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.

Physiological properties of auditory neurons responding to omission deviants in the anesthetized rat.

The detection of novel, low probability events in the environment is critical for survival. To perform this vital task, our brain is continuously building and updating a model of the outside world; an extensively studied phenomenon commonly referred to as predictive coding. Predictive coding posits that the brain is continuously extracting regularities from the environment to generate predictions. These predictions are then used to supress neuronal responses to redundant information, filtering those inputs, which then automatically enhances the remaining, unexpected inputs. We have recently described the ability of auditory neurons to generate predictions about expected sensory inputs by detecting their absence in an oddball paradigm using omitted tones as deviants. Here, we studied the responses of individual neurons to omitted tones by presenting individual sequences of repetitive pure tones, using both random and periodic omissions, presented at both fast and slow rates in the inferior colliculus and auditory cortex neurons of anesthetized rats. Our goal was to determine whether feature-specific dependence of these predictions exists. Results showed that omitted tones could be detected at both high (8 Hz) and slow repetition rates (2 Hz), with detection being more robust at the non-lemniscal auditory pathway.

Cortical region-specific recovery of auditory temporal processing following noise-induced hearing loss.

Noise-induced hearing loss (NIHL) studies have focused on the lemniscal auditory pathway, but little is known about how NIHL impacts different cortical regions. Here we compared response recovery trajectories in the auditory and frontal cortices (AC, FC) of mice following NIHL. We recorded EEG responses from awake mice (male n = 15, female n = 14) before and following NIHL (longitudinal design) to quantify event related potentials and gap-in-noise temporal processing. Hearing loss was verified by measuring the auditory brainstem response (ABR) before and at 1-, 10-, 23-, and 45-days after noise-exposure. Resting EEG, event related potentials (ERP) and auditory steady state responses (ASSR) were recorded at the same time-points after NIHL. The inter-trial phase coherence (ITPC) of the ASSR was measured to quantify the ability of AC and FC to synchronize responses to short gaps embedded in noise. Despite the absence of click-evoked ABRs up to 90 dB SPL and up to 45-days post-exposure, ERPs from the AC and FC showed full recovery in âˆ¼ 50 % of the mice to pre-NIHL levels in both AC and FC. The ASSR ITPC was reduced following NIHL in AC and FC in all the mice on day 1 after NIHL. The AC showed full recovery of ITPC over 45-days. Despite ERP amplitude recovery, the FC does not show recovery of ASSR ITPC. These results indicate post-NIHL plasticity with similar response amplitude recovery across AC and FC, but cortical region-specific trajectories in temporal processing recovery.

Sparse representation of neurons for encoding complex sounds in the auditory cortex.

Listening in complex sound environments requires rapid segregation of different sound sources, e.g., having a conversation with multiple speakers or other environmental sounds. Efficient processing requires fast encoding of inputs to adapt to target sounds and identify relevant information from past experiences. This adaptation process represents an early phase of implicit learning of the sound statistics to form auditory memory. The auditory cortex (ACtx) plays a crucial role in this implicit learning process, but the underlying circuits are unknown. In awake mice, we recorded neuronal responses in different ACtx subfields using in vivo 2-photon imaging of excitatory and inhibitory (parvalbumin; PV) neurons. We used a paradigm adapted from human studies that induced rapid implicit learning from passively presented complex sounds and imaged A1 Layer 4 (L4), A1 L2/3, and A2 L2/3. In this paradigm, a frozen spectro-temporally complex 'Target' sound randomly re-occurred within a stream of other random complex sounds. All ACtx subregions contained distinct groups of cells specifically responsive to complex acoustic sequences, indicating that even thalamocortical input layers (A1 L4) respond to complex sounds. Subgroups of excitatory and inhibitory cells in all subfields showed decreased responses for re-occurring Target sounds, indicating that ACtx is highly involved in the early implicit learning phase. At the population level, activity was more decorrelated to Target sounds independent of the duration of frozen token, subregions, and cell type. These findings suggest that ACtx and its input layers contribute to the early phase of auditory memory for complex sounds, suggesting a parallel strategy across ACtx areas and between excitatory and inhibitory neurons.

Speech-induced suppression and vocal feedback sensitivity in human cortex.

Across the animal kingdom, neural responses in the auditory cortex are suppressed during vocalization, and humans are no exception. A common hypothesis is that suppression increases sensitivity to auditory feedback, enabling the detection of vocalization errors. This hypothesis has been previously confirmed in non-human primates, however a direct link between auditory suppression and sensitivity in human speech monitoring remains elusive. To address this issue, we obtained intracranial electroencephalography (iEEG) recordings from 35 neurosurgical participants during speech production. We first characterized the detailed topography of auditory suppression, which varied across superior temporal gyrus (STG). Next, we performed a delayed auditory feedback (DAF) task to determine whether the suppressed sites were also sensitive to auditory feedback alterations. Indeed, overlapping sites showed enhanced responses to feedback, indicating sensitivity. Importantly, there was a strong correlation between the degree of auditory suppression and feedback sensitivity, suggesting suppression might be a key mechanism that underlies speech monitoring. Further, we found that when participants produced speech with simultaneous auditory feedback, posterior STG was selectively activated if participants were engaged in a DAF paradigm, suggesting that increased attentional load can modulate auditory feedback sensitivity.

The brain lowers its response to inputs we generate ourselves, such as moving or speaking. Essentially, our brain 'knows' what will happen next when we carry out these actions, and therefore does not need to react as strongly as it would to unexpected events. This is why we cannot tickle ourselves, and why the brain does not react as much to our own voice as it does to someone else's. Quieting down the brain's response also allows us to focus on things that are new or important without getting distracted by our own movements or sounds. Studies in non-human primates showed that neurons in the auditory cortex (the region of the brain responsible for processing sound) displayed suppressed levels of activity when the animals made sounds. Interestingly, when the primates heard an altered version of their own voice, many of these same neurons became more active. But it was unclear whether this also happens in humans. To investigate, Ozker et al. used a technique called electrocorticography to record neural activity in different regions of the human brain while participants spoke. The results showed that most areas of the brain involved in auditory processing showed suppressed activity when individuals were speaking. However, when people heard an altered version of their own voice which had an unexpected delay, those same areas displayed increased activity. In addition, Ozker et al. found that the higher the level of suppression in the auditory cortex, the more sensitive these areas were to changes in a person's speech. These findings suggest that suppressing the brain's response to self-generated speech may help in detecting errors during speech production. Speech deficits are common in various neurological disorders, such as stuttering, Parkinson's disease, and aphasia. Ozker et al. hypothesize that these deficits may arise because individuals fail to suppress activity in auditory regions of the brain, causing a struggle when detecting and correcting errors in their own speech. However, further experiments are needed to test this theory.

Comparative study on structural and functional brain differences in mild cognitive impairment patients with tinnitus.

Objective: Tinnitus may be associated with various brain changes. However, the degenerative changes in patients with tinnitus have not been extensively investigated. We aimed to evaluate degenerative, structural, and functional brain changes in patients with mild cognitive impairment (MCI) who also suffer from tinnitus. Materials and methods: This study included participants aged 60 to 80 years with MCI and a hearing level better than 40 dB. The participants were classified into two groups: MCI with tinnitus (MCI-T) and MCI without tinnitus (MCI-NT). All patients underwent Tinnitus Handicap Inventory (THI), 3 T brain MRI, F18-florapronol PET, and F18-FDG PET. Results: The MCI-T group exhibited higher ß-amyloid deposition in the superior temporal gyrus, temporal pole, and middle temporal gyrus compared to the MCI-NT group (p < 0.05 for all). Additionally, the MCI-T group showed increased metabolism in the inferior frontal gyrus, insula, and anterior cingulate cortex (ACC) (p < 0.005 for all). The THI score was strongly correlated with increased volume in the insula, ACC, superior frontal gyrus, supplementary motor area, white matter near the hippocampus, and precentral gyrus (p < 0.05 for all). Moreover, the MCI-T group demonstrated higher metabolic activity in the default mode network (DMN) and lower activity in the executive control network (ECN) (p < 0.05 for all). In the MCI-T group, the posterior DMN was positively correlated with the visual network and negatively with the ECN, whereas in the MCI-NT group, it correlated positively with the ECN. Conclusion: The MCI-T group exhibited greater ß-amyloid accumulation in the auditory cortex and more extensive changes across various brain networks compared with the MCI-NT group, potentially leading to diverse clinical symptoms such as dementia with semantic deficits or depression. Tinnitus in MCI patients may serve as a biomarker for degenerative changes in the temporal lobe and alterations in brain network dynamics.

Receptive-field nonlinearities in primary auditory cortex: a comparative perspective.

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.

Analyzing the transient response dynamics of long-term depression in the mouse auditory cortex in vitro through multielectrode-array-based spatiotemporal recordings.

In the auditory cortex, synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), plays crucial roles in information processing and adaptation to the auditory environment. Previous rodent studies have shown lifelong cortical map plasticity, even beyond the critical period of development. While thalamocortical synapses exhibit LTD during the critical period, little is known about LTD in the cortico-cortical connections of the adult mouse auditory cortex. Here, we investigated the transient response dynamics of LTD in layers 2-5 of the mouse auditory cortex following tetanic stimulation (TS) to layer 4. To characterize LTD properties, we developed a recording protocol to monitor activity levels at multiple sites, including those more than 0.45 mm from the TS site. This allowed us to distinguish LTD-induced reductions in neural excitability from other types, including neural activity depletion. Our findings revealed that LTD induced in layer 4 persisted for over 40-min post-TS, indicating robust cortico-cortical LTD. Using electrophysiological data and a modified synaptic model, we identified key receptors involved in synaptic plasticity and their effects on response dynamics, proposing a method for studying LTD in the mature mouse auditory cortex. Particularly, by employing a simple dynamical model, we analyzed and discussed the involvement of key receptors during the transient period of LTD. This study expands our understanding of synaptic plasticity in the mature mouse auditory cortex beyond the critical period, potentially informing future treatments for hearing disorders.

Bidirectional generative adversarial representation learning for natural stimulus synthesis.

Thousands of species use vocal signals to communicate with one another. Vocalizations carry rich information, yet characterizing and analyzing these complex, high-dimensional signals is difficult and prone to human bias. Moreover, animal vocalizations are ethologically relevant stimuli whose representation by auditory neurons is an important subject of research in sensory neuroscience. A method that can efficiently generate naturalistic vocalization waveforms would offer an unlimited supply of stimuli with which to probe neuronal computations. Although unsupervised learning methods allow for the projection of vocalizations into low-dimensional latent spaces learned from the waveforms themselves, and generative modeling allows for the synthesis of novel vocalizations for use in downstream tasks, we are not aware of any model that combines these tasks to synthesize naturalistic vocalizations in the waveform domain for stimulus playback. In this paper, we demonstrate BiWaveGAN: a bidirectional generative adversarial network (GAN) capable of learning a latent representation of ultrasonic vocalizations (USVs) from mice. We show that BiWaveGAN can be used to generate, and interpolate between, realistic vocalization waveforms. We then use these synthesized stimuli along with natural USVs to probe the sensory input space of mouse auditory cortical neurons. We show that stimuli generated from our method evoke neuronal responses as effectively as real vocalizations, and produce receptive fields with the same predictive power. BiWaveGAN is not restricted to mouse USVs but can be used to synthesize naturalistic vocalizations of any animal species and interpolate between vocalizations of the same or different species, which could be useful for probing categorical boundaries in representations of ethologically relevant auditory signals.NEW & NOTEWORTHY A new type of artificial neural network is presented that can be used to generate animal vocalization waveforms and interpolate between them to create new vocalizations. We find that our synthetic naturalistic stimuli drive auditory cortical neurons in the mouse equally well and produce receptive field features with the same predictive power as those obtained with natural mouse vocalizations, confirming the quality of the stimuli produced by the neural network.

Dysregulation of parvalbumin expression and neurotransmitter imbalance in the auditory cortex of the BTBR mouse model of autism spectrum disorder.

Individuals diagnosed with autism spectrum disorder (ASD) frequently exhibit abnormalities in auditory perception, a phenomenon potentially attributed to alterations in the excitatory and inhibitory cells constituting cortical circuits. However, the exact genetic factors and cell types affected by ASD remain unclear. The present study investigated the balance of excitatory and inhibitory activity in the auditory cortex using BTBR T+ Itpr3tf/J (BTBR) mice, a well-established model for autism research. Our investigation unveiled a reduction in parvalbumin-positive (PV+) neurons within the AC of BTBR mice. Remarkably, in vivo magnetic resonance spectroscopy studies disclosed an elevation in glutamate (Glu) levels alongside a decrement in γ-aminobutyric acid (GABA) levels in this cortical region. Additionally, transcriptomic analysis of the mouse model facilitated the classification of several ASD-associated genes based on their cellular function and pathways. By comparing autism risk genes with RNA transcriptome sequencing data from the ASD mouse model, we identified the recurrent target gene Scn1a and performed validation. Intriguingly, we uncovered the specific expression of Scn1a in cortical inhibitory neurons. These findings hold significant value for understanding the underlying neural mechanisms of abnormal sensory perception in animal models of ASD.

Task-specific invariant representation in auditory cortex.

Categorical sensory representations are critical for many behaviors, including speech perception. In the auditory system, categorical information is thought to arise hierarchically, becoming increasingly prominent in higher-order cortical regions. The neural mechanisms that support this robust and flexible computation remain poorly understood. Here, we studied sound representations in the ferret primary and non-primary auditory cortex while animals engaged in a challenging sound discrimination task. Population-level decoding of simultaneously recorded single neurons revealed that task engagement caused categorical sound representations to emerge in non-primary auditory cortex. In primary auditory cortex, task engagement caused a general enhancement of sound decoding that was not specific to task-relevant categories. These findings are consistent with mixed selectivity models of neural disentanglement, in which early sensory regions build an overcomplete representation of the world and allow neurons in downstream brain regions to flexibly and selectively read out behaviorally relevant, categorical information.

Vocalization modulates the mouse auditory cortex even in the absence of hearing.

Vocal communication depends on distinguishing self-generated vocalizations from other sounds. Vocal motor corollary discharge (CD) signals are thought to support this ability by adaptively suppressing auditory cortical responses to auditory feedback. One challenge is that vocalizations, especially those produced during courtship and other social interactions, are accompanied by other movements and are emitted during a state of heightened arousal, factors that could potentially modulate auditory cortical activity. Here, we monitor auditory cortical activity, ultrasonic vocalizations (USVs), and other non-vocal courtship behaviors in a head-fixed male mouse while he interacts with a female mouse. This approach reveals a vocalization-specific signature in the auditory cortex that suppresses the activity of USV playback-excited neurons, emerges before vocal onset, and scales with USV band power. Notably, this vocal modulatory signature is also present in the auditory cortex of congenitally deaf mice, revealing an adaptive vocal CD signal that manifests independently of auditory feedback or auditory experience.

Laminar pattern of sensory-evoked dynamic high-frequency oscillatory activity in the macaque auditory cortex.

High-frequency (>60 Hz) neuroelectric signals likely have functional roles distinct from low-frequency (<30 Hz) signals. While high-gamma activity (>60 Hz) does not simply equate to neuronal spiking, they are highly correlated, having similar information encoding. High-gamma activity is typically considered broadband and poorly phase-locked to sensory stimuli and thus is typically analyzed after transformations into absolute amplitude or spectral power. However, those analyses discard signal polarity, compromising the interpretation of neuroelectric events that are essentially dipolar. In the spectrotemporal profiles of field potentials in auditory cortex, we show high-frequency spectral peaks not phase-locked to sound onset, which follow the broadband peak of phase-locked onset responses. Isolating the signal components comprising the high-frequency peaks reveals narrow-band high-frequency oscillatory events, whose instantaneous frequency changes rapidly from >150 to 60 Hz, which may underlie broadband high-frequency spectral peaks in previous reports. The laminar amplitude distributions of the isolated activity had two peak positions, while the laminar phase patterns showed a counterphase relationship between those peaks, indicating the formation of dipoles. Our findings suggest that nonphase-locked HGA arises in part from oscillatory or recurring activity of supragranular-layer neuronal ensembles in auditory cortex.

Primary auditory thalamus relays directly to cortical layer 1 interneurons.

Inhibitory interneurons within cortical layer 1 (L1-INs) integrate inputs from diverse brain regions to modulate sensory processing and plasticity, but the sensory inputs that recruit these interneurons have not been identified. Here we used monosynaptic retrograde tracing and whole-cell electrophysiology to characterize the thalamic inputs onto two major subpopulations of L1-INs in the mouse auditory cortex. We find that the vast majority of auditory thalamic inputs to these L1-INs unexpectedly arise from the ventral subdivision of the medial geniculate body (MGBv), the tonotopically-organized primary auditory thalamus. Moreover, these interneurons receive robust functional monosynaptic MGBv inputs that are comparable to those recorded in the L4 excitatory pyramidal neurons. Our findings identify a direct pathway from the primary auditory thalamus to the L1-INs, suggesting that these interneurons are uniquely positioned to integrate thalamic inputs conveying precise sensory information with top-down inputs carrying information about brain states and learned associations.

Noises on-How the Brain Deals with Acoustic Noise.

What is noise? When does a sound form part of the acoustic background and when might it come to our attention as part of the foreground? Our brain seems to filter out irrelevant sounds in a seemingly effortless process, but how this is achieved remains opaque and, to date, unparalleled by any algorithm. In this review, we discuss how noise can be both background and foreground, depending on what a listener/brain is trying to achieve. We do so by addressing questions concerning the brain's potential bias to interpret certain sounds as part of the background, the extent to which the interpretation of sounds depends on the context in which they are heard, as well as their ethological relevance, task-dependence, and a listener's overall mental state. We explore these questions with specific regard to the implicit, or statistical, learning of sounds and the role of feedback loops between cortical and subcortical auditory structures.

Neurophysiological, structural, and molecular alterations in the prefrontal and auditory cortices following noise-induced hearing loss.

It is well established that hearing loss can lead to widespread plasticity within the central auditory pathway, which is thought to contribute to the pathophysiology of audiological conditions such as tinnitus and hyperacusis. Emerging evidence suggests that hearing loss can also result in plasticity within brain regions involved in higher-level cognitive functioning like the prefrontal cortex; findings which may underlie the association between hearing loss and cognitive impairment documented in epidemiological studies. Using the 40-Hz auditory steady state response to assess sound-evoked gamma oscillations, we previously showed that noise-induced hearing loss results in impaired gamma phase coherence within the prefrontal but not the auditory cortex. To determine whether region-specific structural or molecular changes accompany this differential plasticity following hearing loss, in the present study we utilized Golgi-Cox staining to assess dendritic organization and synaptic density, as well as Western blotting to measure changes in synaptic signaling proteins in these cortical regions. We show that following noise exposure, impaired gamma phase coherence within the prefrontal cortex is accompanied by alterations in pyramidal cell dendritic morphology and decreased expression of proteins involved in GABAergic (GAD65) and glutamatergic (NR2B) neurotransmission; findings that were not observed in the auditory cortex, where gamma phase coherence remained unchanged post-noise exposure. In contrast to the noise-induced effects we observed in the prefrontal cortex, plasticity in the auditory cortex was characterized by an increase in NR2B suggesting increased excitability, as well as increases in the synaptic proteins PSD95 and synaptophysin within the auditory cortex. Overall, our results highlight the disparate effect of noise-induced hearing loss on auditory and higher-level brain regions as well as potential structural and molecular mechanisms by which hearing loss may contribute to impaired cognitive and sensory functions mediated by the prefrontal and auditory cortices.

Orbitofrontal cortex modulates auditory cortical sensitivity and sound perception in Mongolian gerbils.

Sensory perception is dynamic, quickly adapting to sudden shifts in environmental or behavioral context. Although decades of work have established that these dynamics are mediated by rapid fluctuations in sensory cortical activity, we have a limited understanding of the brain regions and pathways that orchestrate these changes. Neurons in the orbitofrontal cortex (OFC) encode contextual information, and recent data suggest that some of these signals are transmitted to sensory cortices. Whether and how these signals shape sensory encoding and perceptual sensitivity remain uncertain. Here, we asked whether the OFC mediates context-dependent changes in auditory cortical sensitivity and sound perception by monitoring and manipulating OFC activity in freely moving Mongolian gerbils of both sexes under two behavioral contexts: passive sound exposure and engagement in an amplitude modulation (AM) detection task. We found that the majority of OFC neurons, including the specific subset that innervates the auditory cortex, were strongly modulated by task engagement. Pharmacological inactivation of the OFC prevented rapid context-dependent changes in auditory cortical firing and significantly impaired behavioral AM detection. Our findings suggest that contextual information from the OFC mediates rapid plasticity in the auditory cortex and facilitates the perception of behaviorally relevant sounds.

Does pre-speech auditory modulation reflect processes related to feedback monitoring or speech movement planning?

Previous studies have revealed that auditory processing is modulated during the planning phase immediately prior to speech onset. To date, the functional relevance of this pre-speech auditory modulation (PSAM) remains unknown. Here, we investigated whether PSAM reflects neuronal processes that are associated with preparing auditory cortex for optimized feedback monitoring as reflected in online speech corrections. Combining electroencephalographic PSAM data from a previous data set with new acoustic measures of the same participants' speech, we asked whether individual speakers' extent of PSAM is correlated with the implementation of within-vowel articulatory adjustments during /b/-vowel-/d/ word productions. Online articulatory adjustments were quantified as the extent of change in inter-trial formant variability from vowel onset to vowel midpoint (a phenomenon known as centering). This approach allowed us to also consider inter-trial variability in formant production and its possible relation to PSAM at vowel onset and midpoint separately. Results showed that inter-trial formant variability was significantly smaller at vowel midpoint than at vowel onset. PSAM was not significantly correlated with this amount of change in variability as an index of within-vowel adjustments. Surprisingly, PSAM was negatively correlated with inter-trial formant variability not only in the middle but also at the very onset of the vowels. Thus, speakers with more PSAM produced formants that were already less variable at vowel onset. Findings suggest that PSAM may reflect processes that influence speech acoustics as early as vowel onset and, thus, that are directly involved in motor command preparation (feedforward control) rather than output monitoring (feedback control).

Subcortical origin of nonlinear sound encoding in auditory cortex.

A major challenge in neuroscience is to understand how neural representations of sensory information are transformed by the network of ascending and descending connections in each sensory system. By recording from neurons at several levels of the auditory pathway, we show that much of the nonlinear encoding of complex sounds in auditory cortex can be explained by transformations in the midbrain and thalamus. Modeling cortical neurons in terms of their inputs across these subcortical populations enables their responses to be predicted with unprecedented accuracy. By contrast, subcortical responses cannot be predicted from descending cortical inputs, indicating that ascending transformations are irreversible, resulting in increasingly lossy, higher-order representations across the auditory pathway. Rather, auditory cortex selectively modulates the nonlinear aspects of thalamic auditory responses and the functional coupling between subcortical neurons without affecting the linear encoding of sound. These findings reveal the fundamental role of subcortical transformations in shaping cortical responses.

Direct piriform-to-auditory cortical projections shape auditory-olfactory integration.

In a real-world environment, the brain must integrate information from multiple sensory modalities, including the auditory and olfactory systems. However, little is known about the neuronal circuits governing how odors influence and modulate sound processing. Here, we investigated the mechanisms underlying auditory-olfactory integration using anatomical, electrophysiological, and optogenetic approaches, focusing on the auditory cortex as a key locus for cross-modal integration. First, retrograde and anterograde viral tracing strategies revealed a direct projection from the piriform cortex to the auditory cortex. Next, using in vivo electrophysiological recordings of neuronal activity in the auditory cortex of awake male or female mice, we found that odors modulate auditory cortical responses to sound. Finally, we used in vivo optogenetic manipulations during electrophysiology to demonstrate that olfactory modulation in auditory cortex, specifically, odor-driven enhancement of sound responses, depends on direct input from the piriform cortex. Together, our results identify a novel role of piriform-to-auditory cortical circuitry in shaping olfactory modulation in the auditory cortex, shedding new light on the neuronal mechanisms underlying auditory-olfactory integration.