A thalamic-primary auditory cortex circuit mediates resilience to stress.

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.

Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

Parallel and distributed encoding of speech across human auditory cortex.

Speech perception is thought to rely on a cortical feedforward serial transformation of acoustic into linguistic representations. Using intracranial recordings across the entire human auditory cortex, electrocortical stimulation, and surgical ablation, we show that cortical processing across areas is not consistent with a serial hierarchical organization. Instead, response latency and receptive field analyses demonstrate parallel and distinct information processing in the primary and nonprimary auditory cortices. This functional dissociation was also observed where stimulation of the primary auditory cortex evokes auditory hallucination but does not distort or interfere with speech perception. Opposite effects were observed during stimulation of nonprimary cortex in superior temporal gyrus. Ablation of the primary auditory cortex does not affect speech perception. These results establish a distributed functional organization of parallel information processing throughout the human auditory cortex and demonstrate an essential independent role for nonprimary auditory cortex in speech processing.

High-Throughput Mapping of Long-Range Neuronal Projection Using In Situ Sequencing.

Understanding neural circuits requires deciphering interactions among myriad cell types defined by spatial organization, connectivity, gene expression, and other properties. Resolving these cell types requires both single-neuron resolution and high throughput, a challenging combination with conventional methods. Here, we introduce barcoded anatomy resolved by sequencing (BARseq), a multiplexed method based on RNA barcoding for mapping projections of thousands of spatially resolved neurons in a single brain and relating those projections to other properties such as gene or Cre expression. Mapping the projections to 11 areas of 3,579 neurons in mouse auditory cortex using BARseq confirmed the laminar organization of the three top classes (intratelencephalic [IT], pyramidal tract-like [PT-like], and corticothalamic [CT]) of projection neurons. In depth analysis uncovered a projection type restricted almost exclusively to transcriptionally defined subtypes of IT neurons. By bridging anatomical and transcriptomic approaches at cellular resolution with high throughput, BARseq can potentially uncover the organizing principles underlying the structure and formation of neural circuits.

Sensory Neuron Diversity in the Inner Ear Is Shaped by Activity.

In the auditory system, type I spiral ganglion neurons (SGNs) convey complex acoustic information from inner hair cells (IHCs) to the brainstem. Although SGNs exhibit variation in physiological and anatomical properties, it is unclear which features are endogenous and which reflect input from synaptic partners. Using single-cell RNA sequencing, we derived a molecular classification of mouse type I SGNs comprising three subtypes that express unique combinations of Ca2+ binding proteins, ion channel regulators, guidance molecules, and transcription factors. Based on connectivity and susceptibility to age-related loss, these subtypes correspond to those defined physiologically. Additional intrinsic differences among subtypes and across the tonotopic axis highlight an unexpectedly active role for SGNs in auditory processing. SGN identities emerge postnatally and are disrupted in a mouse model of deafness that lacks IHC-driven activity. These results elucidate the range, nature, and origins of SGN diversity, with implications for treatment of congenital deafness.

Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain.

Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.

Adaptation in auditory processing.

Adaptation is an essential feature of auditory neurons, which reduces their responses to unchanging and recurring sounds and allows their response properties to be matched to the constantly changing statistics of sounds that reach the ears. As a consequence, processing in the auditory system highlights novel or unpredictable sounds and produces an efficient representation of the vast range of sounds that animals can perceive by continually adjusting the sensitivity and, to a lesser extent, the tuning properties of neurons to the most commonly encountered stimulus values. Together with attentional modulation, adaptation to sound statistics also helps to generate neural representations of sound that are tolerant to background noise and therefore plays a vital role in auditory scene analysis. In this review, we consider the diverse forms of adaptation that are found in the auditory system in terms of the processing levels at which they arise, the underlying neural mechanisms, and their impact on neural coding and perception. We also ask what the dynamics of adaptation, which can occur over multiple timescales, reveal about the statistical properties of the environment. Finally, we examine how adaptation to sound statistics is influenced by learning and experience and changes as a result of aging and hearing loss.

Diversity matters - extending sound intensity coding by inner hair cells via heterogeneous synapses.

Our sense of hearing enables the processing of stimuli that differ in sound pressure by more than six orders of magnitude. How to process a wide range of stimulus intensities with temporal precision is an enigmatic phenomenon of the auditory system. Downstream of dynamic range compression by active cochlear micromechanics, the inner hair cells (IHCs) cover the full intensity range of sound input. Yet, the firing rate in each of their postsynaptic spiral ganglion neurons (SGNs) encodes only a fraction of it. As a population, spiral ganglion neurons with their respective individual coding fractions cover the entire audible range. How such "dynamic range fractionation" arises is a topic of current research and the focus of this review. Here, we discuss mechanisms for generating the diverse functional properties of SGNs and formulate testable hypotheses. We postulate that an interplay of synaptic heterogeneity, molecularly distinct subtypes of SGNs, and efferent modulation serves the neural decomposition of sound information and thus contributes to a population code for sound intensity.

Acoustic Pattern Recognition and Courtship Songs: Insights from Insects.

Across the animal kingdom, social interactions rely on sound production and perception. From simple cricket chirps to more elaborate bird songs, animals go to great lengths to communicate information critical for reproduction and survival via acoustic signals. Insects produce a wide array of songs to attract a mate, and the intended receivers must differentiate these calls from competing sounds, analyze the quality of the sender from spectrotemporal signal properties, and then determine how to react. Insects use numerically simple nervous systems to analyze and respond to courtship songs, making them ideal model systems for uncovering the neural mechanisms underlying acoustic pattern recognition. We highlight here how the combination of behavioral studies and neural recordings in three groups of insects-crickets, grasshoppers, and fruit flies-reveals common strategies for extracting ethologically relevant information from acoustic patterns and how these findings might translate to other systems.

Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems.

The genetic approach, based on the study of inherited forms of deafness, has proven to be particularly effective for deciphering the molecular mechanisms underlying the development of the peripheral auditory system, the cochlea and its afferent auditory neurons, and how this system extracts the physical parameters of sound. Although this genetic dissection has provided little information about the central auditory system, scattered data suggest that some genes may have a critical role in both the peripheral and central auditory systems. Here, we review the genes controlling the development and function of the peripheral and central auditory systems, focusing on those with demonstrated intrinsic roles in both systems and highlighting the current underappreciation of these genes. Their encoded products are diverse, from transcription factors to ion channels, as are their roles in the central auditory system, mostly evaluated in brainstem nuclei. We examine the ontogenetic and evolutionary mechanisms that may underlie their expression at different sites.

Developmental hearing loss-induced perceptual deficits are rescued by genetic restoration of cortical inhibition.

Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABAA, Gabra1; GABAB, Gabbr1b) in pyramidal neurons, and an enzyme that mediates GABA synthesis (GAD65) presynaptically in parvalbumin-expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABAB receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABAB receptor-dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.

Auditory cortical regions show resting-state functional connectivity with the default mode-like network in echolocating bats.

Echolocating bats are among the most social and vocal of all mammals. These animals are ideal subjects for functional MRI (fMRI) studies of auditory social communication given their relatively hypertrophic limbic and auditory neural structures and their reduced ability to hear MRI gradient noise. Yet, no resting-state networks relevant to social cognition (e.g., default mode-like networks or DMLNs) have been identified in bats since there are few, if any, fMRI studies in the chiropteran order. Here, we acquired fMRI data at 7 Tesla from nine lightly anesthetized pale spear-nosed bats (Phyllostomus discolor). We applied independent components analysis (ICA) to reveal resting-state networks and measured neural activity elicited by noise ripples (on: 10 ms; off: 10 ms) that span this species' ultrasonic hearing range (20 to 130 kHz). Resting-state networks pervaded auditory, parietal, and occipital cortices, along with the hippocampus, cerebellum, basal ganglia, and auditory brainstem. Two midline networks formed an apparent DMLN. Additionally, we found four predominantly auditory/parietal cortical networks, of which two were left-lateralized and two right-lateralized. Regions within four auditory/parietal cortical networks are known to respond to social calls. Along with the auditory brainstem, regions within these four cortical networks responded to ultrasonic noise ripples. Iterative analyses revealed consistent, significant functional connectivity between the left, but not right, auditory/parietal cortical networks and DMLN nodes, especially the anterior-most cingulate cortex. Thus, a resting-state network implicated in social cognition displays more distributed functional connectivity across left, relative to right, hemispheric cortical substrates of audition and communication in this highly social and vocal species.

Cell-type-specific enhancement of deviance detection by synaptic zinc in the mouse auditory cortex.

Stimulus-specific adaptation is a hallmark of sensory processing in which a repeated stimulus results in diminished successive neuronal responses, but a deviant stimulus will still elicit robust responses from the same neurons. Recent work has established that synaptically released zinc is an endogenous mechanism that shapes neuronal responses to sounds in the auditory cortex. Here, to understand the contributions of synaptic zinc to deviance detection of specific neurons, we performed wide-field and 2-photon calcium imaging of multiple classes of cortical neurons. We find that intratelencephalic (IT) neurons in both layers 2/3 and 5 as well as corticocollicular neurons in layer 5 all demonstrate deviance detection; however, we find a specific enhancement of deviance detection in corticocollicular neurons that arises from ZnT3-dependent synaptic zinc in layer 2/3 IT neurons. Genetic deletion of ZnT3 from layer 2/3 IT neurons removes the enhancing effects of synaptic zinc on corticocollicular neuron deviance detection and results in poorer acuity of detecting deviant sounds by behaving mice.

Dissonant music engages early visual processing.

The neuroscientific examination of music processing in audio-visual contexts offers a valuable framework to assess how auditory information influences the emotional encoding of visual information. Using fMRI during naturalistic film viewing, we investigated the neural mechanisms underlying the effect of music on valence inferences during mental state attribution. Thirty-eight participants watched the same short-film accompanied by systematically controlled consonant or dissonant music. Subjects were instructed to think about the main character's intentions. The results revealed that increasing levels of dissonance led to more negatively valenced inferences, displaying the profound emotional impact of musical dissonance. Crucially, at the neuroscientific level and despite music being the sole manipulation, dissonance evoked the response of the primary visual cortex (V1). Functional/effective connectivity analysis showed a stronger coupling between the auditory ventral stream (AVS) and V1 in response to tonal dissonance and demonstrated the modulation of early visual processing via top-down feedback inputs from the AVS to V1. These V1 signal changes indicate the influence of high-level contextual representations associated with tonal dissonance on early visual cortices, serving to facilitate the emotional interpretation of visual information. Our results highlight the significance of employing systematically controlled music, which can isolate emotional valence from the arousal dimension, to elucidate the brain's sound-to-meaning interface and its distributive crossmodal effects on early visual encoding during naturalistic film viewing.

Evolutionary continuity and divergence of auditory dorsal and ventral pathways in primates revealed by ultra-high field diffusion MRI.

Auditory dorsal and ventral pathways in the human brain play important roles in supporting speech and language processing. However, the evolutionary root of the dual auditory pathways in the primate brain is unclear. By parcellating the auditory cortex of marmosets (a New World monkey species), macaques (an Old World monkey species), and humans using the same individual-based analysis method and tracking the pathways from the auditory cortex based on multi-shell diffusion-weighted MRI (dMRI), homologous auditory dorsal and ventral fiber tracks were identified in these primate species. The ventral pathway was found to be well conserved in all three primate species analyzed but extend to more anterior temporal regions in humans. In contrast, the dorsal pathway showed a divergence between monkey and human brains. First, frontal regions in the human brain have stronger connections to the higher-level auditory regions than to the lower-level auditory regions along the dorsal pathway, while frontal regions in the monkey brain show opposite connection patterns along the dorsal pathway. Second, the left lateralization of the dorsal pathway is only found in humans. Moreover, the connectivity strength of the dorsal pathway in marmosets is more similar to that of humans than macaques. These results demonstrate the continuity and divergence of the dual auditory pathways in the primate brains along the evolutionary path, suggesting that the putative neural networks supporting human speech and language processing might have emerged early in primate evolution.

AIF translocation into nucleus caused by Aifm1 R450Q mutation: generation and characterization of a mouse model for AUNX1.

Mutations in AIFM1, encoding for apoptosis-inducing factor (AIF), cause AUNX1, an X-linked neurologic disorder with late-onset auditory neuropathy (AN) and peripheral neuropathy. Despite significant research on AIF, there are limited animal models with the disrupted AIFM1 representing the corresponding phenotype of human AUNX1, characterized by late-onset hearing loss and impaired auditory pathways. Here, we generated an Aifm1 p.R450Q knock-in mouse model (KI) based on the human AIFM1 p.R451Q mutation. Hemizygote KI male mice exhibited progressive hearing loss from P30 onward, with greater severity at P60 and stabilization until P210. Additionally, muscle atrophy was observed at P210. These phenotypic changes were accompanied by a gradual reduction in the number of spiral ganglion neuron cells (SGNs) at P30 and ribbons at P60, which coincided with the translocation of AIF into the nucleus starting from P21 and P30, respectively. The SGNs of KI mice at P210 displayed loss of cytomembrane integrity, abnormal nuclear morphology, and dendritic and axonal demyelination. Furthermore, the inner hair cells and myelin sheath displayed abnormal mitochondrial morphology, while fibroblasts from KI mice showed impaired mitochondrial function. In conclusion, we successfully generated a mouse model recapitulating AUNX1. Our findings indicate that disruption of Aifm1 induced the nuclear translocation of AIF, resulting in the impairment in the auditory pathway.

A novel copy number variant in the murine Cdh23 gene gives rise to profound deafness and vestibular dysfunction.

Hearing loss is the most common congenital sensory deficit worldwide and exhibits high genetic heterogeneity, making molecular diagnoses elusive for most individuals. Detecting novel mutations that contribute to hearing loss is crucial to providing accurate personalized diagnoses, tailored interventions, and improving prognosis. Copy number variants (CNVs) are structural mutations that are understudied, potential contributors to hearing loss. Here, we present the Abnormal Wobbly Gait (AWG) mouse, the first documented mutant exhibiting waltzer-like locomotor dysfunction, hyperactivity, circling behaviour, and profound deafness caused by a spontaneous CNV deletion in cadherin 23 (Cdh23). We were unable to identify the causative mutation through a conventional whole-genome sequencing (WGS) and variant detection pipeline, but instead found a linked variant in hexokinase 1 (Hk1) that was insufficient to recapitulate the AWG phenotype when introduced into C57BL/6J mice using CRISPR-Cas9. Investigating nearby deafness-associated genes revealed a pronounced downregulation of Cdh23 mRNA and a complete absence of full-length CDH23 protein, which is critical for the development and maintenance of inner ear hair cells, in whole head extracts from AWG neonates. Manual inspection of WGS read depth plots of the Cdh23 locus revealed a putative 10.4 kb genomic deletion of exons 11 and 12 that was validated by PCR and Sanger sequencing. This study underscores the imperative to refine variant detection strategies to permit identification of pathogenic CNVs easily missed by conventional variant calling to enhance diagnostic precision and ultimately improve clinical outcomes for individuals with genetically heterogenous disorders such as hearing loss.

Cortical Coding of Auditory Features.

How the cerebral cortex encodes auditory features of biologically important sounds, including speech and music, is one of the most important questions in auditory neuroscience. The pursuit to understand related neural coding mechanisms in the mammalian auditory cortex can be traced back several decades to the early exploration of the cerebral cortex. Significant progress in this field has been made in the past two decades with new technical and conceptual advances. This article reviews the progress and challenges in this area of research.

Bilateral widefield calcium imaging reveals circuit asymmetries and lateralized functional activation of the mouse auditory cortex.

Coordinated functioning of the two cortical hemispheres is crucial for perception. The human auditory cortex (ACx) shows functional lateralization with the left hemisphere specialized for processing speech, whereas the right analyzes spectral content. In mice, virgin females demonstrate a left-hemisphere response bias to pup vocalizations that strengthens with motherhood. However, how this lateralized function is established is unclear. We developed a widefield imaging microscope to simultaneously image both hemispheres of mice to bilaterally monitor functional responses. We found that global ACx topography is symmetrical and stereotyped. In both male and virgin female mice, the secondary auditory cortex (A2) in the left hemisphere shows larger responses than right to high-frequency tones and adult vocalizations; however, only virgin female mice show a left-hemisphere bias in A2 in response to adult pain calls. These results indicate hemispheric bias with both sex-independent and -dependent aspects. Analyzing cross-hemispheric functional correlations showed that asymmetries exist in the strength of correlations between DM-AAF and A2-AAF, while other ACx areas showed smaller differences. We found that A2 showed lower cross-hemisphere correlation than other cortical areas, consistent with the lateralized functional activation of A2. Cross-hemispheric activity correlations are lower in deaf, otoferlin knockout (OTOF-/-) mice, indicating that the development of functional cross-hemispheric connections is experience dependent. Together, our results reveal that ACx is topographically symmetric at the macroscopic scale but that higher-order A2 shows sex-dependent and independent lateralized responses due to asymmetric intercortical functional connections. Moreover, our results suggest that sensory experience is required to establish functional cross-hemispheric connectivity.

Modulation of potassium conductances optimizes fidelity of auditory information.

Potassium channels in auditory neurons are rapidly modified by changes in the auditory environment. In response to elevated auditory stimulation, short-term mechanisms such as protein phosphorylation and longer-term mechanisms such as accelerated channel synthesis increase the amplitude of currents that promote high-frequency firing. It has been suggested that this allows neurons to fire at high rates in response to high sound levels. We have carried out simple simulations of the response to postsynaptic neurons to patterns of neurotransmitter release triggered by auditory stimuli. These demonstrate that the amplitudes of potassium currents required for optimal encoding of a low-amplitude auditory signal differ from those for louder sounds. Specifically, the cross-correlation of the output of a neuron with an auditory stimulus is improved by increasing potassium currents as sound amplitude increases. Temporal fidelity for low-frequency stimuli is improved by increasing potassium currents that activate at negative potentials, while that for high-frequency stimuli requires increases in currents that activate at positive membrane potentials. These effects are independent of the firing rate. Moreover, levels of potassium currents that maximize the fidelity of the output of an ensemble of neurons differ from those that maximize fidelity for a single neuron. This suggests that the modulatory mechanisms must coordinate channel activity in groups of neurons or an entire nucleus. The simulations provide an explanation for the modulation of the intrinsic excitability of auditory brainstem neurons by changes in environmental sound levels, and the results may extend to information processing in other neural systems.