Auditory Neurophysiology publications

Introduction Repeatedly pairing a tone with vagus nerve stimulation (VNS) alters frequency tuning across the auditory pathway. Pairing VNS with speech sounds selectively enhances the primary auditory cortex response to the paired sounds. It is not yet known how altering the speech sounds paired with VNS alters responses. In this study, we test the hypothesis that the sounds that are presented and paired with VNS will influence the neural plasticity observed following VNS-sound pairing. Methods To explore the relationship between acoustic experience and neural plasticity, responses were recorded from primary auditory cortex (A1) after VNS was repeatedly paired with the speech sounds ‘rad’ and ‘lad’ or paired with only the speech sound ‘rad’ while ‘lad’ was an unpaired background sound. Results Pairing both sounds with VNS increased the response strength and neural discriminability of the paired sounds in the primary auditory cortex. Surprisingly, pairing only ‘rad’ with VNS did not alter A1 responses. Discussion These results suggest that the specific acoustic contrasts associated with VNS can powerfully shape neural activity in the auditory pathway. Methods to promote plasticity in the central auditory system represent a new therapeutic avenue to treat auditory processing disorders. Understanding how different sound contrasts and neural activity patterns shape plasticity could have important clinical implications.

Little is known about how populations of neurons within cortical circuits encode sensory stimuli in the presence of competing stimuli at other spatial locations. Here, we investigate this problem in auditory cortex using a recently proposed information-theoretic approach. We find a small subset of neurons nearly maximizes information about target sounds in the presence of competing maskers, approaching information levels for isolated stimuli, and provides a noise-robust code for sounds in a complex auditory scene.

Despite lacking ears, the nematode C. elegans senses airborne sound and engages in phonotaxis behavior, enabling it to locate and avoid sound sources.1 How worms sense sound, however, is not well understood. Here, we report an interesting observation that worms respond only to sounds emitted by small but not large speakers, indicating that they preferentially respond to localized sound sources. Notably, sounds emitted by small speakers form a sharp sound pressure gradient across the worm body, while sounds from large speakers do not, suggesting that worms sense sound pressure gradients rather than absolute sound pressure. Analysis of phonotaxis behavior, sound-evoked skin vibration, and sound-sensitive neuron activities further support this model. We suggest that the ability to sense sound pressure gradients provides a potential mechanism for worms to distinguish sounds generated by their predators, which are typically small animals, from those produced by large animals or background noise. As vertebrate cochlea and some insect ears can also detect sound pressure gradients, our results reveal that sensing of sound pressure gradients may represent a common mechanism in auditory sensation across animal phyla. VIDEO ABSTRACT.

Context modulates how information is processed in the mammalian brain. For example, brain responses are amplified to contextually unusual stimuli. This phenomenon, known as "deviance detection,"1,2 is well documented in early, primary sensory cortex, where large responses are generated to simple stimuli that deviate from their context in low-order properties, such as line orientation, size, or pitch.2,3,4,5 However, the extent to which neural deviance detection manifests (1) in broader cortical networks and (2) to simple versus complex stimuli, which deviate only in their higher-order, multisensory properties, is not known. Consistent with a predictive processing framework,6,7 we hypothesized that deviance detection manifests in a hierarchical manner across cortical networks,8,9 emerging later and further downstream when stimulus deviance is complex. To test this, we examined brain responses of awake mice to simple unisensory deviants (e.g., visual line gratings, deviating from context in their orientation alone) versus complex multisensory deviants (i.e., audiovisual pairs, deviating from context only in their audiovisual pairing but not visual or auditory content alone). We find that mouse parietal associative area-a higher cortical region-displays robust multisensory deviance detection. In contrast, primary visual cortex exhibits strong unisensory visual deviance detection but weaker multisensory deviance detection. These results suggest that deviance detection signals in the cortex may be conceptualized as "prediction errors," which are primarily fed forward-or downstream-in cortical networks.6,7.

Study of the inferior colliculus (IC) has largely focused on the central nucleus, with little exploration of the outer cortices. Here, we systematically assessed the acoustic response properties from over 2,000 locations in different subregions of the IC. The results revealed spatial trends in temporal response patterns that span all subregions. Furthermore, two populations of temporal response types emerged for neurons in the outer cortices that may contribute to their functional roles in auditory tasks.

Direct neural recordings from human auditory cortex have demonstrated encoding for acoustic-phonetic features of consonants and vowels. Neural responses also encode distinct acoustic amplitude cues related to timing, such as those that occur at the onset of a sentence after a silent period or the onset of the vowel in each syllable. Here, we used a group reduced rank regression model to show that distributed cortical responses support a low-dimensional latent state representation of temporal context in speech. The timing cues each capture more unique variance than all other phonetic features and exhibit rotational or cyclical dynamics in latent space from activity that is widespread over the superior temporal gyrus. We propose that these spatially distributed timing signals could serve to provide temporal context for, and possibly bind across time, the concurrent processing of individual phonetic features, to compose higher-order phonological (e.g. word-level) representations.

The ability to process and act upon incoming sounds during locomotion is critical for survival and adaptive behavior. Despite the established role that the auditory cortex (AC) plays in behavior- and context-dependent sound processing, previous studies have found that auditory cortical activity is on average suppressed during locomotion as compared to immobility. While suppression of auditory cortical responses to self-generated sounds results from corollary discharge, which weakens responses to predictable sounds, the functional role of weaker responses to unpredictable external sounds during locomotion remains unclear. In particular, whether suppression of external sound-evoked responses during locomotion reflects reduced involvement of the AC in sound processing or whether it results from masking by an alternative neural computation in this state remains unresolved. Here, we tested the hypothesis that rather than simple inhibition, reduced sound-evoked responses during locomotion reflect a tradeoff with the emergence of explicit and reliable coding of locomotion velocity. To test this hypothesis, we first used neural inactivation in behaving mice and found that the AC plays a critical role in sound-guided behavior during locomotion. To investigate the nature of this processing, we used two-photon calcium imaging of local excitatory auditory cortical neural populations in awake mice. We found that locomotion had diverse influences on activity of different neurons, with a net suppression of baseline-subtracted sound-evoked responses and neural stimulus detection, consistent with previous studies. Importantly, we found that the net inhibitory effect of locomotion on baseline-subtracted sound-evoked responses was strongly shaped by elevated ongoing activity that compressed the response dynamic range, and that rather than reflecting enhanced “noise,” this ongoing activity reliably encoded the animal’s locomotion speed. Decoding analyses revealed that locomotion speed and sound are robustly co-encoded by auditory cortical ensemble activity. Finally, we found consistent patterns of joint coding of sound and locomotion speed in electrophysiologically recorded activity in freely moving rats. Together, our data suggest that rather than being suppressed by locomotion, auditory cortical ensembles explicitly encode it alongside sound information to support sound perception during locomotion.

Understanding central auditory processing critically depends on defining underlying auditory cortical networks and their relationship to the rest of the brain. We addressed these questions using resting state functional connectivity derived from human intracranial electroencephalography. Mapping recording sites into a low-dimensional space where proximity represents functional similarity revealed a hierarchical organization. At a fine scale, a group of auditory cortical regions excluded several higher-order auditory areas and segregated maximally from the prefrontal cortex. On mesoscale, the proximity of limbic structures to the auditory cortex suggested a limbic stream that parallels the classically described ventral and dorsal auditory processing streams. Identities of global hubs in anterior temporal and cingulate cortex depended on frequency band, consistent with diverse roles in semantic and cognitive processing. On a macroscale, observed hemispheric asymmetries were not specific for speech and language networks. This approach can be applied to multivariate brain data with respect to development, behavior, and disorders.

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome. MECP2 codes for methyl CpG binding protein 2 (MECP2), a transcriptional regulator that activates genetic programs for experience-dependent plasticity. Many neural and behavioral symptoms of Rett syndrome may result from dysregulated timing and thresholds for plasticity. As a model of adult plasticity, we examine changes to auditory cortex inhibitory circuits in female mice when they are first exposed to pups; this plasticity facilitates behavioral responses to pups emitting distress calls. Brainwide deletion of Mecp2 alters expression of markers associated with GABAergic parvalbumin interneurons (PVins) and impairs the emergence of pup retrieval. We hypothesized that loss of Mecp2 in PVins disproportionately contributes to the phenotype. Here, we find that deletion of Mecp2 from PVins delayed the onset of maternal retrieval behavior and recapitulated the major molecular and neurophysiological features of brainwide deletion of Mecp2 . We observed that when PVin-selective mutants were exposed to pups, auditory cortical expression of PVin markers increased relative to that in wild-type littermates. PVin-specific mutants also failed to show the inhibitory auditory cortex plasticity seen in wild-type mice on exposure to pups and their vocalizations. Finally, using an intersectional viral genetic strategy, we demonstrate that postdevelopmental loss of Mecp2 in PVins of the auditory cortex is sufficient to delay onset of maternal retrieval. Our results support a model in which PVins play a central role in adult cortical plasticity and may be particularly impaired by loss of Mecp2 . SIGNIFICANCE STATEMENT Rett syndrome is a neurodevelopmental disorder that includes deficits in both communication and the ability to update brain connections and activity during learning (plasticity). This condition is caused by mutations in the gene MECP2 . We use a maternal behavioral test in mice requiring both vocal perception and neural plasticity to probe the role of Mecp2 in social and sensory learning. Mecp2 is normally active in all brain cells, but here we remove it from a specific population (parvalbumin neurons). We find that this is sufficient to delay learned behavioral responses to pups and recreates many deficits seen in whole-brain Mecp2 deletion. Our findings suggest that parvalbumin neurons specifically are central to the consequences of loss of Mecp2 activity and yield clues as to possible mechanisms by which Rett syndrome impairs brain function.

Background Behavior consists of the interaction between an organism and its environment, and is controlled by the brain. Brain activity varies at sub-second time scales, but behavioral measures are usually coarse (often consisting of only binary trial outcomes). Results To overcome this mismatch, we developed the Rat Interactive Foraging Facility (RIFF): a programmable interactive arena for freely moving rats with multiple feeding areas, multiple sound sources, high-resolution behavioral tracking, and simultaneous electrophysiological recordings. The paper provides detailed information about the construction of the RIFF and the software used to control it. To illustrate the flexibility of the RIFF, we describe two complex tasks implemented in the RIFF, a foraging task and a sound localization task. Rats quickly learned to obtain rewards in both tasks. Neurons in the auditory cortex as well as neurons in the auditory field in the posterior insula had sound-driven activity during behavior. Remarkably, neurons in both structures also showed sensitivity to non-auditory parameters such as location in the arena and head-to-body angle. Conclusions The RIFF provides insights into the cognitive capabilities and learning mechanisms of rats and opens the way to a better understanding of how brains control behavior. The ability to do so depends crucially on the combination of wireless electrophysiology and detailed behavioral documentation available in the RIFF.

Lots of adrenergic receptors (ARs) are widely present across the auditory pathways and are positioned to affect auditory and vestibular functions. However, noradrenergic regulation in the cochlea has not been well characterized. In this study, a rat model of noise-induced hearing loss was developed to investigate the expression of α2A-adrenergic receptor (AR) after acoustic trauma, then, we investigated the expression of α2A-AR in the developing rat cochlea using immunofluorescence, qRT-PCR, and Western blotting. We found that the expression of α2A-AR significantly increased in rats exposed to noise compared with controls. Immunofluorescence analysis demonstrated that α2A-AR is localized on hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV) in the postnatal developing cochlea from post-natal day (P) 0 to P28. Furthermore, we observed α2A-AR mRNA reached a maximum level at P14 and P28 when compared with P0, while no significant differences in α2A-AR protein levels at the various stages when compared with P0. This study provides direct evidence for the expression of α2A-AR in HCs, SGNs, and the SV of the cochlea, indicating that norepinephrine might play a vital role in hearing function within the cochlea through α2A-AR.

Mouse ultrasonic vocalizations (USVs) contain predictable sequential structures like bird songs and speech. Neural representation of USVs in the mouse primary auditory cortex (Au1) and its plasticity with experience has been largely studied with single-syllables or dyads, without using the predictability in USV sequences. Studies using playback of USV sequences have used randomly selected sequences from numerous possibilities. The current study uses mutual information to obtain context-specific natural sequences (NSeqs) of USV syllables capturing the observed predictability in male USVs in different contexts of social interaction with females. Behavioral and physiological significance of NSeqs over random sequences (RSeqs) lacking predictability were examined. Female mice, never having the social experience of being exposed to males, showed higher selectivity for NSeqs behaviorally and at cellular levels probed by expression of immediate early gene c- fos in Au1. The Au1 supragranular single units also showed higher selectivity to NSeqs over RSeqs. Social-experience-driven plasticity in encoding NSeqs and RSeqs in adult females was probed by examining neural selectivities to the same sequences before and after the above social experience. Single units showed enhanced selectivity for NSeqs over RSeqs after the social experience. Further, using two-photon Ca 2+ imaging, we observed social experience-dependent changes in the selectivity of sequences of excitatory and somatostatin-positive inhibitory neurons but not parvalbumin-positive inhibitory neurons of Au1. Using optogenetics, somatostatin-positive neurons were identified as a possible mediator of the observed social-experience-driven plasticity. Our study uncovers the importance of predictive sequences and introduces mouse USVs as a promising model to study context-dependent speech like communications. SIGNIFICANCE STATEMENT Humans need to detect patterns in the sensory world. For instance, speech is meaningful sequences of acoustic tokens easily differentiated from random ordered tokens. The structure derives from the predictability of the tokens. Similarly, mouse vocalization sequences have predictability and undergo context-dependent modulation. Our work investigated whether mice differentiate such informative predictable sequences (NSeqs) of communicative significance from RSeqs at the behavioral, molecular, and neuronal levels. Following a social experience in which NSeqs occur as a crucial component, mouse auditory cortical neurons become more sensitive to differences between NSeqs and RSeqs, although preference for individual tokens is unchanged. Thus, speech-like communication and its dysfunction may be studied in circuit, cellular, and molecular levels in mice.

Synaptic zinc signaling modulates synaptic activity and is present in specific populations of cortical neurons, suggesting that synaptic zinc contributes to the diversity of intracortical synaptic microcircuits and their functional specificity. To understand the role of zinc signaling in the cortex, we performed whole-cell patch-clamp recordings from intratelencephalic (IT)-type neurons and pyramidal tract (PT)-type neurons in layer 5 of the mouse auditory cortex during optogenetic stimulation of specific classes of presynaptic neurons. Our results show that synaptic zinc potentiates AMPA receptor (AMPAR) function in a synapse-specific manner. We performed in vivo 2-photon calcium imaging of the same classes of neurons in awake mice and found that changes in synaptic zinc can widen or sharpen the sound-frequency tuning bandwidth of IT-type neurons but only widen the tuning bandwidth of PT-type neurons. These results provide evidence for synapse- and cell-type-specific actions of synaptic zinc in the cortex.

Schroeder-phase harmonic tone complexes can have a flat temporal envelope and rising or falling instantaneous-frequency sweeps within F0 periods, depending on the phase-scaling parameter C. Human tone-detection thresholds in a concurrent Schroeder masker are 10-15 dB lower for positive C values (rising frequency sweeps) compared to negative (falling sweeps), potentially due to cochlear mechanics, though this hypothesis remains controversial. Birds provide an interesting model for studies of Schroeder masking because many species produce vocalizations containing frequency sweeps. Prior behavioral studies in birds suggest less behavioral threshold difference between maskers with opposite C values than in humans, but focused on low masker F0s and did not explore neural mechanisms. We performed behavioral Schroeder-masking experiments in budgerigars (Melopsittacus undulatus) using a wide range of masker F0 and C values. Signal frequency was 2800 Hz. Neural recordings from the midbrain characterized encoding of behavioral stimuli in awake animals. Behavioral thresholds increased with increasing masker F0 and showed minimal difference between opposite C values, consistent with prior budgerigar studies. Midbrain recordings showed prominent temporal and rate-based encoding of Schroeder F0, and in many cases, marked asymmetry in Schroeder responses between C polarities. Neural thresholds for Schroeder-masked tone detection were often based on a response decrement compared to the masker alone, consistent with prominent modulation tuning in midbrain neurons, and were generally similar between opposite C values. The results highlight the likely importance of envelope cues in Schroeder masking and show that differences in supra-threshold Schroeder responses do not necessarily result in neural threshold differences.

So-called duplex speech stimuli with perceptually ambiguous spectral cues to one ear and isolated low- versus high-frequency third formant “chirp” to the opposite ear yield a coherent percept supporting their phonetic categorization. Critically, such dichotic sounds are only perceived categorically upon binaural integration. Here, we used frequency-following responses (FFRs), scalp-recorded potentials reflecting phase-locked subcortical activity, to investigate brainstem responses to fused speech percepts and to determine whether FFRs reflect binaurally integrated category-level representations. We recorded FFRs to diotic and dichotic stop-consonants (/da/, /ga/) that either did or did not require binaural fusion to properly label along with perceptually ambiguous sounds without clear phonetic identity. Behaviorally, listeners showed clear categorization of dichotic speech tokens confirming they were heard with a fused, phonetic percept. Neurally, we found FFRs were stronger for categorically perceived speech relative to category-ambiguous tokens but also differentiated phonetic categories for both diotically and dichotically presented speech sounds. Correlations between neural and behavioral data further showed FFR latency predicted the degree to which listeners labeled tokens as “da” versus “ga.” The presence of binaurally integrated, category-level information in FFRs suggests human brainstem processing reflects a surprisingly abstract level of the speech code typically circumscribed to much later cortical processing.

Background Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. Methods In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. Results We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. Conclusions These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD.

We have 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. Using optogenetics and electrical stimulation, we investigated the functional properties of these descending connections in vivo in anaesthetised rats. A retrograde virus encoding green fluorescent protein (GFP) and channelrhodopsin (ChR2) injected into the central nucleus of the inferior colliculus (ICC), labelled discrete groups of cells in multiple areas of the cerebral cortex. Light stimulation of AC and 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. Electrical stimulation of M1, secondary motor, somatosensory and prefrontal cortical regions evoked short, fixed latency firing events in ICC as well as longer latency, longer duration increases in firing activity. The short latency events were singular spikes of consistent shape and size likely resulting from monosynaptic excitation of individual ICC units. The longer latency responses comprised multiple units and spikes occurred with significant temporal jitter suggesting polysynaptic activation of local circuits within the ICC. The probability of the monosynaptic event, the magnitude of the polysynaptic response, and the area of ICC affected were dependent on the stimulus current. Our data are consistent with cortical regions exerting an important excitatory direct and indirect regulation of ICc neurones. Significance statement We have recently described inputs from motor, somatosensory, and executive cortices to the inferior colliculus (IC, auditory midbrain). Here we provide functional evidence for such connections. Optogenetics, using a retrograde virus encoding channelrhodopsin injected into IC revealed a direct excitatory influence of neurones in auditory and motor cortices on firing in IC. Electrical stimulation of discrete cortical regions revealed that multiple non-auditory cortical regions have a direct monosynaptic excitatory influence on neurones in the IC which, in turn, activates local circuits increasing the firing probability of multiple neurones in the IC. This is the first evidence for circuitry by which auditory processing can be influenced at an early stage by activity in the sensory, motor and executive domains.

Sensorineural hearing loss is associated with dysfunction of cochlear cells. Although immune cells play a critical role in maintaining the inner ear microenvironment, the precise immune-related molecular mechanisms underlying the pathophysiology of hearing loss remain unclear. The complement cascade contributes to the regulation of immune cell activity. Additionally, activation of the complement cascade can lead to the cellular opsonization of cells and pathogens, resulting in their engulfment and elimination by phagocytes. Complement factor B (fB) is an essential activator protein in the alternative complement pathway, and variations in the fB gene are associated with age-related macular degeneration. Here we show that mice of both sexes deficient in fB functional alleles (fB −/− ) demonstrate progressive hearing impairment. Transcriptomic analysis of auditory nerves from adult mice detected 706 genes that were significantly differentially expressed between fB −/− and wild-type control animals, including genes related to the extracellular matrix and neural development processes. Additionally, a subset of differentially expressed genes was related to myelin function and neural crest development. Histological and immunohistochemical investigations revealed pathological alterations in auditory nerve myelin sheathes of fB −/− mice. Pathological alterations were also seen in the stria vascularis of the cochlear lateral wall in these mice. Our results implicate fB as an integral regulator of myelin maintenance and stria vascularis integrity, underscoring the importance of understanding the involvement of immune signaling pathways in sensorineural hearing loss.

Cochlear inner hair cells (IHCs) form specialized ribbon synapses with spiral ganglion neurons that tirelessly transmit sound information at high rates over long time periods with extreme temporal precision. This functional specialization is essential for sound encoding and is attributed to a distinct molecular machinery with unique players or splice variants compared to conventional neuronal synapses. Among these is the active zone (AZ) scaffold protein piccolo/aczonin, which is represented by its short splice variant piccolino at cochlear and retinal ribbon synapses. While the function of piccolo at synapses of the central nervous system has been intensively investigated, the role of piccolino at IHC synapses remains unclear. In this study, we characterize the structure and function of IHC synapses in piccolo gene-trap mutant rats (Pclogt/gt ). We find a mild hearing deficit with elevated thresholds and reduced amplitudes of auditory brainstem responses. Ca2+ channel distribution and ribbon morphology are altered in apical IHCs, while their presynaptic function seems to be unchanged. We conclude that piccolino contributes to the AZ organization in IHCs and is essential for normal hearing.

Cortical representations supporting many cognitive abilities emerge from underlying circuits comprised of several different cell types. However, cell type-specific contributions to rate and timing-based cortical coding are not well-understood. Here, we investigated the role of parvalbumin neurons in cortical complex scene analysis. Many complex scenes contain sensory stimuli which are highly dynamic in time and compete with stimuli at other spatial locations. Parvalbumin neurons play a fundamental role in balancing excitation and inhibition in cortex and sculpting cortical temporal dynamics; yet their specific role in encoding complex scenes via timing-based coding, and the robustness of temporal representations to spatial competition, has not been investigated. Here, we address these questions in auditory cortex of mice using a cocktail party-like paradigm, integrating electrophysiology, optogenetic manipulations, and a family of spike-distance metrics, to dissect parvalbumin neurons’ contributions towards rate and timing-based coding. We find that suppressing parvalbumin neurons degrades cortical discrimination of dynamic sounds in a cocktail party-like setting via changes in rapid temporal modulations in rate and spike timing, and over a wide range of time-scales. Our findings suggest that parvalbumin neurons play a critical role in enhancing cortical temporal coding and reducing cortical noise, thereby improving representations of dynamic stimuli in complex scenes.