Auditory Neurophysiology publications

To obtain combined behavioural and electrophysiological measures of pitch perception, we presented harmonic complexes, bandpass filtered to contain only high-numbered harmonics, to normal-hearing listeners. These stimuli resemble bandlimited pulse trains and convey pitch using a purely temporal code. A core set of conditions consisted of six stimuli with baseline pulse rates of 94, 188 and 280 pps, filtered into a HIGH (3365–4755 Hz) or VHIGH (7800–10,800 Hz) region, alternating with a 36% higher pulse rate. Brainstem and cortical processing were measured using the frequency following response (FFR) and auditory change complex (ACC), respectively. Behavioural rate change difference limens (DLs) were measured by requiring participants to discriminate between a stimulus that changed rate twice (up-down or down-up) during its 750-ms presentation from a constant-rate pulse train. FFRs revealed robust brainstem phase locking whose amplitude decreased with increasing rate. Moderate-sized but reliable ACCs were obtained in response to changes in purely temporal pitch and, like the psychophysical DLs, did not depend consistently on the direction of rate change or on the pulse rate for baseline rates between 94 and 280 pps. ACCs were larger and DLs lower for stimuli in the HIGH than in the VHGH region. We argue that the ACC may be a useful surrogate for behavioural measures of rate discrimination, both for normal-hearing listeners and for cochlear-implant users. We also showed that rate DLs increased markedly when the baseline rate was reduced to 48 pps, and compared the behavioural and electrophysiological findings to recent cat data obtained with similar stimuli and methods.

CHARGE syndrome is a multiple anomaly developmental disorder characterized by a variety of sensory deficits, including sensorineural hearing loss of unknown etiology. Most cases of CHARGE are caused by heterozygous pathogenic variants in CHD7, the gene encoding Chromodomain DNA-binding Protein 7 (CHD7), a chromatin remodeler important for the development of neurons and glial cells. Previous studies in the Chd7Gt/+ mouse model of CHARGE syndrome showed substantial neuron loss in the early stages of the developing inner ear that are compensated for by mid-gestation. In this study, we sought to determine if early developmental delays caused by Chd7 haploinsufficiency affect neurons, glial cells, and inner hair cell innervation in the mature cochlea. Analysis of auditory brainstem response recordings in Chd7Gt/+ adult animals showed elevated thresholds at 4 kHz and 16 kHz, but no differences in ABR Wave I peak latency or amplitude compared to wild type controls. Proportions of neurons in the Chd7Gt/+ adult spiral ganglion and densities of nerve projections from the spiral ganglion to the organ of Corti were not significantly different from wild type controls. Inner hair cell synapse formation also appeared unaffected in mature Chd7Gt/+ cochleae. However, histological analysis of adult Chd7Gt/+ cochleae revealed diminished satellite glial cells and hypermyelinated Type I spiral ganglion axons. We characterized the expression of CHD7 in developing inner ear glia and found CHD7 to be expressed during a tight window of inner ear development at the Schwann cell precursor stage at E9.5. While cochlear neurons appear to differentiate normally in the setting of Chd7 haploinsufficiency, our results suggest an important role for CHD7 in glial cells in the inner ear. This study highlights the dynamic nature of CHD7 activity during inner ear development in mice and contributes to understanding CHARGE syndrome pathology.

The human brain networks responsible for selectively listening to a voice amid other talkers remain to be clarified. The present study aimed to investigate relationships between cortical activity and performance in a speech-in-speech task, before (Experiment I) and after training-induced improvements (Experiment II). In Experiment I, 74 participants performed a speech-in-speech task while their cortical activity was measured using a functional near infrared spectroscopy (fNIRS) device. One target talker and one masker talker were simultaneously presented at three different target-to-masker ratios (TMRs): adverse, intermediate and favorable. Behavioral results show that performance may increase monotonically with TMR in some participants and failed to decrease, or even improved, in the adverse-TMR condition for others. On the neural level, an extensive brain network including the frontal (left prefrontal cortex, right dorsolateral prefrontal cortex and bilateral inferior frontal gyri) and temporal (bilateral auditory cortex) regions was more solicited by the intermediate condition than the two others. Additionally, bilateral frontal gyri and left auditory cortex activities were found to be positively correlated with behavioral performance in the adverse-TMR condition. In Experiment II, 27 participants, whose performance was the poorest in the adverse-TMR condition of Experiment I, were trained to improve performance in that condition. Results show significant performance improvements along with decreased activity in bilateral inferior frontal gyri, the right dorsolateral prefrontal cortex, the left inferior parietal cortex and the right auditory cortex in the adverse-TMR condition after training. Arguably, lower neural activity reflects higher efficiency in processing masker inhibition after speech-in-speech training. As speech-in-noise tasks also imply frontal and temporal regions, we suggest that regardless of the type of masking (speech or noise) the complexity of the task will prompt the implication of a similar brain network. Furthermore, the initial significant cognitive recruitment will be reduced following a training leading to an economy of cognitive resources.

Sound stimulation is generally used for tinnitus and hyperacusis treatment. Recent studies found that long-term noise exposure can change synaptic and firing properties in the central auditory system, which will be detected by the acoustic startle reflex. However, the perceptual consequences of long-term low-intensity sound exposure are indistinct. This study will detect the effects of moderate-level noise exposure (83 dB SPL) on auditory loudness, and temporal processing was evaluated using CBA/CaJ mice. C-Fos staining was used to detect neural activity changes in the central auditory pathway. With two weeks of 83 dB SPL noise exposure (8 hours per day), no persistent threshold shift of the auditory brainstem response (ABR) was identified. On the other hand, noise exposure enhanced the acoustic startle response (ASR) and gap-induced prepulse inhibition significantly (gap-PPI). Low-level noise exposure, according to the findings, can alter temporal acuity. Noise exposure increased the number of c-Fos labeled neurons in the dorsal cochlear nucleus (DCN) and caudal pontine reticular nucleus (PnC) but not at a higher level in the central auditory nuclei. Our results suggested that noise stimulation can change acoustical temporal processing presumably by increasing the excitability of auditory brainstem neurons.

From myriads of ongoing stimuli, the brain creates a fused percept of the environment. This process, which culminates in perceptual binding, is presumed to occur through the operations of multisensory neurons that occur throughout the brain. However, because different brain areas receive different inputs and have different cytoarchitechtonics, it would be expected that local multisensory features would also vary across regions. The present study investigated that hypothesis using multiple single-unit recordings from anesthetized cats in response to controlled, electronically-generated separate and combined auditory, visual, and somatosensory stimulation. These results were used to compare the multisensory features of neurons in cat primary auditory cortex (A1) with those identified in the nearby higher-order auditory region, the Dorsal Zone (DZ). Both regions exhibited the same forms of multisensory neurons, albeit in different proportions. Multisensory neurons exhibiting excitatory or inhibitory properties occurred in similar proportions in both areas. Also, multisensory neurons in both areas expressed similar levels of multisensory integration. Because responses to auditory cues alone were so similar to those that included non-auditory stimuli, it is proposed that this effect represents a mechanism by which multisensory neurons subserve the process of perceptual binding.

The study aimed to investigate the potential role of lysine-specific demethylase 5A (KDM5A) in cisplatin-induced ototoxicity. The effect of the KDM5A inhibitor CPI-455 was assessed by apoptosis assay, immunofluorescence, flow cytometry, seahorse respirometry assay, and auditory brainstem response test. RNA sequencing, qRT-PCR, and CUT&Tag assays were used to explore the mechanism underlying CPI-455-induced protection. Our results demonstrated that the expression of KDM5A was increased in cisplatin-injured cochlear hair cells compared with controls. CPI-455 treatment markedly declined KDM5A and elevated H3K4 trimethylation levels in cisplatin-injured cochlear hair cells. Moreover, CPI-455 effectively prevented the death of hair cells and spiral ganglion neurons and increased the number of ribbon synapses in a cisplatin-induced ototoxicity mouse model both in vitro and in vivo. In HEI-OC1 cells, KDM5A knockdown reduced reactive oxygen species accumulation and improved mitochondrial membrane potential and oxidative phosphorylation under cisplatin-induced stress. Mechanistically, through transcriptomics and epigenomics analyses, a set of apoptosis-related genes, including Sos1 , Sos2 , and Map3k3 , were regulated by CPI-455. Altogether, our findings indicate that inhibition of KDM5A may represent an effective epigenetic therapeutic target for preventing cisplatin-induced hearing loss.

To date, the effect of resveratrol on tinnitus has not been reported. The attenuative effects of resveratrol (RSV) on a salicylate-induced tinnitus model were evaluated by in vitro and in vivo experiments. The gene expression of the activity-regulated cytoskeleton-associated protein (ARC), tumor necrosis factor-alpha (TNFα), and NMDA receptor subunit 2B (NR2B) in SH-SY5Y cells was examined using qPCR. Phosphorylated cAMP response element-binding protein (p-CREB), apoptosis markers, and reactive oxygen species (ROS) were evaluated by in vitro experiments. The in vivo experiment evaluated the gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and auditory brainstem response (ABR) level. The NR2B expression in the auditory cortex (AC) was determined by immunohistochemistry. RSV significantly reduced the salicylate-induced expression of NR2B, ARC, and TNFα in neuronal cells; the GPIAS and ABR thresholds altered by salicylate in rats were recovered close to their normal range. RSV also reduced the salicylate-induced NR2B overexpression of the AC. These results confirmed that resveratrol exerted an attenuative effect on salicylate-induced tinnitus and may have a therapeutic potential.

Animal communication sounds exhibit complex temporal structure because of the amplitude fluctuations that comprise the sound envelope. In human speech, envelope modulations drive synchronized activity in auditory cortex (AC), which correlates strongly with comprehension (Giraud and Poeppel, 2012; Peelle and Davis, 2012; Haegens and Zion Golumbic, 2018). Studies of envelope coding in single neurons, performed in nonhuman animals, have focused on periodic amplitude modulation (AM) stimuli and use response metrics that are not easy to juxtapose with data from humans. In this study, we sought to bridge these fields. Specifically, we looked directly at the temporal relationship between stimulus envelope and spiking, and we assessed whether the apparent diversity across neurons' AM responses contributes to the population representation of speech-like sound envelopes. We gathered responses from single neurons to vocoded speech stimuli and compared them to sinusoidal AM responses in auditory cortex (AC) of alert, freely moving Mongolian gerbils of both sexes. While AC neurons displayed heterogeneous tuning to AM rate, their temporal dynamics were stereotyped. Preferred response phases accumulated near the onsets of sinusoidal AM periods for slower rates (<8 Hz), and an over-representation of amplitude edges was apparent in population responses to both sinusoidal AM and vocoded speech envelopes. Crucially, this encoding bias imparted a decoding benefit: a classifier could discriminate vocoded speech stimuli using summed population activity, while higher frequency modulations required a more sophisticated decoder that tracked spiking responses from individual cells. Together, our results imply that the envelope structure relevant to parsing an acoustic stream could be read-out from a distributed, redundant population code. SIGNIFICANCE STATEMENT Animal communication sounds have rich temporal structure and are often produced in extended sequences, including the syllabic structure of human speech. Although the auditory cortex (AC) is known to play a crucial role in representing speech syllables, the contribution of individual neurons remains uncertain. Here, we characterized the representations of both simple, amplitude-modulated sounds and complex, speech-like stimuli within a broad population of cortical neurons, and we found an overrepresentation of amplitude edges. Thus, a phasic, redundant code in auditory cortex can provide a mechanistic explanation for segmenting acoustic streams like human speech.

An increasing level of anthropogenic underwater noise (shipping, drilling, sonar use, etc .) impairs acoustic orientation and communication in fish by hindering signal transmission or detection. Different noise regimes can reduce the ability to detect sounds of conspecifics due to an upward shift of the hearing threshold, a phenomenon termed masking. We therefore investigated the masking effect of white noise on the auditory thresholds in female croaking gouramis ( Trichopsis vittata , Osphronemidae). We hypothesized that noise would influence the detection of conspecific vocalizations and thus acoustic communication. The auditory evoked potentials (AEP) thresholds were measured at six different frequencies between 0.1 and 4 kHz using the AEP recording technique. Sound pressure level audiograms were determined under quiet laboratory conditions (no noise) and continuous white noise of 110 dB RMS. Thresholds increased in the presence of white noise at all tested frequencies by 12–18 dB, in particular at 1.5 kHz. Moreover, hearing curves were compared to spectra of conspecific sounds to assess sound detection in the presence of noise in various contexts. We showed that masking hinders the detection of conspecific sounds, which have main energies between 1.0 and 1.5 kHz. We predict that this will particularly affect hearing of female’s low-intensity purring sounds during mating. Accordingly, noise will negatively affect acoustic communication and most likely reproductive success.

Specialized sound localization circuit development requires synapse strengthening, refinement, and pruning. Many of these functions are carried out by microglia, immune cells that aid in regulating neurogenesis, synaptogenesis, apoptosis, and synaptic removal. We previously showed that postnatal treatment with BLZ945 (BLZ), an inhibitor of colony stimulating factor 1 receptor (CSF1R), eliminates microglia in the brainstem and disables calyceal pruning and maturation of astrocytes in the medial nucleus of the trapezoid body (MNTB). BLZ treatment results in elevated hearing thresholds and delayed signal propagation as measured by auditory brainstem responses (ABR). However, when microglia repopulate the brain following the cessation of BLZ, most of the deficits are repaired. It is unknown whether this recovery is achievable without the return of microglia. Here, we induced sustained microglial elimination with a two-drug approach using BLZ and PLX5622 (PLX). We found that BLZ/PLX treated mice had impaired calyceal pruning, diminished astrocytic GFAP in the lateral, low frequency, region of MNTB, and elevated glycine transporter 2 (GLYT2) levels. BLZ/PLX treated mice had elevated hearing thresholds, diminished peak amplitudes, and altered latencies and inter-peak latencies. These findings suggest that microglia are required to repopulate the brain in order to rectify deficits from their ablation.

Intrinsically generated neural activity propagates through the developing auditory system to promote maturation and refinement of sound processing circuits prior to hearing onset. This early patterned activity is induced by non-sensory supporting cells in the organ of Corti, which are highly interconnected through gap junctions containing connexin 26 ( Gjb2 ). Although loss of function mutations in Gjb2 impair cochlear development and are the most common cause of congenital deafness, it is not known if these mutations disrupt spontaneous activity and the developmental trajectory of sound processing circuits in the brain. Here, we show in a new mouse model of Gjb2- mediated congenital deafness that cochlear supporting cells unexpectedly retained intercellular coupling and the capacity to generate spontaneous activity, exhibiting only modest deficits prior to hearing onset. This coordinated activation of IHCs led to coincident bursts of activity in central auditory neurons that will later process similar frequencies of sound. Despite alterations in the structure of the sensory epithelium, hair cells within the cochlea of Gjb2 deficient mice were intact and central auditory neurons could be activated within appropriate tonotopic domains by loud sounds at hearing onset, indicating that early maturation and refinement of auditory circuits was preserved. Only after cessation of spontaneous activity following hearing onset did progressive hair cell degeneration and enhanced auditory neuron excitability manifest. This preservation of cochlear spontaneous activity in the absence of connexin 26 may increase the effectiveness of early therapeutic interventions to restore hearing.

Neurons that process sensory information exhibit bursts of electrical activity during development, providing early training to circuits that will later encode similar features of the external world. In the mammalian auditory system, this intrinsically generated activity emerges from the cochlea prior to hearing onset, but its role in maturation of auditory circuitry remains poorly understood. We show that selective suppression of cochlear supporting cell spontaneous activity disrupts patterned burst firing of central auditory neurons without affecting cell survival or acoustic thresholds. However, neurons in the inferior colliculus of these mice exhibit enhanced acoustic sensitivity and broader frequency tuning, resulting in wider isofrequency laminae. Despite this enhanced neural responsiveness, total tone-responsive regions in the auditory cortex are substantially smaller. Thus, disruption of pre-hearing cochlear activity causes profound changes in neural encoding of sound, with important implications for restoration of hearing in individuals who experience reduced activity during this critical developmental period.

Many of the sensations experienced by an organism are caused by their own actions, and accurately anticipating both the sensory features and timing of self-generated stimuli is crucial to a variety of behaviors. In the auditory cortex, neural responses to self-generated sounds exhibit frequency-specific suppression, suggesting that movement-based predictions may be implemented early in sensory processing. However, it remains unknown whether this modulation results from a behaviorally specific and temporally precise prediction, nor is it known whether corresponding expectation signals are present locally in the auditory cortex. To address these questions, we trained mice to expect the precise acoustic outcome of a forelimb movement using a closed-loop sound-generating lever. Dense neuronal recordings in the auditory cortex revealed suppression of responses to self-generated sounds that was specific to the expected acoustic features, to a precise position within the movement, and to the movement that was coupled to sound during training. Prediction-based suppression was concentrated in L2/3 and L5, where deviations from expectation also recruited a population of prediction-error neurons that was otherwise unresponsive. Recording in the absence of sound revealed abundant movement signals in deep layers that were biased toward neurons tuned to the expected sound, as well as expectation signals that were present throughout the cortex and peaked at the time of expected auditory feedback. Together, these findings identify distinct populations of auditory cortical neurons with movement, expectation, and error signals consistent with a learned internal model linking an action to its specific acoustic outcome.

Experimental evidence in animals demonstrates cortical neurons innervate subcortex bilaterally to tune brainstem auditory coding. Yet, the role of the descending (corticofugal) auditory system in modulating earlier sound processing in humans during speech perception remains unclear. Here, we measured EEG activity as listeners performed speech identification tasks in different noise backgrounds designed to tax perceptual and attentional processing. We hypothesized brainstem speech coding might be tied to attention and arousal states (indexed by cortical α power) that actively modulate the interplay of brainstem-cortical signal processing. When speech-evoked brainstem frequency-following responses (FFRs) were categorized according to cortical α states, we found low α FFRs in noise were weaker, correlated positively with behavioral response times, and were more "decodable" via neural classifiers. Our data provide new evidence for online corticofugal interplay in humans and establish that brainstem sensory representations are continuously yoked to (i.e., modulated by) the ebb and flow of cortical states to dynamically update perceptual processing.

Neurexins are presynaptic transmembrane proteins crucial for synapse development and organization. Deletion and missense mutations in all three Neurexin genes have been identified in psychiatric disorders, with mutations in the NRXN1 gene most strongly linked to schizophrenia (SZ) and autism spectrum disorder (ASD). While the consequences of NRXN1 deletion have been extensively studied on the synaptic and behavioral levels, circuit endophenotypes that translate to the human condition have not been characterized yet. Therefore, we investigated the electrophysiology of cortico-striatal-thalamic circuits in Nrxn1α −/− rats and wildtype littermates focusing on a set of translational readouts, including spontaneous oscillatory activity, auditory-evoked oscillations and potentials, as well as mismatch negativity-like (MMN) responses and responses to social stimuli. On the behavioral level Nrxn1α −/− rats showed locomotor hyperactivity. In vivo freely moving electrophysiology revealed pronounced increases of spontaneous oscillatory power within the gamma band in all studied brain areas and elevation of gamma coherence in cortico-striatal and thalamocortical circuits of Nrxn1α −/− rats. In contrast, auditory-evoked oscillations driven by chirp-modulated tones showed reduced power in cortical areas confined to slower oscillations. Finally, Nrxn1α −/− rats exhibited altered auditory evoked-potentials and profound deficits in MMN-like responses, explained by reduced prediction error. Despite deficits for auditory stimuli, responses to social stimuli appeared intact. A central hypothesis for psychiatric and neurodevelopmental disorders is that a disbalance of excitation-to-inhibition is underlying oscillatory and sensory deficits. In a first attempt to explore the impact of inhibitory circuit modulation, we assessed the effects of enhancing tonic inhibition via δ-containing GABA A receptors (using Gaboxadol) on endophenotypes possibly associated with network hyperexcitability. Pharmacological experiments applying Gaboxadol showed genotype-specific differences, but failed to normalize oscillatory or sensory processing abnormalities. In conclusion, our study revealed endophenotypes in Nrxn1α −/− rats that could be used as translational biomarkers for drug development in psychiatric disorders.

Age-related hearing loss (presbycusis) affects one-third of the world's population. One hallmark of presbycusis is difficulty hearing in noisy environments. Presbycusis can be separated into two components: the aging ear and the aging brain. To date, the role of the aging brain in presbycusis is not well understood. Activity in the primary auditory cortex (A1) during a behavioral task is because of a combination of responses representing the acoustic stimuli, attentional gain, and behavioral choice. Disruptions in any of these aspects can lead to decreased auditory processing. To investigate how these distinct components are disrupted in aging, we performed in vivo 2-photon Ca 2+ imaging in both male and female mice ( Thy1-GCaMP6s × CBA/CaJ mice) that retain peripheral hearing into old age. We imaged A1 neurons of young adult (2-6 months) and old mice (16-24 months) during a tone detection task in broadband noise. While young mice performed well, old mice performed worse at low signal-to-noise ratios. Calcium imaging showed that old animals have increased prestimulus activity, reduced attentional gain, and increased noise correlations. Increased correlations in old animals exist regardless of cell tuning and behavioral outcome, and these correlated networks exist over a much larger portion of cortical space. Neural decoding techniques suggest that this prestimulus activity is predictive of old animals making early responses. Together, our results suggest a model in which old animals have higher and more correlated prestimulus activity and cannot fully suppress this activity, leading to the decreased representation of targets among distracting stimuli. SIGNIFICANCE STATEMENT Aging inhibits the ability to hear clearly in noisy environments. We show that the aging auditory cortex is unable to fully suppress its responses to background noise. During an auditory behavior, fewer neurons were suppressed in the old relative to young animals, which leads to higher prestimulus activity and more false alarms. We show that this excess activity additionally leads to increased correlations between neurons, reducing the amount of relevant stimulus information in the auditory cortex. Future work identifying the lost circuits that are responsible for proper background suppression could provide new targets for therapeutic strategies to preserve auditory processing ability into old age.

The pattern of ups and downs in a sequence with varying pitch can be heard as a melodic contour. Contrary to single pitch, the neural representation of melodic contour information in the auditory cortex is rarely investigated, and it is not clear whether the processing entails a hemispheric asymmetry. The present magnetoencephalography study assessed the neuromagnetic responses of N = 18 normal-hearing adults to four-note sequences with fixed vs. varying pitch that were presented either monaurally or diotically; data were analyzed using minimum-norm reconstructions. The first note of the sequences elicited prominent transient activity in posterior auditory regions (Planum temporale), especially contralateral to the ear of entry. In contrast, the response to the subsequent notes originated from more anterior areas (Planum polare) and was larger for melodic contours than for fixed pitch sequences, independent from the ear of entry and without hemispheric asymmetry. Together, the results point to a gradient in the early cortical processing of melodic contours, both in spatial and functional terms, where posterior auditory activity reflects the onset of a pitch sequence and anterior activity reflects its subsequent notes, including the difference between sequences with fixed pitch and melodic contours.

Octopus cells are remarkable projection neurons of the mammalian cochlear nucleus, with extremely fast membranes and wide-frequency tuning. They are considered prime examples of coincidence detectors but are poorly characterized in vivo. We discover that octopus cells are selective to frequency sweep direction, a feature that is absent in their auditory nerve inputs. In vivo intracellular recordings reveal that direction selectivity does not derive from across-frequency coincidence detection but hinges on the amplitudes and activation sequence of auditory nerve inputs tuned to clusters of hot spot frequencies. A simple biophysical octopus cell model excited with real nerve spike trains recreates direction selectivity through interaction of intrinsic membrane conductances with the activation sequence of clustered excitatory inputs. We conclude that octopus cells are sequence detectors, sensitive to temporal patterns across cochlear frequency channels. The detection of sequences rather than coincidences is a much simpler but powerful operation to extract temporal information.

Brain asymmetry in the sensitivity to spectrotemporal modulation is an established functional feature that underlies the perception of speech and music. The left auditory cortex (ACx) is believed to specialize in processing fast temporal components of speech sounds, and the right ACx slower components. However, the circuit features and neural computations behind these lateralized spectrotemporal processes are poorly understood. To answer these mechanistic questions we use mice, an animal model that captures some relevant features of human communication systems. In this study, we screened for circuit features that could subserve temporal integration differences between the left and right ACx. We mapped excitatory input to principal neurons in all cortical layers and found significantly stronger recurrent connections in the superficial layers of the right ACx compared to the left. We hypothesized that the underlying recurrent neural dynamics would exhibit differential characteristic timescales corresponding to their hemispheric specialization. To investigate, we recorded spike trains from awake mice and estimated the network time constants using a statistical method to combine evidence from multiple weak signal-to-noise ratio neurons. We found longer temporal integration windows in the superficial layers of the right ACx compared to the left as predicted by stronger recurrent excitation. Our study shows substantial evidence linking stronger recurrent synaptic connections to longer network timescales. These findings support speech processing theories that purport asymmetry in temporal integration is a crucial feature of lateralization in auditory processing.

The lateral superior olive (LSO) is a key structure in the central auditory system of mammals that exerts efferent control on cochlear sensitivity and is involved in the processing of binaural level differences for sound localization. Understanding how the LSO contributes to these processes requires knowledge about the resident cells and their connections with other auditory structures. We used standard histological stains and retrograde tracer injections into the inferior colliculus (IC) and cochlea in order to characterize two basic groups of neurons: (1) Principal and periolivary (PO) neurons have projections to the IC as part of the ascending auditory pathway; and (2) lateral olivocochlear (LOC) intrinsic and shell efferents have descending projections to the cochlea. Principal and intrinsic neurons are intermixed within the LSO, exhibit fusiform somata, and have disk-shaped dendritic arborizations. The principal neurons have bilateral, symmetric, and tonotopic projections to the IC. The intrinsic efferents have strictly ipsilateral projections, known to be tonotopic from previous publications. PO and shell neurons represent much smaller populations (<10% of principal and intrinsic neurons, respectively), have multipolar somata, reside outside the LSO, and have non-topographic, bilateral projections. PO and shell neurons appear to have widespread projections to their targets that imply a more diffuse modulatory function. The somata and dendrites of principal and intrinsic neurons form a laminar matrix within the LSO and share quantifiably similar alignment to the tonotopic axis. Their restricted projections emphasize the importance of frequency in binaural processing and efferent control for auditory perception. This study addressed and expanded on previous findings of cell types, circuit laterality, and projection tonotopy in the LSO of the mouse.