Single Unit publications

The detection of unexpected sounds, or auditory deviance detection, is thought to be achieved by comparing prediction signals and sensory inputs in the auditory cortex. This process is markedly impaired in patients with schizophrenia. However, the local circuit properties underlying deviance detection, together with their dysfunction in schizophrenia-related conditions, remain poorly understood. We used two-photon calcium imaging to monitor the population activity of cortical neurons during auditory deviance detection. The deviance-detecting component was predominant in layer 2/3 neurons of the higher-order auditory cortex. The deviance-detecting cells were spatially clustered, exhibited robust synchronization, and constitutively expressed immediate-early genes. In the Del(1.5 megabase)/+ mouse model of 22q11.2 deletion syndrome, a model of schizophrenia, deviance-detecting activity in the upper-layer network was disrupted, accompanied by dysregulated gene expression and selective loss of dendritic spines in immediate-early gene–positive neurons. Our findings support the hypothesis that ensemble activation of this neuronal subpopulation amplifies unexpected inputs, driving error signals that propagate to higher-order cortical areas.

Purpose: In anesthesia research and clinical practice, the level of consciousness is often assessed by stimulating subjects and observing their responses. It is possible that such stimulation alters the very state of consciousness being assessed. Whether this phenomenon is accompanied by specific cortical activities remains unknown. Here, we tested the effects of behavioral assessments on neuronal activity in the rat primary auditory cortex (A1) and perirhinal cortex (PrC). Methods: Neuronal spiking activity was recorded from microwire arrays targeting A1 and/or PrC in rats (n = 9), whilst presenting 40 Hz click-trains and gradually increasing infusion rates of propofol, remifentanil, ketamine or dexmedetomidine. We assessed righting reflex, pain withdrawal, whisking reflex, and corneal reflex every 12 minutes (every 360 auditory trials). We searched for significant changes in baseline firing rate and stimulus-evoked activities (where present) due to the behavioral assessments, by comparing 4 min intervals before and after the behavioral tests. Results: Out of 1004 units in 20 sessions, we found significantly elevated activity (p < 0.01) following behavioral tests in 32% and 20% of A1 auditory-responsive units and 8.6% and 5.3% of auditory-unresponsive units under propofol and dexmedetomidine, respectively, but not under remifentanil or ketamine. A higher proportion of units modulated their firing following behavioral tests in A1 compared to PrC, with median gains ranging from +0.23 to +1.06, depending on the specific response feature. Conclusion: Behavioral testing increases ongoing firing rate and responses to sounds in some cortical neurons. This increase is more prevalent in A1 than in PrC, mirroring clinical observations that patients exhibit basic responses under sedation, while complex processing, such as memory encoding, is impaired. The degree of neuronal modulation due to behavioral testing varies between anesthetic agents, mirroring their clinical phenotypes.

Atypical sensory processing is a common feature of autism, yet the neural computations that give rise to these differences, particularly in relation to biological sex and etiological origin, remain unclear. Here we examine predictive auditory processing at the single-neuron level in the inferior colliculus of two adult rat models of autism: a genetic model with a heterozygous Grin2b deletion (Grin2b + /-) and an environmental model based on prenatal valproic acid exposure. We recorded neuronal responses to an auditory oddball paradigm and a cascade control sequence across lemniscal and non-lemniscal IC divisions under high-intensity stimulation, allowing us to derive indices of repetition suppression, prediction error and neuronal mismatch. Using generalized linear mixed-effects models that accounted for animal identity, inferior colliculus division, sex, and rat model, followed by hierarchical group-level comparisons, we identified robust alterations in predictive processing in both autism-like models. These effects varied across inferior colliculus divisions and differed between sexes, revealing distinct phenotype-specific signatures. The results indicate that sex and etiology jointly modulate early auditory computations in autism. More broadly, our findings highlight the translational value of predictive coding frameworks and support the use of complementary animal models to capture neurobiological heterogeneity across the autism spectrum.

This work presents three open datasets featuring various levels of processing, containing neural recordings from the auditory cortex of rats. These recordings were obtained during experiments using the auditory oddball paradigm before, during and after the local microiontophoretic application of acetylcholine. The primary objective of these datasets is to investigate how the brain processes predictable versus unexpected auditory stimuli, and the role of cholinergic inputs during such processing. The data include multi-unit recordings of neuronal activity during the presentation of standard and deviant tones, classified by stimulus type and cortical sub-region. These resources enable quantitative investigations of deviance detection, stimulus-specific adaptation, cholinergic modulation and predictive-coding mechanisms at multiple temporal scales.

The hippocampus is classically linked to memory, yet increasing evidence points to a broader role in perceptual inference and deviance detection. Predictive coding theories propose that perception minimizes mismatches between expected and actual sensory input, expressed in neural signatures such as mismatch negativity (MMN) and P300. Although MMN arises mainly from sensory and prefrontal cortices, the hippocampus is anatomically interconnected with both and may also contribute to prediction error processing. We recorded single- and multi-unit activity and local field potentials (LFPs) from DG and CA1 in urethane-anesthetized rats during an auditory oddball paradigm and a no-repetition control sequence to dissociate prediction error from repetition suppression. Approximately 20% of hippocampal neurons were sound responsive, and a subset showed deviant selectivity. Spiking activity predominantly reflected prediction errors, while LFPs revealed complementary contributions from repetition suppression and prediction error. Early LFP components were enhanced for randomly presented deviants, whereas later components within the P300 latency range were stronger for predictable deviants, indicating temporally distinct phases of error signaling and top-down modulation. These findings identify the hippocampus as an active contributor to auditory deviance detection and support a hierarchical model in which hippocampal circuits participate in predictive sensory processing beyond memory.

The axon initial segment (AIS) is the site of action potential generation and exhibits structural and functional plasticity upon adaptation of neuronal excitability and disease. Performing in vivo longitudinal two-photon imaging of AIS in the medial prefrontal cortex of male mice, we reveal dynamic AIS remodeling during associative fear learning and extinction. These results demonstrate that AIS plasticity is not only crucial for homeostatic adaptation but also a hallmark of memory formation.

The neural representations of acoustic features that differ in the location or timbre of the emitter elicit similar perceptions, suggesting the existence of a robust stimulus‐response function between complex sounds and the activity of neural populations at all stages of the auditory system. This hypothesis is tested by decoding a random sound stream, using spike trains from a biophysical model of the auditory nerve and from large‐scale recordings in the inferior colliculus, the auditory thalamus, and the auditory cortex of awake mice. At the level of individual neurons, the reliability of temporal and rate codes is found to decrease along the ascending auditory pathways. Rate coding is progressively favored with increasing independence of neuron frequency tuning. Firing in the auditory cortex is found to be synergistic, whereas that in subcortical areas is more redundant. Finally, combinatorial codes involving neural firing and neural silence within neuron pairs are shown to efficiently encode sound information, particularly in the auditory cortex. Overall, these findings reveal a progressive transformation of the neural code from an individual, redundant, and temporal code at the periphery to a more distributed rate‐based code in the auditory cortex.

The ability to recognize speakers by their voice despite acoustical variation plays a substantial role in primate social interactions. Although neurons in the macaque anterior temporal lobe (ATL) show invariance to face viewpoint, whether they also encode abstract representations of caller identity is not known. Here, we demonstrate that neurons in the voice-selective ATL of two macaques support invariant voice identity representations through dynamic population-level coding. These representations minimize neural distances across different vocalizations from the same individual while preserving distinct trajectories for different callers. This structure emerged from the coordinated activity of the broader neuronal ensemble, although a small subset of highly identity-selective neurons carried high identity information. Our findings provide a neural basis for voice identity recognition in primates and highlight the ATL as a key hub for integrating perceptual voice features into higher-level identity representations.

Diverse biological factors, such as sex and age, confer heterogeneity on sensory processing challenges in autism. These factors result in major difficulties in the processing of contextual information in social and non-social situations. To assess divergence in autistic traits, it is critical to consider sex- and age-related variability. Nevertheless, these differences remain largely elusive. Animal models of autism offer the possibility to examine contextual processing at the single-neuron level. Here, we investigated predictive processing of contextual auditory cues in the auditory midbrain of control and prenatally valproic acid-induced rats, a well-established animal model of autism. The rats were prepubertal and adult female and male animals. We performed single-unit recordings in the inferior colliculus of control and prenatally, or in utero , exposed rats under the classical oddball paradigm and non-repetitive cascade control sequences to study neuronal mismatch. This is the neuronal correlate of mismatch negativity, the brain’s automatic response to interruptions in environmental regularity. When comparing control and exposed rats, our results demonstrated a reduction in neuronal mismatch in rats exposed to valproic acid. However, exposed adult females exhibited an increased neuronal mismatch compared to their control counterparts. With respect to sex distinctions, valproic acid induced sex differences in neuronal mismatch of prepubertal and adult rats that are not observable in control animals. Moreover, we detected an age-dependent refinement in prediction error that is not affected by the drug. But valproic acid altered typical developmental trajectory of neuronal mismatch in both sexes. Such observations support sex- and age-related effects of in utero valproic acid exposure in contextual auditory processing at the neural level of the inferior colliculus. In autism, atypical predictive processing of environmental regularities underlies unusual responses to novel experiences. The present study highlights the importance of sex and age, that confer heterogeneity to these challenges.

Fragile X Syndrome (FXS) is a leading genetic cause of autism spectrum disorders (ASD)- associated behaviors, including sensory processing deficits. Sensory sensitivity and temporal processing deficits in the auditory domain will affect development of language and cognitive functions. The mouse model for FXS, Fmr1 KO, has shown remarkably similar auditory processing phenotypes to patients with FXS. In vitro cortical slice recordings show layer-specific differences in Fmr1 KO mouse local circuits, but it is unclear how these differences translate to changes in sensory processing. In this study, we used a depth multielectrode to record in vivo spikes and local field potentials across layers of the auditory cortex in Fmr1 KO and wildtype mice (WT), converting the latter to current source density (CSD) profiles for improved spatial resolution analysis. We observed reduced CSD sink amplitudes and inter-trial phase coherence, and an increase in trial-to-trial variability for temporally modulated stimuli in the KO mice. Results indicated a differential cortical layer pattern of activity in KO mice, with higher baseline gamma power in superficial and deep layers and higher resting delta and theta power in granular layers. Significantly elevated inter-trial variability was observed for CSD and spikes in KO mice. Auditory steady state responses to clicks or gaps at 40 Hz showed considerable trial-to-trial variability in a layer-specific manner in KO mice. Neural generators in the Fmr1 KO mouse auditory cortex failed to detect short gaps in noise, indicating severe temporal processing deficits. Altogether, this study indicates layer-specific cortical mechanisms of sensory hypersensitivity and temporal processing deficits in FXS.

Introduction Tinnitus is the perception of non-meaningful sound in the absence of external stimuli. Although tinnitus behavior in animal models is associated with altered central nervous system activity, it is not currently possible to identify tinnitus using neuronal activity alone. In the mouse inferior colliculus (IC), a subpopulation of neurons demonstrates a sustained increase in spontaneous activity after a long-duration sound (LDS). Methods Here, we use the “ LDS test ” to reveal tinnitus-specific differences in sound-evoked plasticity through IC extracellular recordings and the auditory brainstem response (ABR LDS ) in CBA/CaJ mice after sound exposure and behavioral tinnitus assessment. Results Sound-exposed mice showed stronger and shorter tone-evoked responses in the IC compared to unexposed controls, but these differences were not strong predictors of tinnitus. In contrast, in the LDS test, non-tinnitus mice had a significantly stronger suppression in tone-evoked spike rate compared to tinnitus and unexposed control mice. ABR peak amplitudes also revealed robust differences between tinnitus and non-tinnitus mice, with ABR peaks from non-tinnitus mice exhibiting significantly stronger suppression in the LDS test compared to tinnitus and control mice. No significant differences were seen between cohorts in ABR amplitude, latency, wave V:I ratio, wave V:III ratio, I-V intra-peak latency, and I-VI intra-peak latency. We found high-frequency tone stimuli better suited to reveal tinnitus-specific differences for both extracellular IC and ABR recordings. Discussion We successfully used the LDS test to demonstrate that tinnitus-specific differences in sound-evoked plasticity can be shown using both multi-unit near-field recordings in the IC and non-invasive far-field recordings, providing a foundation for future electrophysiological research into the causes and treatment of tinnitus.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

Background Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent and debilitating phenotype of FXS is auditory hypersensitivity that may lead to delayed language and high anxiety. Consistent with findings in FXS human studies, the mouse model of FXS, the Fmr1 knock out (KO) mouse, shows auditory hypersensitivity and temporal processing deficits. In electroencephalograph (EEG) recordings from humans and mice, these deficits manifest as increased N1 amplitudes in event-related potentials (ERP), increased gamma band single trial power (STP) and reduced phase locking to rapid temporal modulations of sound. In our previous study, we found that administration of the selective serotonin-1 A (5-HT 1A )receptor biased agonist, NLX-101, protected Fmr1 KO mice from auditory hypersensitivity-associated seizures. Here we tested the hypothesis that NLX-101 will normalize EEG phenotypes in developing Fmr1 KO mice. Methods To test this hypothesis, we examined the effect of NLX-101 on EEG phenotypes in male and female wildtype (WT) and Fmr1 KO mice. Using epidural electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at two ages, postnatal (P) 21 and 30 days, from both auditory and frontal cortices of awake, freely moving mice, following NLX-101 (at 1.8 mg/kg i.p.) or saline administration. Results Saline-injected Fmr1 KO mice showed increased N1 amplitudes, increased STP and reduced phase locking to auditory gap-in-noise stimuli versus wild-type mice, reproducing previously published EEG phenotypes. An acute injection of NLX-101 did not alter ERP amplitudes at either P21 or P30, but significantly reduces STP at P30. Inter-trial phase clustering was significantly increased in both age groups with NLX-101, indicating improved temporal processing. The differential effects of serotonin modulation on ERP, background power and temporal processing suggest different developmental mechanisms leading to these phenotypes. Conclusions These results suggest that NLX-101 could constitute a promising treatment option for targeting post-synaptic 5-HT 1A receptors to improve auditory temporal processing, which in turn may improve speech and language function in FXS.

The ability of the brain to process auditory information across multiple temporal scales is crucial for perception. This study introduces an innovative experimental approach using nonlinguistic structured stimuli composed of click trains that alternate at different rates to investigate auditory processing across 3 distinct temporal scales: individual clicks (tens of milliseconds), click trains forming auditory objects (hundreds of milliseconds), and higher-order click trains in neuronal novelty detection (seconds) in both rhesus monkeys and humans. Electrocorticography recordings in the auditory cortex of rhesus monkeys unveil the primate brain’s remarkable ability to process intricate auditory temporal patterns at timescales of tens and hundreds of milliseconds. Furthermore, extracellular recordings in monkeys demonstrate pronounced responsiveness to deviant click trains at longer temporal scales in the primary auditory cortex (A1), accompanied by synchronization with both individual clicks and click trains. By contrast, neurons in the auditory thalamus prefer individual clicks only. Notably, neurons in A1 exhibit the ability to synchronize with individual clicks while simultaneously integrating these clicks into cohesive train objects, a phenomenon we term “temporal integration during synchronization”. Additional human electroencephalography recordings complement and support these findings, highlighting the paradigm’s potential for clinical applications. Our research offers novel insights into the neural mechanisms underpinning auditory information processing across various temporal scales at the neuronal level.

Offset responses are traditionally viewed as indicators of sound cessation. Here, we investigate offset responses to auditory click trains, examining how they are modulated by inter-click intervals (ICIs) and train duration. Using extracellular recordings and electrocorticography (ECoG) in non-human primates, alongside electroencephalography (EEG) in humans, we show that offset responses are significantly influenced by both ICI and train length, thereby establishing them as markers of temporal integration. We introduce the concept of the 'Neuronal Integrative Window' (NIW), defined as the temporal span during which neurons integrate stimuli to produce or modulate the temporal integration signal. Our data reveal that on the neuronal level, the auditory cortex (AC) exhibits a more expansive NIW than the medial geniculate body (MGB), integrating stimuli over longer durations and showing a preference for larger ICIs. Furthermore, our results indicate that offset responses could serve as potential biomarkers for neurological and psychiatric conditions, highlighted by their sensitivity to pharmacological modulation with ketamine. This study advances our understanding of auditory temporal processing and proposes a novel approach for assessing and monitoring brain health.

Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.

Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular ‘non-classically responsive’ firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

Many animals can extract useful information from the vocalizations of other species. Neuroimaging studies have evidenced areas sensitive to conspecific vocalizations in the cerebral cortex of primates, but how these areas process heterospecific vocalizations remains unclear. Using fMRI-guided electrophysiology, we recorded the spiking activity of individual neurons in the anterior temporal voice patches of two macaques while they listened to complex sounds including vocalizations from several species. In addition to cells selective for conspecific macaque vocalizations, we identified an unsuspected subpopulation of neurons with strong selectivity for human voice, not merely explained by spectral or temporal structure of the sounds. The auditory representational geometry implemented by these neurons was strongly related to that measured in the human voice areas with neuroimaging and only weakly to low-level acoustical structure. These findings provide new insights into the neural mechanisms involved in auditory expertise and the evolution of communication systems in primates.

Background Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. Methods To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. Results The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. Conclusions These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.

Salicylate is commonly used to induce tinnitus in animals, but its underlying mechanism of action is still debated. We therefore tested its effects on the firing properties of neurons in the mouse inferior colliculus (IC). Salicylate induced a large decrease in the spontaneous activity and an increase of ∼20 dB SPL in the minimum threshold of single units. In response to sinusoidally modulated noise (SAM noise) single units showed both an increase in phase locking and improved rate coding. Mice also became better at detecting amplitude modulations, and a simple threshold model based on the IC population response could reproduce this improvement. The responses to dynamic random chords (DRCs) suggested that the improved AM encoding was due to a linearization of the cochlear output, resulting in larger contrasts during SAM noise. These effects of salicylate are not consistent with the presence of tinnitus, but should be taken into account when studying hyperacusis.