Auditory Neurophysiology publications

In nature, animals learn to replace predisposed behaviors with new strategies, yet the neural constraints on these transitions are unclear. Using an ethological search task in mice, we reveal medial prefrontal cortical (mPFC) neural correlates of a predisposed win-stay strategy that decays as animals learn to follow a more reliable auditory cue. Auditory cortex (ACx) activity predicts correct trial-by-trial sound-guided search, even on day one of training. This prognostic coding strengthens with learning and emerges from suppressed spiking, most pronounced in neurons tuned laterally to the cue’s spectrum. Chemogenetic disruption reveals ACx contributions to improving performance. Unexpectedly, the global silencing of mPFC accelerates successful usage of sound-tracking, contrary to its canonical role in flexible or stimulus-dependent behavior. Instead, a decentralized multiexpert competition model best predicts behavior and causal perturbations. These findings suggest that mPFC implements a default strategy based on prior knowledge, which actively hinders the expression of more efficient strategies.

Background Peripheral hearing loss is associated with auditory hallucinations and increased risk for psychotic disorder, particularly in genetically vulnerable individuals. Moreover, both hearing loss and schizophrenia disrupt auditory temporal acuity, a sensitive measure of auditory brain function. Here, we used mouse models of hearing loss and schizophrenia to reveal how neural mechanisms of auditory cortical temporal acuity depend on sensory and genetic risk factors for psychosis. Methods We quantified auditory cortical temporal acuity in mice with or without hearing loss and with or without the 22q11.2 deletion — one of the strongest known genetic risk factors for schizophrenia. Cortical single-unit and population activity were recorded in awake mice (N = 23) during presentations of loudness-adjusted gap-in-noise stimuli with varying durations of silent gap, which are commonly used to assess auditory temporal acuity in humans. Results Both hearing loss and the 22q11.2 deletion disrupted auditory cortical temporal acuity, but through distinct mechanisms. Hearing loss broadly degraded temporal acuity at the level of single-unit responses and neural population activity. In contrast, the 22q11.2 deletion selectively impaired gap duration thresholds in regular-spiking (putative excitatory) but not fast-spiking (putative inhibitory) neurons. Mice with comorbid hearing loss and 22q11.2 deletion exhibited both abnormalities in auditory cortical temporal acuity. Conclusions Sensory and genetic risk factors for psychosis can disrupt auditory cortical temporal acuity via distinct mechanisms that remain partially dissociable even under comorbid conditions. These findings underscore the importance of accounting for hearing loss comorbidity when interpreting auditory cortical dysfunction in psychotic disorder.

In bats, which express a complex vocal repertoire and are considered vocal learners, the frontal auditory field (FAF) is supposedly placed in a frontal cortico‐striatal network for vocal–motor control. The FAF receives input from the auditory cortex (AC) and other auditory nuclei via multiple pathways. However, not much is known about the transition of information on vocalizations from the AC to the FAF. The bat AC consists of different subfields, among which the dorsal fields (dAC) are characterized by precise coding of the temporal envelope of vocalizations. The dAC should, therefore, be a major source of auditory feedback information about self‐produced or perceived vocalizations to the FAF. Our study aimed to investigate the specificity of encoding for different types of vocalizations in FAF and dAC neurons. Using extracellular recordings in anesthetized Phyllostomus discolor , we describe basic response properties in both cortical areas and compare responses to different types of prerecorded vocalizations. The specificity of encoding for different behaviorally relevant call categories and single calls was higher in dAC than in FAF neurons, both in terms of temporal firing patterns and response strength. These findings highlight the importance of the dAC in the neural network for control of vocal communication in bats.

Cortical processing of auditory information can be affected by interspecies differences as well as brain states. Here we compare multifeature spectro-temporal receptive fields (STRFs) and associated input/output functions or nonlinearities (NLs) of neurons in primary auditory cortex (AC) of four mammalian species. Single-unit recordings were performed in awake animals (female squirrel monkeys, female, and male mice) and anesthetized animals (female squirrel monkeys, rats, and cats). Neuronal responses were modeled as consisting of two STRFs and their associated NLs. The NLs for the STRF with the highest information content show a broad distribution between linear and quadratic forms. In awake animals, we find a higher percentage of quadratic-like NLs as opposed to more linear NLs in anesthetized animals. Moderate sex differences of the shape of NLs were observed between male and female unanesthetized mice. This indicates that the core AC possesses a rich variety of potential computations, particularly in awake animals, suggesting that multiple computational algorithms are at play to enable the auditory system’s robust recognition of auditory events.

The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin ( Nptn ) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice ( Nptn −/− ) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn −/− mice. Adult Nptn −/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn −/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn −/− mice. Conditional ablation of neuroplastin in Nptn lox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult Nptn Δlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca 2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

Exposure to loud noises results in neuroinflammatory responses in the central auditory pathway. Noise-induced neuroinflammation is implicated in auditory processing deficits such as impairment in gap detection. In this study, we examined whether strain differences between the FVB and C57BL/6 mice in noise-induced impairment in gap detection are correlated with strain differences in neuroinflammatory responses. We found that noise induced more robust TNF-α expression in C57BL/6 than in FVB mice. Noise-induced microglial deramification was observed in C57BL/6 mice, but not in FVB mice. Furthermore, noise exposure resulted in a reduction in parvalbumin-positive (PV+) neuron density in the C57BL/6 mice, but not in FVB mice. These results suggest that neuroinflammatory responses and loss of PV+ neurons may contribute to strain differences in noise-induced impairment in gap detection.

Neuroinflammation has been implicated in noise-induced auditory processing disorder and tinnitus. Certain non-auditory neurological disorders can also increase the levels of proinflammatory cytokines in the brain. To investigate the impact of increased brain proinflammatory cytokine levels on the central auditory pathway, we infused recombinant TNF-α into the right lateral cerebral ventricle, and examined auditory processing and cytoarchitecture of the auditory cortex. Microglial deramification was observed in the auditory cortex of mice that had received both TNF-α infusion and exposure to an 86-dB noise, but not in mice that had received either TNF-α infusion or noise exposure alone. In addition, we observed reduced cortical PV+ neuron density and impaired performances in gap detection and prepulse inhibition (PPI) only in mice that received both TNF-α infusion and the noise exposure. These results suggest that disease-related increase in brain proinflammatory cytokine release could be a risk factor for noise-induced auditory processing disorder and tinnitus.

Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that selectively increasing NMDA receptor activity in inhibitory neurons using an NMDAR positive allosteric modulator (PAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. In vivo infusion of PAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. In addition, PAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. These results reveal that selectively enhancing endogenous NMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory–inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.

Time-dependent frequency trajectories are an inherent feature of many behaviorally relevant sounds, such as species-specific vocalizations. Dynamic frequency trajectories, even in short sounds, often convey meaningful information, which may be used to differentiate sound categories. However, it is not clear what and where neural responses in the auditory cortical pathway are critical for conveying information about behaviorally relevant frequency trajectories, and how these responses change with experience. Here, we uncover tuning to subtle variations in frequency trajectories in auditory cortex of female mice. We found that auditory cortical responses could be modulated by variations in a pure tone trajectory as small as 1/24th of an octave, comparable to what has been reported in primates. In particular, late spiking after the end of a sound stimulus was more often sensitive to the sound's subtle frequency variation compared with spiking during the sound. Such “Off” responses in the adult A2, but not those in core auditory cortex, were plastic in a way that may enhance the representation of a newly acquired, behaviorally relevant sound category. We illustrate this with the maternal mouse paradigm for natural vocalization learning. By using an ethologically inspired paradigm to drive auditory responses in higher-order neurons, our results demonstrate that mouse auditory cortex can track fine frequency changes, which allows A2 Off responses in particular to better respond to pitch trajectories that distinguish behaviorally relevant, natural sound categories. SIGNIFICANCE STATEMENT A whistle's pitch conveys meaning to its listener, as when dogs learn that distinct pitch trajectories whistled by their owner differentiate specific commands. Many species use pitch trajectories in their own vocalizations to distinguish sound categories, such as in human languages, such as Mandarin. How and where auditory neural activity encodes these pitch trajectories as their meaning is learned but not well understood, especially for short-duration sounds. We studied this in mice, where infants use ultrasonic whistles to communicate to adults. We found that late neural firing after a sound ends can be tuned to how the pitch changes in time, and that this response in a secondary auditory cortical field changes with experience to acquire a pitch change's meaning.

Active mechanical amplification of sound occurs in cochlear outer hair cells (OHCs) that change their length with oscillations of their membrane potential. Such length changes are the proposed cellular source of the cochlear amplifier, and prestin is the motor protein responsible for OHC electromotility. Previous findings have shown that mice lacking prestin displayed a loss of OHC electromotility, subsequent loss of distortion-product otoacoustic emissions, and a 40-60 dB increase in hearing thresholds. In this study we were interested in studying the functional consequences of the complete loss of cochlear amplification on neural coding of frequency selectivity, tuning, and temporal processing in the auditory midbrain. We recorded near-field auditory evoked potentials and multi-unit activity from the inferior colliculus (IC) of prestin (-/-) null and prestin (+/+) wild-type control mice and determined frequency response areas (FRAs), tuning sharpness, and gap detection to tone bursts and silent gaps embedded in broadband noise. We were interested in determining if the moderate to severe sensorineural hearing loss associated with the loss of motor protein prestin would also impair auditory midbrain temporal-processing measures, or if compensatory mechanisms within the brainstem could compensate for the loss of prestin. In prestin knockout mice we observed that there are severe impairments in midbrain tuning, thresholds, excitatory drive, and gap detection suggesting that brainstem and midbrain processing could not overcome the auditory processing deficits afforded by the loss of OHC electromotility mediated by the prestin protein.

It is well known that auditory experience during early development shapes response properties of auditory cortex (AC) neurons, influencing, for example, tonotopical arrangement, response thresholds and strength, or frequency selectivity. Here, we show that rearing rat pups in a complex acoustically enriched environment leads to an increased reliability of responses of AC neurons, affecting both the rate and the temporal codes. For a repetitive stimulus, the neurons exhibit a lower spike count variance, indicating a more stable rate coding. At the level of individual spikes, the discharge patterns of individual neurons show a higher degree of similarity across stimulus repetitions. Furthermore, the neurons follow more precisely the temporal course of the stimulus, as manifested by improved phase-locking to temporally modulated sounds. The changes are persistent and present up to adulthood. The results document that besides basic alterations of receptive fields presented in our previous study, the acoustic environment during the critical period of postnatal development also leads to a decreased stochasticity and a higher reproducibility of neuronal spiking patterns.

Spike sorting is an essential first step in most analyses of extracellular in vivo electrophysiological recordings. Here we show that spike-sorting success depends critically on characteristics of coordinated population activity that can differ between anesthetic states. In tetrode recordings from mouse auditory cortex, spike sorting was significantly less successful under ketamine/medetomidine (ket/med) than urethane anesthesia. Surprisingly, this difficulty with sorting under ket/med anesthesia did not appear to result from either greater millisecond-scale burstiness of neural activity or increased coordination of activity among neighboring neurons. Rather, the key factor affecting sorting success appeared to be the amount of coordinated population activity at long time intervals and across large cortical distances. We propose that spike-sorting success is directly dependent on overall coordination of activity, and is most disrupted by large-scale fluctuations in cortical population activity. Reliability of single-unit recording may therefore differ not only between urethane-anesthetized and ket/med-anesthetized states as demonstrated here, but also between synchronized and desynchronized states, asleep and awake states, or inattentive and attentive states in unanesthetized animals.

The auditory cortex is an essential center for sound localization. In echolocating bats, combination sensitive neurons tuned to specific delays between call emission and echo perception represent target distance. In many bats, these neurons are organized as a chronotopically organized map of echo delay. However, it is still unclear to what extend these neurons can process directional information and thereby form a three-dimensional representation of space. We investigated the representation of three-dimensional space in the auditory cortex of Phyllostomus discolor. Specifically, we hypothesized that combination sensitive neurons encoding target distance in the AC can also process directional information. We used typical echolocation pulses of P. discolor combined with simulated echoes from different positions in virtual 3D-space and measured the evoked neuronal responses in the AC of the anesthetized bats. Our results demonstrate that combination sensitive neurons in the AC responded selectively to specific positions in 3-D space. While these neurons were sharply tuned to echo delay and formed a precise target distance map, the neurons' specificity in azimuth and elevation depended on the presented sound pressure level. Our data further reveal a topographic distribution of best elevation of the combination sensitive neurons along the rostro-caudal axis i.e., neurons in the rostral part of the target distance map representing short delays prefer elevations below the horizon. Due to their spatial directionality and selectivity to specific echo delays representing target distance, combination sensitive cortical neurons are suited to encode three-dimensional spatial information.

Feedback signals from the primary auditory cortex (A1) can shape the receptive field properties of neurons in the ventral division of the medial geniculate body (MGBv). However, the behavioral significance of corticothalamic modulation is unknown. The aim of this study was to elucidate the role of this descending pathway in the perception of complex sounds. We tested the ability of adult female ferrets to detect the presence of a mistuned harmonic in a complex tone using a positive conditioned go/no-go behavioral paradigm before and after the input from layer VI in A1 to MGBv was bilaterally and selectively eliminated using chromophore-targeted laser photolysis. MGBv neurons were identified by their short latencies and sharp tuning curves. They responded robustly to harmonic complex tones and exhibited an increase in firing rate and temporal pattern changes when one frequency component in the complex tone was mistuned. Injections of fluorescent microbeads conjugated with a light-sensitive chromophore were made in MGBv, and, following retrograde transport to the cortical cell bodies, apoptosis was induced by infrared laser illumination of A1. This resulted in a selective loss of ∼60% of layer VI A1-MGBv neurons. After the lesion, mistuning detection was impaired, as indicated by decreased d' values, a shift of the psychometric curves toward higher mistuning values, and increased thresholds, whereas discrimination performance was unaffected when level cues were also available. Our results suggest that A1-MGBv corticothalamic feedback contributes to the detection of harmonicity, one of the most important grouping cues in the perception of complex sounds.SIGNIFICANCE STATEMENT Perception of a complex auditory scene is based on the ability of the brain to group those sound components that belong to the same source and to segregate them from those belonging to different sources. Because two people talking simultaneously may differ in their voice pitch, perceiving the harmonic structure of sounds is very important for auditory scene analysis. Here we demonstrate mistuning sensitivity in the thalamus and that feedback from the primary auditory cortex is required for the normal ability of ferrets to detect a mistuned harmonic within a complex sound. These results provide novel insight into the function of descending sensory pathways in the brain and suggest that this corticothalamic circuit plays an important role in scene analysis.

The occurrence of tinnitus can be linked to hearing loss in the majority of cases, but there is nevertheless a large degree of unexplained heterogeneity in the relation between hearing loss and tinnitus. Part of the problem might be that hearing loss is usually quantified in terms of increased hearing thresholds, which only provides limited information about the underlying cochlear damage. Moreover, noise exposure that does not cause hearing threshold loss can still lead to "hidden hearing loss" (HHL), i.e., functional deafferentation of auditory nerve fibers (ANFs) through loss of synaptic ribbons in inner hair cells. While it is known that increased hearing thresholds can trigger increases in spontaneous neural activity in the central auditory system, i.e., a putative neural correlate of tinnitus, the central effects of HHL have not yet been investigated. Here, we exposed mice to octave-band noise at 100 and 105 dB SPL to generate HHL and permanent increases of hearing thresholds, respectively. Deafferentation of ANFs was confirmed through measurement of auditory brainstem responses and cochlear immunohistochemistry. Acute extracellular recordings from the auditory midbrain (inferior colliculus) demonstrated increases in spontaneous neuronal activity (a putative neural correlate of tinnitus) in both groups. Surprisingly, the increase in spontaneous activity was most pronounced in the mice with HHL, suggesting that the relation between hearing loss and neuronal hyperactivity might be more complex than currently understood. Our computational model indicated that these differences in neuronal hyperactivity could arise from different degrees of deafferentation of low-threshold ANFs in the two exposure groups. Our results demonstrate that HHL is sufficient to induce changes in central auditory processing, and they also indicate a non-monotonic relationship between cochlear damage and neuronal hyperactivity, suggesting an explanation for why tinnitus might occur without obvious hearing loss and conversely why hearing loss does not always lead to tinnitus.

Successful speech perception in real-world environments requires that the auditory system segregate competing voices that overlap in frequency and time into separate streams. Vowels are major constituents of speech and are comprised of frequencies (harmonics) that are integer multiples of a common fundamental frequency (F0). The pitch and identity of a vowel are determined by its F0 and spectral envelope (formant structure), respectively. When two spectrally overlapping vowels differing in F0 are presented concurrently, they can be readily perceived as two separate “auditory objects” with pitches at their respective F0s. A difference in pitch between two simultaneous vowels provides a powerful cue for their segregation, which in turn, facilitates their individual identification. The neural mechanisms underlying the segregation of concurrent vowels based on pitch differences are poorly understood. Here, we examine neural population responses in macaque primary auditory cortex (A1) to single and double concurrent vowels (/a/ and /i/) that differ in F0 such that they are heard as two separate auditory objects with distinct pitches. We find that neural population responses in A1 can resolve, via a rate-place code, lower harmonics of both single and double concurrent vowels. Furthermore, we show that the formant structures, and hence the identities, of single vowels can be reliably recovered from the neural representation of double concurrent vowels. We conclude that A1 contains sufficient spectral information to enable concurrent vowel segregation and identification by downstream cortical areas.

There has been continued interest in clinical objective measures of binaural processing. One commonly proposed measure is the binaural interaction component (BIC), which is obtained typically by recording auditory brainstem responses (ABRs)—the BIC reflects the difference between the binaural ABR and the sum of the monaural ABRs (i.e., binaural − (left + right)). We have recently developed an alternative, direct measure of sensitivity to interaural time differences, namely, a following response to modulations in interaural phase difference (the interaural phase modulation following response; IPM-FR). To obtain this measure, an ongoing diotically amplitude-modulated signal is presented, and the interaural phase difference of the carrier is switched periodically at minima in the modulation cycle. Such periodic modulations to interaural phase difference can evoke a steady state following response. BIC and IPM-FR measurements were compared from 10 normal-hearing subjects using a 16-channel electroencephalographic system. Both ABRs and IPM-FRs were observed most clearly from similar electrode locations—differential recordings taken from electrodes near the ear (e.g., mastoid) in reference to a vertex electrode (Cz). Although all subjects displayed clear ABRs, the BIC was not reliably observed. In contrast, the IPM-FR typically elicited a robust and significant response. In addition, the IPM-FR measure required a considerably shorter recording session. As the IPM-FR magnitude varied with interaural phase difference modulation depth, it could potentially serve as a correlate of perceptual salience. Overall, the IPM-FR appears a more suitable clinical measure than the BIC.

For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF (Pax2) -KO) versus the auditory cortex and hippocampus (BDNF (TrkC) -KO). We demonstrate that BDNF (Pax2) -KO but not BDNF (TrkC) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF (Pax2) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF (Pax2) -KO, but not of BDNF (TrkC) -KO mice. Also, BDNF (Pax2) -WT but not BDNF (Pax2) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.