Alpha9alpha10 knockout mice show altered physiological and behavioral responses to signals in masking noise.

Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (α9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (α9α10KOs) may exhibit more severe MOC-related phenotypes. Like α9KOs, α9α10KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in α9α10KO mice. Wild-type (WT) and α9α10KO mice had similar ABR thresholds and acoustic startle response amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. α9α10KO mice had larger ABR Wave I amplitudes than WTs in quiet and noise. Other ABR metrics of hearing-in-noise function yielded conflicting findings regarding α9α10KO susceptibility to masking effects. α9α10KO mice also had larger startle amplitudes in tone backgrounds than WTs. Overall, α9α10KO mice had grossly normal auditory function in quiet and noise, although their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.

Neurometric amplitude modulation detection in the inferior colliculus of Young and Aged rats.

Amplitude modulation is an important acoustic cue for sound discrimination, and humans and animals are able to detect small modulation depths behaviorally. In the inferior colliculus (IC), both firing rate and phase-locking may be used to detect amplitude modulation. How neural representations that detect modulation change with age are poorly understood, including the extent to which age-related changes may be attributed to the inherited properties of ascending inputs to IC neurons. Here, simultaneous measures of local field potentials (LFPs) and single-unit responses were made from the inferior colliculus of Young and Aged rats using both noise and tone carriers in response to sinusoidally amplitude-modulated sounds of varying depths. We found that Young units had higher firing rates than Aged for noise carriers, whereas Aged units had higher phase-locking (vector strength), especially for tone carriers. Sustained LFPs were larger in Young animals for modulation frequencies 8-16 Hz and comparable at higher modulation frequencies. Onset LFP amplitudes were much larger in Young animals and were correlated with the evoked firing rates, while LFP onset latencies were shorter in Aged animals. Unit neurometric thresholds by synchrony or firing rate measures did not differ significantly across age and were comparable to behavioral thresholds in previous studies whereas LFP thresholds were lower than behavior.

Aging effects on the neural representation and perception of consonant transition cues.

Older listeners have difficulty processing temporal cues that are important for word discrimination, and deficient processing may limit their ability to benefit from these cues. Here, we investigated aging effects on perception and neural representation of the consonant transition and the factors that contribute to successful perception. To further understand the neural mechanisms underlying the changes in processing from brainstem to cortex, we also examined the factors that contribute to exaggerated amplitudes in cortex. We enrolled 30 younger normal-hearing and 30 older normal-hearing participants who met the criteria of clinically normal hearing. Perceptual identification functions were obtained for the words BEAT and WHEAT on a 7-step continuum of consonant-transition duration. Auditory brainstem responses (ABRs) were recorded to click stimuli and frequency-following responses (FFRs) and cortical auditory-evoked potentials were recorded to the endpoints of the BEAT-WHEAT continuum. Perceptual performance for identification of BEAT vs. WHEAT did not differ between younger and older listeners. However, both subcortical and cortical measures of neural representation showed age group differences, such that FFR phase locking was lower but cortical amplitudes (P1 and N1) were higher in older compared to younger listeners. ABR Wave I amplitude and FFR phase locking, but not audiometric thresholds, predicted early cortical amplitudes. Phase locking to the transition region and early cortical peak amplitudes (P1) predicted performance on the perceptual identification function. Overall, results suggest that the neural representation of transition durations and cortical overcompensation may contribute to the ability to perceive transition duration contrasts. Cortical overcompensation appears to be a maladaptive response to decreased neural firing/synchrony.

Basic Properties of Coordinated Neuronal Ensembles in the Auditory Thalamus.

Coordinated neuronal activity has been identified to play an important role in information processing and transmission in the brain. However, current research predominantly focuses on understanding the properties and functions of neuronal coordination in hippocampal and cortical areas, leaving subcortical regions relatively unexplored. In this study, we use single-unit recordings in female Sprague Dawley rats to investigate the properties and functions of groups of neurons exhibiting coordinated activity in the auditory thalamus-the medial geniculate body (MGB). We reliably identify coordinated neuronal ensembles (cNEs), which are groups of neurons that fire synchronously, in the MGB. cNEs are shown not to be the result of false-positive detections or by-products of slow-state oscillations in anesthetized animals. We demonstrate that cNEs in the MGB have enhanced information-encoding properties over individual neurons. Their neuronal composition is stable between spontaneous and evoked activity, suggesting limited stimulus-induced ensemble dynamics. These MGB cNE properties are similar to what is observed in cNEs in the primary auditory cortex (A1), suggesting that ensembles serve as a ubiquitous mechanism for organizing local networks and play a fundamental role in sensory processing within the brain.

Motor, somatosensory, and executive cortical areas elicit monosynaptic and polysynaptic neuronal activity in the auditory midbrain.

We recently reported that the central nucleus of the inferior colliculus (the auditory midbrain) is innervated by glutamatergic pyramidal cells originating not only in auditory cortex (AC), but also in multiple 'non-auditory' regions of the cerebral cortex. Here, in anaesthetised rats, we used optogenetics and electrical stimulation, combined with recording in the inferior colliculus to determine the functional influence of these descending connections. Specifically, we determined the extent of monosynaptic excitation and the influence of these descending connections on spontaneous activity in the inferior colliculus. A retrograde virus encoding both green fluorescent protein (GFP) and channelrhodopsin (ChR2) injected into the central nucleus of the inferior colliculus (ICc) resulted in GFP expression in discrete groups of cells in multiple areas of the cerebral cortex. Light stimulation of AC and primary motor cortex (M1) caused local activation of cortical neurones and increased the firing rate of neurones in ICc indicating a direct excitatory input from AC and M1 to ICc with a restricted distribution. In naïve animals, electrical stimulation at multiple different sites within M1, secondary motor, somatosensory, and prefrontal cortices increased firing rate in ICc. However, it was notable that stimulation at some adjacent sites failed to influence firing at the recording site in ICc. Responses in ICc comprised singular spikes of constant shape and size which occurred with a short, and fixed latency (∼ 5 ms) consistent with monosynaptic excitation of individual ICc units. Increasing the stimulus current decreased the latency of these spikes, suggesting more rapid depolarization of cortical neurones, and increased the number of (usually adjacent) channels on which a monosynaptic spike was seen, suggesting recruitment of increasing numbers of cortical neurons. Electrical stimulation of cortical regions also evoked longer latency, longer duration increases in firing activity, comprising multiple units with spikes occurring with significant temporal jitter, consistent with polysynaptic excitation. Increasing the stimulus current increased the number of spikes in these polysynaptic responses and increased the number of channels on which the responses were observed, although the magnitude of the responses always diminished away from the most activated channels. Together our findings indicate descending connections from motor, somatosensory and executive cortical regions directly activate small numbers of ICc neurones and that this in turn leads to extensive polysynaptic activation of local circuits within the ICc.

Auditory Competition and Coding of Relative Stimulus Strength across Midbrain Space Maps of Barn Owls.

The natural environment challenges the brain to prioritize the processing of salient stimuli. The barn owl, a sound localization specialist, exhibits a circuit called the midbrain stimulus selection network, dedicated to representing locations of the most salient stimulus in circumstances of concurrent stimuli. Previous competition studies using unimodal (visual) and bimodal (visual and auditory) stimuli have shown that relative strength is encoded in spike response rates. However, open questions remain concerning auditory-auditory competition on coding. To this end, we present diverse auditory competitors (concurrent flat noise and amplitude-modulated noise) and record neural responses of awake barn owls of both sexes in subsequent midbrain space maps, the external nucleus of the inferior colliculus (ICx) and optic tectum (OT). While both ICx and OT exhibit a topographic map of auditory space, OT also integrates visual input and is part of the global-inhibitory midbrain stimulus selection network. Through comparative investigation of these regions, we show that while increasing strength of a competitor sound decreases spike response rates of spatially distant neurons in both regions, relative strength determines spike train synchrony of nearby units only in the OT. Furthermore, changes in synchrony by sound competition in the OT are correlated to gamma range oscillations of local field potentials associated with input from the midbrain stimulus selection network. The results of this investigation suggest that modulations in spiking synchrony between units by gamma oscillations are an emergent coding scheme representing relative strength of concurrent stimuli, which may have relevant implications for downstream readout.

Two Prediction Error Systems in the Nonlemniscal Inferior Colliculus: "Spectral" and "Nonspectral".

According to the predictive processing framework, perception emerges from the reciprocal exchange of predictions and prediction errors (PEs) between hierarchically organized neural circuits. The nonlemniscal division of the inferior colliculus (IC) is the earliest source of auditory PE signals, but their neuronal generators, properties, and functional relevance have remained mostly undefined. We recorded single-unit mismatch responses to auditory oddball stimulation at different intensities, together with activity evoked by two sequences of alternating tones to control frequency-specific effects. Our results reveal a differential treatment of the unpredictable "many-standards" control and the predictable "cascade" control by lemniscal and nonlemniscal IC neurons that is not present in the auditory thalamus or cortex. Furthermore, we found that frequency response areas of nonlemniscal IC neurons reflect their role in subcortical predictive processing, distinguishing three hierarchical levels: (1) nonlemniscal neurons with sharply tuned receptive fields exhibit mild repetition suppression without signaling PEs, thereby constituting the input level of the local predictive processing circuitry. (2) Neurons with broadly tuned receptive fields form the main, "spectral" PE signaling system, which provides dynamic gain compensation to near-threshold unexpected sounds. This early enhancement of saliency reliant on spectral features was not observed in the auditory thalamus or cortex. (3) Untuned neurons form an accessory, "nonspectral" PE signaling system, which reports all surprising auditory deviances in a robust and consistent manner, resembling nonlemniscal neurons in the auditory cortex. These nonlemniscal IC neurons show unstructured and unstable receptive fields that could result from inhibitory input controlled by corticofugal projections conveying top-down predictions.

Mouse auditory cortex sub-fields receive neuronal projections from MGB subdivisions independently.

Mouse auditory cortex is composed of six sub-fields: primary auditory field (AI), secondary auditory field (AII), anterior auditory field (AAF), insular auditory field (IAF), ultrasonic field (UF) and dorsoposterior field (DP). Previous studies have examined thalamo-cortical connections in the mice auditory system and learned that AI, AAF, and IAF receive inputs from the ventral division of the medial geniculate body (MGB). However, the functional and thalamo-cortical connections between nonprimary auditory cortex (AII, UF, and DP) is unclear. In this study, we examined the locations of neurons projecting to these three cortical sub-fields in the MGB, and addressed the question whether these cortical sub-fields receive inputs from different subsets of MGB neurons or common. To examine the distributions of projecting neurons in the MGB, retrograde tracers were injected into the AII, UF, DP, after identifying these areas by the method of Optical Imaging. Our results indicated that neuron cells which in ventral part of dorsal MGB (MGd) and that of ventral MGB (MGv) projecting to UF and AII with less overlap. And DP only received neuron projecting from MGd. Interestingly, these three cortical areas received input from distinct part of MGd and MGv in an independent manner. Based on our foundings these three auditory cortical sub-fields in mice may independently process auditory information.

Acute Aromatase Inhibition Impairs Neural and Behavioral Auditory Scene Analysis in Zebra Finches.

Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium, NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recorded in vivo awake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly in females. Behaviorally, we trained birds using operant conditioning and tested their ability to detect songs in scenes after administering FAD orally or injected bilaterally into NCM. Oral FAD increased response bias and decreased correct rejections in females, but not in males. FAD in NCM did not affect performance. Thus, FAD in the NCM impaired neuronal ASA but that did not lead to behavioral disruption suggesting the existence of resilience or compensatory responses. Moreover, impaired performance after systemic FAD suggests involvement of other aromatase-rich networks outside the auditory pathway in ASA. This work highlights how transient estrogen synthesis disruption can modulate higher-order processing in an animal model of vocal communication.

Parvalbumin and Somatostatin: Biomarkers for Two Parallel Tectothalamic Pathways in the Auditory Midbrain.

The inferior colliculus (IC) represents a crucial relay station in the auditory pathway, located in the midbrain's tectum and primarily projecting to the thalamus. Despite the identification of distinct cell classes based on various biomarkers in the IC, their specific contributions to the organization of auditory tectothalamic pathways have remained poorly understood. In this study, we demonstrate that IC neurons expressing parvalbumin (ICPV+) or somatostatin (ICSOM+) represent two minimally overlapping cell classes throughout the three IC subdivisions in mice of both sexes. Strikingly, regardless of their location within the IC, these neurons predominantly project to the primary and secondary auditory thalamic nuclei, respectively. Cell class-specific input tracing suggested that ICPV+ neurons primarily receive auditory inputs, whereas ICSOM+ neurons receive significantly more inputs from the periaqueductal gray and the superior colliculus (SC), which are sensorimotor regions critically involved in innate behaviors. Furthermore, ICPV+ neurons exhibit significant heterogeneity in both intrinsic electrophysiological properties and presynaptic terminal size compared with ICSOM+ neurons. Notably, approximately one-quarter of ICPV+ neurons are inhibitory neurons, whereas all ICSOM+ neurons are excitatory neurons. Collectively, our findings suggest that parvalbumin and somatostatin expression in the IC can serve as biomarkers for two functionally distinct, parallel tectothalamic pathways. This discovery suggests an alternative way to define tectothalamic pathways and highlights the potential usefulness of Cre mice in understanding the multifaceted roles of the IC at the circuit level.

A Developmental Switch in Cholinergic Mechanisms of Modulation in the Medial Nucleus of the Trapezoid Body.

The medial nucleus of the trapezoid body (MNTB) has been intensively investigated as a primary source of inhibition in brainstem auditory circuitry. MNTB-derived inhibition plays a critical role in the computation of sound location, as temporal features of sounds are precisely conveyed through the calyx of Held/MNTB synapse. In adult gerbils, cholinergic signaling influences sound-evoked responses of MNTB neurons via nicotinic acetylcholine receptors (nAChRs; Zhang et al., 2021) establishing a modulatory role for cholinergic input to this nucleus. However, the cellular mechanisms through which acetylcholine (ACh) mediates this modulation in the MNTB remain obscure. To investigate these mechanisms, we used whole-cell current and voltage-clamp recordings to examine cholinergic physiology in MNTB neurons from Mongolian gerbils (Meriones unguiculatus) of both sexes. Membrane excitability was assessed in brain slices, in pre-hearing (postnatal days 9-13) and post-hearing onset (P18-20) MNTB neurons during bath application of agonists and antagonists of nicotinic (nAChRs) and muscarinic receptors (mAChRs). Muscarinic activation induced a potent increase in excitability most prominently prior to hearing onset with nAChR modulation emerging at later time points. Pharmacological manipulations further demonstrated that the voltage-gated K+ channel KCNQ (Kv7) is the downstream effector of mAChR activation that impacts excitability early in development. Cholinergic modulation of Kv7 reduces outward K+ conductance and depolarizes resting membrane potential. Immunolabeling revealed expression of Kv7 channels as well as mAChRs containing M1 and M3 subunits. Together, our results suggest that mAChR modulation is prominent but transient in the developing MNTB and that cholinergic modulation functions to shape auditory circuit development.

Volume electron microscopy reveals age-related ultrastructural differences of globular bush cell axons in mouse central auditory system.

In mammals, thick axonal calibers wrapped with heavy myelin sheaths are prevalent in the auditory nervous system. These features are crucial for fast traveling of nerve impulses with minimal attenuation required for sound signal transmission. In particular, the long-range projections from the cochlear nucleus - the axons of globular bush cells (GBCs) - to the medial nucleus of the trapezoid body (MNTB) are tonotopically organized. However, it remains controversial in gerbils and mice whether structural and functional adaptations are present among the GBC axons targeting different MNTB frequency regions. By means of high-throughput volume electron microscopy, we compared the GBC axons in full-tonotopy-ranged MNTB slices from the C57BL/6 mice at different ages. Our quantification reveals distinct caliber diameter and myelin profile of the GBC axons with endings at lateral and medial MNTB, arguing for modulation of functionally heterogeneous axon subgroups. In addition, we reported axon-specific differences in axon caliber, node of Ranvier, and myelin sheath among juvenile, adult, and old mice, indicating the age-related changes of GBC axon morphology over time. These findings provide structural insight into the maturation and degeneration of GBC axons with frequency tuning across the lifespan of mice.

Dissociable Roles of the Auditory Midbrain and Cortex in Processing the Statistical Features of Natural Sound Textures.

Sound texture perception takes advantage of a hierarchy of time-averaged statistical features of acoustic stimuli, but much remains unclear about how these statistical features are processed along the auditory pathway. Here, we compared the neural representation of sound textures in the inferior colliculus (IC) and auditory cortex (AC) of anesthetized female rats. We recorded responses to texture morph stimuli that gradually add statistical features of increasingly higher complexity. For each texture, several different exemplars were synthesized using different random seeds. An analysis of transient and ongoing multiunit responses showed that the IC units were sensitive to every type of statistical feature, albeit to a varying extent. In contrast, only a small proportion of AC units were overtly sensitive to any statistical features. Differences in texture types explained more of the variance of IC neural responses than did differences in exemplars, indicating a degree of "texture type tuning" in the IC, but the same was, perhaps surprisingly, not the case for AC responses. We also evaluated the accuracy of texture type classification from single-trial population activity and found that IC responses became more informative as more summary statistics were included in the texture morphs, while for AC population responses, classification performance remained consistently very low. These results argue against the idea that AC neurons encode sound type via an overt sensitivity in neural firing rate to fine-grain spectral and temporal statistical features.

Research progress of the inferior colliculus: from Neuron, neural circuit to auditory disease.

The auditory midbrain, also known as the inferior colliculus (IC), serves as a crucial hub in the auditory pathway. Comprising diverse cell types, the IC plays a pivotal role in various auditory functions, including sound localization, auditory plasticity, sound detection, and sound-induced behaviors. Notably, the IC is implicated in several auditory central disorders, such as tinnitus, age-related hearing loss, autism and Fragile X syndrome. Accurate classification of IC neurons is vital for comprehending both normal and dysfunctional aspects of IC function. Various parameters, including dendritic morphology, neurotransmitter synthesis, potassium currents, biomarkers, and axonal targets, have been employed to identify distinct neuron types within the IC. However, the challenge persists in effectively classifying IC neurons into functional categories due to the limited clustering capabilities of most parameters. Recent studies utilizing advanced neuroscience technologies have begun to shed light on biomarker-based approaches in the IC, providing insights into specific cellular properties and offering a potential avenue for understanding IC functions. This review focuses on recent advancements in IC research, spanning from neurons and neural circuits to aspects related to auditory diseases.

Multielectrode array use in insect auditory neuroscience to unravel the spatio-temporal response pattern in the prothoracic ganglion of Mecopoda elongata.

Mechanoreceptors in hearing organs transduce sound-induced mechanical responses into neuronal signals, which are further processed and forwarded to the brain along a chain of neurons in the auditory pathway. Bushcrickets (katydids) have their ears in the front leg tibia, and the first synaptic integration of sound-induced neuronal signals takes place in the primary auditory neuropil of the prothoracic ganglion. By combining intracellular recordings of the receptor activity in the ear, extracellular multichannel array recordings on top of the prothoracic ganglion and hook electrode recordings at the neck connective, we mapped the timing of neuronal responses to tonal sound stimuli along the auditory pathway from the ears towards the brain. The use of the multielectrode array allows the observation of spatio-temporal patterns of neuronal responses within the prothoracic ganglion. By eliminating the sensory input from one ear, we investigated the impact of contralateral projecting interneurons in the prothoracic ganglion and added to previous research on the functional importance of contralateral inhibition for binaural processing. Furthermore, our data analysis demonstrates changes in the signal integration processes at the synaptic level indicated by a long-lasting increase in the local field potential amplitude. We hypothesize that this persistent increase of the local field potential amplitude is important for the processing of complex signals, such as the conspecific song.

Multiple Concurrent Predictions Inform Prediction Error in the Human Auditory Pathway.

The key assumption of the predictive coding framework is that internal representations are used to generate predictions on how the sensory input will look like in the immediate future. These predictions are tested against the actual input by the so-called prediction error units, which encode the residuals of the predictions. What happens to prediction errors, however, if predictions drawn by different stages of the sensory hierarchy contradict each other? To answer this question, we conducted two fMRI experiments while female and male human participants listened to sequences of sounds: pure tones in the first experiment and frequency-modulated sweeps in the second experiment. In both experiments, we used repetition to induce predictions based on stimulus statistics (stats-informed predictions) and abstract rules disclosed in the task instructions to induce an orthogonal set of (task-informed) predictions. We tested three alternative scenarios: neural responses in the auditory sensory pathway encode prediction error with respect to (1) the stats-informed predictions, (2) the task-informed predictions, or (3) a combination of both. Results showed that neural populations in all recorded regions (bilateral inferior colliculus, medial geniculate body, and primary and secondary auditory cortices) encode prediction error with respect to a combination of the two orthogonal sets of predictions. The findings suggest that predictive coding exploits the non-linear architecture of the auditory pathway for the transmission of predictions. Such non-linear transmission of predictions might be crucial for the predictive coding of complex auditory signals like speech.Significance Statement Sensory systems exploit our subjective expectations to make sense of an overwhelming influx of sensory signals. It is still unclear how expectations at each stage of the processing pipeline are used to predict the representations at the other stages. The current view is that this transmission is hierarchical and linear. Here we measured fMRI responses in auditory cortex, sensory thalamus, and midbrain while we induced two sets of mutually inconsistent expectations on the sensory input, each putatively encoded at a different stage. We show that responses at all stages are concurrently shaped by both sets of expectations. The results challenge the hypothesis that expectations are transmitted linearly and provide for a normative explanation of the non-linear physiology of the corticofugal sensory system.

Experience-Dependent Plasticity in Nucleus Laminaris of the Barn Owl.

Interaural time differences (ITDs) are a major cue for sound localization and change with increasing head size. Since the barn owl's head width more than doubles in the month after hatching, we hypothesized that the development of their ITD detection circuit might be modified by experience. To test this, we raised owls with unilateral ear inserts that delayed and attenuated the acoustic signal, and then measured the ITD representation in the brainstem nucleus laminaris (NL) when they were adults. The ITD circuit is composed of delay line inputs to coincidence detectors, and we predicted that plastic changes would lead to shorter delays in the axons from the manipulated ear, and complementary shifts in ITD representation on the two sides. In owls that received ear inserts starting around P14, the maps of ITD shifted in the predicted direction, but only on the ipsilateral side, and only in those tonotopic regions that had not experienced auditory stimulation prior to insertion. The contralateral map did not change. Thus, experience-dependent plasticity of the ITD circuit occurs in NL, and our data suggest that ipsilateral and contralateral delays are independently regulated. As a result, altered auditory input during development leads to long-lasting changes in the representation of ITD.Significance Statement The early life of barn owls is marked by increasing sensitivity to sound, and by increasing ITDs. Their prolonged post-hatch development allowed us to examine the role of altered auditory experience in the development of ITD detection circuits. We raised owls with a unilateral ear insert and found that their maps of ITD were altered by experience, but only in those tonotopic regions ipsilateral to the occluded ear that had not experienced auditory stimulation prior to insertion. This experience-induced plasticity allows the sound localization circuits to be customized to individual characteristics, such as the size of the head, and potentially to compensate for imbalanced hearing sensitivities between the left and right ears.

Identifying neuron types and circuit mechanisms in the auditory midbrain.

The inferior colliculus (IC) is a critical computational hub in the central auditory pathway. From its position in the midbrain, the IC receives nearly all the ascending output from the lower auditory brainstem and provides the main source of auditory information to the thalamocortical system. In addition to being a crossroads for auditory circuits, the IC is rich with local circuits and contains more than five times as many neurons as the nuclei of the lower auditory brainstem combined. These results hint at the enormous computational power of the IC, and indeed, systems-level studies have identified numerous important transformations in sound coding that occur in the IC. However, despite decades of effort, the cellular mechanisms underlying IC computations and how these computations change following hearing loss have remained largely impenetrable. In this review, we argue that this challenge persists due to the surprisingly difficult problem of identifying the neuron types and circuit motifs that comprise the IC. After summarizing the extensive evidence pointing to a diversity of neuron types in the IC, we highlight the successes of recent efforts to parse this complexity using molecular markers to define neuron types. We conclude by arguing that the discovery of molecularly identifiable neuron types ushers in a new era for IC research marked by molecularly targeted recordings and manipulations. We propose that the ability to reproducibly investigate IC circuits at the neuronal level will lead to rapid advances in understanding the fundamental mechanisms driving IC computations and how these mechanisms shift following hearing loss.

Auditory Corticofugal Neurons Transmit Auditory and Non-auditory Information During Behavior.

Layer 5 pyramidal neurons of sensory cortices project "corticofugal" axons to myriad sub-cortical targets, thereby broadcasting high-level signals important for perception and learning. Recent studies suggest dendritic Ca2+ spikes as key biophysical mechanisms supporting corticofugal neuron function: these long-lasting events drive burst firing, thereby initiating uniquely powerful signals to modulate sub-cortical representations and trigger learning-related plasticity. However, the behavioral relevance of corticofugal dendritic spikes is poorly understood. We shed light on this issue using 2-photon Ca2+ imaging of auditory corticofugal dendrites as mice of either sex engage in a GO/NO-GO sound-discrimination task. Unexpectedly, only a minority of dendritic spikes were triggered by behaviorally relevant sounds under our conditions. Task related dendritic activity instead mostly followed sound cue termination and co-occurred with mice's instrumental licking during the answer period of behavioral trials, irrespective of reward consumption. Temporally selective, optogenetic silencing of corticofugal neurons during the trial answer period impaired auditory discrimination learning. Thus, auditory corticofugal systems' contribution to learning and plasticity may be partially nonsensory in nature.

Subcortical auditory model including efferent dynamic gain control with inputs from cochlear nucleus and inferior colliculus.

An auditory model has been developed with a time-varying, gain-control signal based on the physiology of the efferent system and subcortical neural pathways. The medial olivocochlear (MOC) efferent stage of the model receives excitatory projections from fluctuation-sensitive model neurons of the inferior colliculus (IC) and wide-dynamic-range model neurons of the cochlear nucleus. The response of the model MOC stage dynamically controls cochlear gain via simulated outer hair cells. In response to amplitude-modulated (AM) noise, firing rates of most IC neurons with band-enhanced modulation transfer functions in awake rabbits increase over a time course consistent with the dynamics of the MOC efferent feedback. These changes in the rates of IC neurons in awake rabbits were employed to adjust the parameters of the efferent stage of the proposed model. Responses of the proposed model to AM noise were able to simulate the increasing IC rate over time, whereas the model without the efferent system did not show this trend. The proposed model with efferent gain control provides a powerful tool for testing hypotheses, shedding insight on mechanisms in hearing, specifically those involving the efferent system.