number of GlyT2 and vGLUT2 neurons did not project to the IC. The somatic size and shape of these neurons match the descriptions of LSO principal cells. A minor but distinct population of small (< 40 μm2) neurons that labeled for GlyT2 did not project to the IC; these cells emerge as candidates for inhibitory local circuit neurons. Our findings indicate a symmetric and bilateral projection of glycine and glutamate neurons from the LSO to the IC. The differences between our results and those from previous studies suggest that species and habitat differences have a significant role in mechanisms of binaural processing and highlight the importance of research methods and comparative neuroscience. These data will be important for modeling how excitatory and inhibitory systems converge to create auditory space in the CBA/CaH mouse.

Review of Binaural Processing With Asymmetrical Hearing Outcomes in Patients With Bilateral Cochlear Implants.

Bilateral cochlear implants (BiCIs) result in several benefits, including improvements in speech understanding in noise and sound source localization. However, the benefit bilateral implants provide among recipients varies considerably across individuals. Here we consider one of the reasons for this variability: difference in hearing function between the two ears, that is, interaural asymmetry. Thus far, investigations of interaural asymmetry have been highly specialized within various research areas. The goal of this review is to integrate these studies in one place, motivating future research in the area of interaural asymmetry. We first consider bottom-up processing, where binaural cues are represented using excitation-inhibition of signals from the left ear and right ear, varying with the location of the sound in space, and represented by the lateral superior olive in the auditory brainstem. We then consider top-down processing via predictive coding, which assumes that perception stems from expectations based on context and prior sensory experience, represented by cascading series of cortical circuits. An internal, perceptual model is maintained and updated in light of incoming sensory input. Together, we hope that this amalgamation of physiological, behavioral, and modeling studies will help bridge gaps in the field of binaural hearing and promote a clearer understanding of the implications of interaural asymmetry for future research on optimal patient interventions.

Integrate-and-fire-type models of the lateral superior olive.

Neurons of the lateral superior olive (LSO) in the auditory brainstem play a fundamental role in binaural sound localization. Previous theoretical studies developed various types of neuronal models to study the physiological functions of the LSO. These models were usually tuned to a small set of physiological data with specific aims in mind. Therefore, it is unclear whether and how they can be related to each other, how widely applicable they are, and which model is suitable for what purposes. In this study, we address these questions for six different single-compartment integrate-and-fire (IF) type LSO models. The models are divided into two groups depending on their subthreshold responses: passive (linear) models with only the leak conductance and active (nonlinear) models with an additional low-voltage-activated potassium conductance that is prevalent among the auditory system. Each of these two groups is further subdivided into three subtypes according to the spike generation mechanism: one with simple threshold-crossing detection and voltage reset, one with threshold-crossing detection plus a current to mimic spike shapes, and one with a depolarizing exponential current for spiking. In our simulations, all six models were driven by identical synaptic inputs and calibrated with common criteria for binaural tuning. The resulting spike rates of the passive models were higher for intensive inputs and lower for temporally structured inputs than those of the active models, confirming the active function of the potassium current. Within each passive or active group, the simulated responses resembled each other, regardless of the spike generation types. These results, in combination with the analysis of computational costs, indicate that an active IF model is more suitable than a passive model for accurately reproducing temporal coding of LSO. The simulation of realistic spike shapes with an extended spiking mechanism added relatively small computational costs.