Neural correlates of tonal loudness, intensity discrimination, and duration discrimination.

A long-standing quest in audition concerns understanding relations between behavioral measures and neural representations of changes in sound intensity. Here, we examined relations between aspects of intensity perception and central neural responses within the inferior colliculus of unanesthetized rabbits (by averaging the population's spike count/level functions). We found parallels between the population's neural output and: (1) how loudness grows with intensity; (2) how loudness grows with duration; (3) how discrimination of intensity improves with increasing sound level; (4) findings that intensity discrimination does not depend on duration; and (5) findings that duration discrimination is a constant fraction of base duration.

Modulatory Effects on Laminar Neural Activity Induced by Near-Infrared Light Stimulation with a Continuous Waveform to the Mouse Inferior Colliculus In Vivo.

Infrared neural stimulation (INS) is a promising area of interest for the clinical application of a neuromodulation method. This is in part because of its low invasiveness, whereby INS modulates the activity of the neural tissue mainly through temperature changes. Additionally, INS may provide localized brain stimulation with less tissue damage. The inferior colliculus (IC) is a crucial auditory relay nucleus and a potential target for clinical application of INS to treat auditory diseases and develop artificial hearing devices. Here, using continuous INS with low to high-power density, we demonstrate the laminar modulation of neural activity in the mouse IC in the presence and absence of sound. We investigated stimulation parameters of INS to effectively modulate the neural activity in a facilitatory or inhibitory manner. A mathematical model of INS-driven brain tissue was first simulated, temperature distributions were numerically estimated, and stimulus parameters were selected from the simulation results. Subsequently, INS was administered to the IC of anesthetized mice, and the modulation effect on the neural activity was measured using an electrophysiological approach. We found that the modulatory effect of INS on the spontaneous neural activity was bidirectional between facilitatory and inhibitory effects. The modulatory effect on sound-evoked responses produced only an inhibitory effect to all examined stimulus intensities. Thus, this study provides important physiological evidence on the response properties of IC neurons to INS. Overall, INS can be used for the development of new therapies for neurological disorders and functional support devices for auditory central processing.

The Mouse Inferior Colliculus Responds Preferentially to Non-Ultrasonic Vocalizations.

The inferior colliculus (IC), the midbrain auditory integration center, analyzes information about social vocalizations and provides substrates for higher level processing of vocal signals. We used multichannel recordings to characterize and localize responses to social vocalizations and synthetic stimuli within the IC of female and male mice, both urethane anesthetized and unanesthetized. We compared responses to ultrasonic vocalizations (USVs) with other vocalizations in the mouse repertoire and related vocal responses to frequency tuning, IC subdivisions, and sex. Responses to lower frequency, broadband social vocalizations were widespread in IC, well represented throughout the tonotopic axis, across subdivisions, and in both sexes. Responses to USVs were much more limited. Although we observed some differences in tonal and vocal responses by sex and subdivision, representations of vocal responses by sex and subdivision were largely the same. For most units, responses to vocal signals occurred only when frequency response areas overlapped with spectra of the vocal signals. Since tuning to frequencies contained within the highest frequency USVs is limited (<15% of IC units), responses to these vocalizations are correspondingly limited (<5% of sound-responsive units). These results highlight a paradox of USV processing in some rodents: although USVs are the most abundant social vocalization, their representation and the representation of corresponding frequencies are less than lower frequency social vocalizations. We interpret this paradox in light of observations suggesting that USVs with lower frequency elements (<50 kHz) are associated with increased emotional intensity and engage a larger population of neurons in the mouse auditory system.

Population coding of time-varying sounds in the nonlemniscal inferior colliculus.

The inferior colliculus (IC) of the midbrain is important for complex sound processing, such as discriminating conspecific vocalizations and human speech. The IC's nonlemniscal, dorsal "shell" region is likely important for this process, as neurons in these layers project to higher-order thalamic nuclei that subsequently funnel acoustic signals to the amygdala and nonprimary auditory cortices, forebrain circuits important for vocalization coding in a variety of mammals, including humans. However, the extent to which shell IC neurons transmit acoustic features necessary to discern vocalizations is less clear, owing to the technical difficulty of recording from neurons in the IC's superficial layers via traditional approaches. Here, we use two-photon Ca2+ imaging in mice of either sex to test how shell IC neuron populations encode the rate and depth of amplitude modulation, important sound cues for speech perception. Most shell IC neurons were broadly tuned, with a low neurometric discrimination of amplitude modulation rate; only a subset was highly selective to specific modulation rates. Nevertheless, neural network classifier trained on fluorescence data from shell IC neuron populations accurately classified amplitude modulation rate, and decoding accuracy was only marginally reduced when highly tuned neurons were omitted from training data. Rather, classifier accuracy increased monotonically with the modulation depth of the training data, such that classifiers trained on full-depth modulated sounds had median decoding errors of ∼0.2 octaves. Thus, shell IC neurons may transmit time-varying signals via a population code, with perhaps limited reliance on the discriminative capacity of any individual neuron.NEW & NOTEWORTHY The IC's shell layers originate a "nonlemniscal" pathway important for perceiving vocalization sounds. However, prior studies suggest that individual shell IC neurons are broadly tuned and have high response thresholds, implying a limited reliability of efferent signals. Using Ca2+ imaging, we show that amplitude modulation is accurately represented in the population activity of shell IC neurons. Thus, downstream targets can read out sounds' temporal envelopes from distributed rate codes transmitted by populations of broadly tuned neurons.

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.

How 'hidden hearing loss' noise exposure affects neural coding in the inferior colliculus of rats.

Exposure to brief, intense sound can produce profound changes in the auditory system, from the internal structure of inner hair cells to reduced synaptic connections between the auditory nerves and the inner hair cells. Moreover, noisy environments can also lead to alterations in the auditory nerve or to processing changes in the auditory midbrain, all without affecting hearing thresholds. This so-called hidden hearing loss (HHL) has been shown in tinnitus patients and has been posited to account for hearing difficulties in noisy environments. However, much of the neuronal research thus far has investigated how HHL affects the response characteristics of individual fibres in the auditory nerve, as opposed to higher stations in the auditory pathway. Human models show that the auditory nerve encodes sound stochastically. Therefore, a sufficient reduction in nerve fibres could result in lowering the sampling of the acoustic scene below the minimum rate necessary to fully encode the scene, thus reducing the efficacy of sound encoding. Here, we examine how HHL affects the responses to frequency and intensity of neurons in the inferior colliculus of rats, and the duration and firing rate of those responses. Finally, we examined how shorter stimuli are encoded less effectively by the auditory midbrain than longer stimuli, and how this could lead to a clinical test for HHL.

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.

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.

Time-dependent effects of acoustic trauma and tinnitus on extracellular levels of amino acids in the inferior colliculus of rats.

Chronic tinnitus is a debilitating condition with very few management options. Acoustic trauma that causes tinnitus has been shown to induce neuronal hyperactivity in multiple brain areas in the auditory pathway, including the inferior colliculus. This neuronal hyperactivity could be attributed to an imbalance between excitatory and inhibitory neurotransmission. However, it is not clear how the levels of neurotransmitters, especially neurotransmitters in the extracellular space, change over time following acoustic trauma and the development of tinnitus. In the present study, a range of amino acids were measured in the inferior colliculus of rats during acoustic trauma as well as at 1 week and 5 months post-trauma using in vivo microdialysis and high-performance liquid chromatography. Amino acid levels in response to sound stimulation were also measured at 1 week and 5 months post-trauma. It was found that unilateral exposure to a 16 kHz pure tone at 115 dB SPL for 1 h caused immediate hearing loss in all the animals and chronic tinnitus in 58 % of the animals. Comparing to the sham condition, extracellular levels of GABA were significantly increased at both the acute and 1 week time points after acoustic trauma. However, there was no significant difference in any of the amino acid levels measured between sham, tinnitus positive and tinnitus negative animals at 5 months post-trauma. There was also no clear pattern in the relationship between neurochemical changes and sound frequency/acoustic trauma/tinnitus status, which might be due to the relatively poorer temporal resolution of the microdialysis compared to electrophysiological responses.

Neural decoding of inferior colliculus multiunit activity for sound category identification with temporal correlation and transfer learning.

Natural sounds are easily perceived and identified by humans and animals. Despite this, the neural transformations that enable sound perception remain largely unknown. It is thought that the temporal characteristics of sounds may be reflected in auditory assembly responses at the inferior colliculus (IC) and which may play an important role in identification of natural sounds. In our study, natural sounds will be predicted from multi-unit activity (MUA) signals collected in the IC. Data is obtained from an international platform publicly accessible. The temporal correlation values of the MUA signals are converted into images. We used two different segment sizes and with a denoising method, we generated four subsets for the classification. Using pre-trained convolutional neural networks (CNNs), features of the images were extracted and the type of heard sound was classified. For this, we applied transfer learning from Alexnet, Googlenet and Squeezenet CNNs. The classifiers support vector machines (SVM), k-nearest neighbour (KNN), Naive Bayes and Ensemble were used. The accuracy, sensitivity, specificity, precision and F1 score were measured as evaluation parameters. By using all the tests and removing the noise, the accuracy improved significantly. These results will allow neuroscientists to make interesting conclusions.

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.

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.

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.

Sensitivity to direction and velocity of fast frequency chirps in the inferior colliculus of awake rabbit.

Neurons in the mammalian inferior colliculus (IC) are sensitive to the velocity (speed and direction) of fast frequency chirps contained in Schroeder-phase harmonic complexes (SCHR). However, IC neurons are also sensitive to stimulus periodicity, a prominent feature of SCHR stimuli. Here, to disentangle velocity sensitivity from periodicity tuning, we introduced a novel stimulus consisting of aperiodic random chirps. Extracellular, single-unit recordings were made in the IC of Dutch-belted rabbits in response to both SCHR and aperiodic chirps. Rate-velocity functions were constructed from aperiodic-chirp responses and compared to SCHR rate profiles, revealing interactions between stimulus periodicity and neural velocity sensitivity. A generalized linear model analysis demonstrated that periodicity tuning influences SCHR response rates more strongly than velocity sensitivity. Principal component analysis of rate-velocity functions revealed that neurons were more often sensitive to the direction of lower-velocity chirps and were less often sensitive to the direction of higher-velocity chirps. Overall, these results demonstrate that sensitivity to chirp velocity is common in the IC. Harmonic sounds with complex phase spectra, such as speech and music, contain chirps, and velocity sensitivity would shape IC responses to these sounds.

Neuropeptide Y Signaling Regulates Recurrent Excitation in the Auditory Midbrain.

Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a class of GABAergic neurons that project locally and outside the IC. Most neurons in the IC have local axon collaterals; however, the organization and function of local circuits in the IC remain unknown. We previously found that excitatory neurons in the IC can express the NPY Y1 receptor (Y1R+) and application of the Y1R agonist, [Leu31, Pro34]-NPY (LP-NPY), decreases the excitability of Y1R+ neurons. As NPY signaling regulates recurrent excitation in other brain regions, we hypothesized that Y1R+ neurons form interconnected local circuits in the IC and that NPY decreases the strength of recurrent excitation in these circuits. To test this hypothesis, we used optogenetics to activate Y1R+ neurons in mice of both sexes while recording from other neurons in the ipsilateral IC. We found that nearly 80% of glutamatergic IC neurons express the Y1 receptor, providing extensive opportunities for NPY signaling to regulate local circuits. Additionally, Y1R+ neuron synapses exhibited modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreased recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Our findings show that Y1R+ excitatory neurons form interconnected local circuits in the IC, and their influence over local circuits is regulated by NPY signaling.SIGNIFICANCE STATEMENT Local networks play fundamental roles in shaping neuronal computations in the brain. The IC, localized in the auditory midbrain, plays an essential role in sound processing, but the organization of local circuits in the IC is largely unknown. Here, we show that IC neurons that express the Neuropeptide Y1 receptor (Y1R+ neurons) make up most of the excitatory neurons in the IC and form interconnected local circuits. Additionally, we found that NPY, which is a powerful neuromodulator known to shape neuronal activity in other brain regions, decreases the extensive recurrent excitation mediated by Y1R+ neurons in local IC circuits. Thus, our results suggest that local NPY signaling is a key regulator of auditory computations in the IC.

Differential projections from the cochlear nucleus to the inferior colliculus in the mouse.

The cochlear nucleus (CN) is often regarded as the gateway to the central auditory system because it initiates all ascending pathways. The CN consists of dorsal and ventral divisions (DCN and VCN, respectively), and whereas the DCN functions in the analysis of spectral cues, circuitry in VCN is part of the pathway focused on processing binaural information necessary for sound localization in horizontal plane. Both structures project to the inferior colliculus (IC), which serves as a hub for the auditory system because pathways ascending to the forebrain and descending from the cerebral cortex converge there to integrate auditory, motor, and other sensory information. DCN and VCN terminations in the IC are thought to overlap but given the differences in VCN and DCN architecture, neuronal properties, and functions in behavior, we aimed to investigate the pattern of CN connections in the IC in more detail. This study used electrophysiological recordings to establish the frequency sensitivity at the site of the anterograde dye injection for the VCN and DCN of the CBA/CaH mouse. We examined their contralateral projections that terminate in the IC. The VCN projections form a topographic sheet in the central nucleus (CNIC). The DCN projections form a tripartite set of laminar sheets; the lamina in the CNIC extends into the dorsal cortex (DC), whereas the sheets to the lateral cortex (LC) and ventrolateral cortex (VLC) are obliquely angled away. These fields in the IC are topographic with low frequencies situated dorsally and progressively higher frequencies lying more ventrally and/or laterally; the laminae nestle into the underlying higher frequency fields. The DCN projections are complementary to the somatosensory modules of layer II of the LC but both auditory and spinal trigeminal terminations converge in the VLC. While there remains much to be learned about these circuits, these new data on auditory circuits can be considered in the context of multimodal networks that facilitate auditory stream segregation, signal processing, and species survival.

Distinct topographic organization and network activity patterns of corticocollicular neurons within layer 5 auditory cortex.

The auditory cortex (AC) modulates the activity of upstream pathways in the auditory brainstem via descending (corticofugal) projections. This feedback system plays an important role in the plasticity of the auditory system by shaping response properties of neurons in many subcortical nuclei. The majority of layer (L) 5 corticofugal neurons project to the inferior colliculus (IC). This corticocollicular (CC) pathway is involved in processing of complex sounds, auditory-related learning, and defense behavior. Partly due to their location in deep cortical layers, CC neuron population activity patterns within neuronal AC ensembles remain poorly understood. We employed two-photon imaging to record the activity of hundreds of L5 neurons in anesthetized as well as awake animals. CC neurons are broader tuned than other L5 pyramidal neurons and display weaker topographic order in core AC subfields. Network activity analyses revealed stronger clusters of CC neurons compared to non-CC neurons, which respond more reliable and integrate information over larger distances. However, results obtained from secondary auditory cortex (A2) differed considerably. Here CC neurons displayed similar or higher topography, depending on the subset of neurons analyzed. Furthermore, specifically in A2, CC activity clusters formed in response to complex sounds were spatially more restricted compared to other L5 neurons. Our findings indicate distinct network mechanism of CC neurons in analyzing sound properties with pronounced subfield differences, demonstrating that the topography of sound-evoked responses within AC is neuron-type dependent.

Tonotopic distribution and inferior colliculus projection pattern of inhibitory and excitatory cell types in the lateral superior olive of mice.

The principal neurons (PNs) of the lateral superior olive nucleus (LSO) are an important component of mammalian brainstem circuits that compare activity between the two ears and extract intensity and timing differences used for sound localization. There are two LSO PN transmitter types, glycinergic and glutamatergic, which also have different ascending projection patterns to the inferior colliculus (IC). Glycinergic LSO PNs project ipsilaterally while glutamatergic one's projections vary in laterality by species. In animals with good low-frequency hearing (<3 kHz) such as cats and gerbils, glutamatergic LSO PNs have both ipsilateral and contralateral projections; however, rats that lack this ability only have the contralateral pathway. Additionally, in gerbils, the glutamatergic ipsilateral projecting LSO PNs are biased to the low-frequency limb of the LSO suggesting this pathway may be an adaptation for low-frequency hearing. To further test this premise, we examined the distribution and IC projection pattern of LSO PNs in another high-frequency specialized species using mice by combining in situ hybridization and retrograde tracer injections. We observed no overlap between glycinergic and glutamatergic LSO PNs confirming they are distinct cell populations in mice as well. We found that mice also lack the ipsilateral glutamatergic projection from LSO to IC and that their LSO PN types do not exhibit pronounced tonotopic biases. These data provide insights into the cellular organization of the superior olivary complex and its output to higher processing centers that may underlie functional segregation of information.

Neuronal responses in mouse inferior colliculus correlate with behavioral detection of amplitude-modulated sound.

Amplitude modulation (AM) is a common feature of natural sounds, including speech and animal vocalizations. Here, we used operant conditioning and in vivo electrophysiology to determine the AM detection threshold of mice as well as its underlying neuronal encoding. Mice were trained in a Go-NoGo task to detect the transition to AM within a noise stimulus designed to prevent the use of spectral side-bands or a change in intensity as alternative cues. Our results indicate that mice, compared with other species, detect high modulation frequencies up to 512 Hz well, but show much poorer performance at low frequencies. Our in vivo multielectrode recordings in the inferior colliculus (IC) of both anesthetized and awake mice revealed a few single units with remarkable phase-locking ability to 512 Hz modulation, but not sufficient to explain the good behavioral detection at that frequency. Using a model of the population response that combined dimensionality reduction with threshold detection, we reproduced the general band-pass characteristics of behavioral detection based on a subset of neurons showing the largest firing rate change (both increase and decrease) in response to AM, suggesting that these neurons are instrumental in the behavioral detection of AM stimuli by the mice.NEW & NOTEWORTHY The amplitude of natural sounds, including speech and animal vocalizations, often shows characteristic modulations. We examined the relationship between neuronal responses in the mouse inferior colliculus and the behavioral detection of amplitude modulation (AM) in sound and modeled how the former can give rise to the latter. Our model suggests that behavioral detection can be well explained by the activity of a subset of neurons showing the largest firing rate changes in response to AM.

Recurrent Circuits Amplify Corticofugal Signals and Drive Feedforward Inhibition in the Inferior Colliculus.

The inferior colliculus (IC) is a midbrain hub critical for perceiving complex sounds, such as speech. In addition to processing ascending inputs from most auditory brainstem nuclei, the IC receives descending inputs from auditory cortex that control IC neuron feature selectivity, plasticity, and certain forms of perceptual learning. Although corticofugal synapses primarily release the excitatory transmitter glutamate, many physiology studies show that auditory cortical activity has a net inhibitory effect on IC neuron spiking. Perplexingly, anatomy studies imply that corticofugal axons primarily target glutamatergic IC neurons while only sparsely innervating IC GABA neurons. Corticofugal inhibition of the IC may thus occur largely independently of feedforward activation of local GABA neurons. We shed light on this paradox using in vitro electrophysiology in acute IC slices from fluorescent reporter mice of either sex. Using optogenetic stimulation of corticofugal axons, we find that excitation evoked with single light flashes is indeed stronger in presumptive glutamatergic neurons compared with GABAergic neurons. However, many IC GABA neurons fire tonically at rest, such that sparse and weak excitation suffices to significantly increase their spike rates. Furthermore, a subset of glutamatergic IC neurons fire spikes during repetitive corticofugal activity, leading to polysynaptic excitation in IC GABA neurons owing to a dense intracollicular connectivity. Consequently, recurrent excitation amplifies corticofugal activity, drives spikes in IC GABA neurons, and generates substantial local inhibition in the IC. Thus, descending signals engage intracollicular inhibitory circuits despite apparent constraints of monosynaptic connectivity between auditory cortex and IC GABA neurons.SIGNIFICANCE STATEMENT Descending "corticofugal" projections are ubiquitous across mammalian sensory systems, and enable the neocortex to control subcortical activity in a predictive or feedback manner. Although corticofugal neurons are glutamatergic, neocortical activity often inhibits subcortical neuron spiking. How does an excitatory pathway generate inhibition? Here we study the corticofugal pathway from auditory cortex to inferior colliculus (IC), a midbrain hub important for complex sound perception. Surprisingly, cortico-collicular transmission was stronger onto IC glutamatergic compared with GABAergic neurons. However, corticofugal activity triggered spikes in IC glutamate neurons with local axons, thereby generating strong polysynaptic excitation and feedforward spiking of GABAergic neurons. Our results thus reveal a novel mechanism that recruits local inhibition despite limited monosynaptic convergence onto inhibitory networks.