Auditory Neurophysiology publications

The latency of the auditory steady-state response (ASSR) may provide valuable information regarding the integrity of the auditory system, as it could potentially reveal the presence of multiple intracerebral sources. To estimate multiple latencies from high-order ASSRs, we propose a novel two-stage procedure that consists of a nonparametric estimation method, called apparent latency from phase coherence (ALPC), followed by a heuristic sequential forward selection algorithm (SFS). Compared with existing methods, ALPC-SFS requires few prior assumptions, and is straightforward to implement for higher-order nonlinear responses to multi-cosine sound complexes with their initial phases set to zero. It systematically evaluates the nonlinear components of the ASSRs by estimating multiple latencies, automatically identifies involved ASSR components, and reports a latency consistency index. To verify the proposed method, we performed simulations for several scenarios: two nonlinear subsystems with different or overlapping outputs. We compared the results from our method with predictions from existing, parametric methods. We also recorded the EEG from ten normal-hearing adults by bilaterally presenting superimposed tones with four frequencies that evoke a unique set of ASSRs. From these ASSRs, two major latencies were found to be stable across subjects on repeated measurement days. The two latencies are dominated by low-frequency (LF) (near 40 Hz, at around 41–52 ms) and high-frequency (HF) (> 80 Hz, at around 21–27 ms) ASSR components. The frontal-central brain region showed longer latencies on LF components, but shorter latencies on HF components, when compared with temporal-lobe regions. In conclusion, the proposed nonparametric ALPC-SFS method, applied to zero-phase, multi-cosine sound complexes is more suitable for evaluating embedded nonlinear systems underlying ASSRs than existing methods. It may therefore be a promising objective measure for hearing performance and auditory cortex (dys)function.

Core auditory cortex (AC) neurons encode slow fluctuations of acoustic stimuli with temporally patterned activity. However, whether temporal encoding is necessary to explain auditory perceptual skills remains uncertain. Here, we recorded from gerbil AC neurons while they discriminated between a 4-Hz amplitude modulation (AM) broadband noise and AM rates >4 Hz. We found a proportion of neurons possessed neural thresholds based on spike pattern or spike count that were better than the recorded session’s behavioral threshold, suggesting that spike count could provide sufficient information for this perceptual task. A population decoder that relied on temporal information outperformed a decoder that relied on spike count alone, but the spike count decoder still remained sufficient to explain average behavioral performance. This leaves open the possibility that more demanding perceptual judgments require temporal information. Thus, we asked whether accurate classification of different AM rates between 4 and 12 Hz required the information contained in AC temporal discharge patterns. Indeed, accurate classification of these AM stimuli depended on the inclusion of temporal information rather than spike count alone. Overall, our results compare two different representations of time-varying acoustic features that can be accessed by downstream circuits required for perceptual judgments.

Detecting the direction of frequency modulation (FM) is essential for vocal communication in both animals and humans. Direction-selective firing of neurons in the primary auditory cortex (A1) has been classically attributed to temporal offsets between feedforward excitatory and inhibitory inputs. However, it remains unclear how cortical recurrent circuitry contributes to this computation. Here, we used two-photon calcium imaging and whole-cell recordings in awake mice to demonstrate that direction selectivity is not caused by temporal offsets between synaptic currents, but by an asymmetry in total synaptic charge between preferred and non-preferred directions. Inactivation of cortical somatostatin-expressing interneurons (SOM cells) reduced direction selectivity, revealing its cortical contribution. Our theoretical models showed that charge asymmetry arises due to broad spatial topography of SOM cell-mediated inhibition which regulates signal amplification in strongly recurrent circuitry. Together, our findings reveal a major contribution of recurrent network dynamics in shaping cortical tuning to behaviorally relevant complex sounds.

Spatial hearing in cochlear implant (CI) patients remains a major challenge, with many early deaf users reported to have no measurable sensitivity to interaural time differences (ITDs). Deprivation of binaural experience during an early critical period is often hypothesized to be the cause of this shortcoming. However, we show that neonatally deafened (ND) rats provided with precisely synchronized CI stimulation in adulthood can be trained to lateralize ITDs with essentially normal behavioral thresholds near 50 μs. Furthermore, comparable ND rats show high physiological sensitivity to ITDs immediately after binaural implantation in adulthood. Our result that ND-CI rats achieved very good behavioral ITD thresholds, while prelingually deaf human CI patients often fail to develop a useful sensitivity to ITD raises urgent questions concerning the possibility that shortcomings in technology or treatment, rather than missing input during early development, may be behind the usually poor binaural outcomes for current CI patients.

Introduction A defect in the cochlear afferent synapse between the inner hair cells and spiral ganglion neurons, after noise exposure, without changes in the hearing threshold has been reported. Animal studies on auditory evoked potentials demonstrated changes in the auditory brainstem response (ABR) measurements of peak I amplitude and the loss of synapses, which affect the temporal resolution of complex sounds. Human studies of auditory evoked potential have reported ambiguous results regarding the relationship between peak I amplitude and noise exposure. Paired click stimuli have been used to investigate the temporal processing abilities of humans and animals. In this study, we investigated the utility of measuring auditory evoked potentials in response to paired click stimuli to assess the temporal processing function of ribbon synapses in noise-induced cochlear synaptopathy. Materials and Methods Twenty-two Sprague Dawley rats were used in this study, and synaptopathy was induced by narrow-band noise exposure (16 kHz with 1 kHz bandwidth, 105 dB sound pressure level for 2 h). ABRs to tone and paired click stimuli were measured before and 1, 3, 7, and 14 days after noise exposure. For histological analyses, hair cells and ribbon synapses were immunostained and the synapses quantified. The relationships among ABR peak I amplitude, number of synapses, and ABR to paired click stimuli were examined. Results Our results showed that ABR thresholds increase 1 day after noise exposure but fully recover to baseline levels after 14 days. Further, we demonstrated test frequency-dependent decreases in peak I amplitude and the number of synapses after noise exposure. These decreases were statistically significant at frequencies of 16 and 32 kHz. However, the ABR recovery threshold to paired click stimuli increased, which represent deterioration in the ability of temporal auditory processing. Our results indicate that the ABR recovery threshold is highly correlated with ABR peak I amplitude after noise exposure. We also established a direct correlation between the ABR recovery threshold and histological findings. Conclusion The result from this study suggests that in animal studies, the ABR to paired click stimuli along with peak I amplitude has potential as an assessment tool for hidden hearing loss.

Envelope following responses (EFRs) may be a useful tool for evaluating the audibility of speech sounds in infants. The present study aimed to evaluate the characteristics of speech-evoked EFRs in infants with normal hearing, relative to adults, and identify age-dependent changes in EFR characteristics during infancy. In 42 infants and 21 young adults, EFRs were elicited by the first (F1) and the second and higher formants (F2+) of the vowels /u/, /a/, and /i/, dominant in low and mid frequencies, respectively, and by amplitude-modulated fricatives /s/ and /∫/, dominant in high frequencies. In a subset of 20 infants, the in-ear stimulus level was adjusted to match that of an average adult ear (65 dB sound pressure level [SPL]). We found that (a) adult–infant differences in EFR amplitude, signal-to-noise ratio, and intertrial phase coherence were larger and spread across the frequency range when in-ear stimulus level was adjusted in infants, (b) adult–infant differences in EFR characteristics were the largest for low-frequency stimuli, (c) infants demonstrated adult-like phase coherence when they received a higher (i.e., unadjusted) stimulus level, and (d) EFR phase coherence and signal-to-noise ratio changed with age in the first year of life for a few F2+ vowel stimuli in a level-specific manner. Together, our findings reveal that development-related changes in EFRs during infancy likely vary by stimulus frequency, with low-frequency stimuli demonstrating the largest adult–infant differences. Consistent with previous research, our findings emphasize the significant role of stimulus level calibration methods while investigating developmental trends in EFRs.

This work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/gamma) were demonstrated in primary auditory cortex in medial Heschl's gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. This work demonstrates sustained activity patterns during AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions.

Corticothalamic (CT) neurons comprise the largest component of the descending sensory corticofugal pathway, but their contributions to brain function and behavior remain an unsolved mystery. To address the hypothesis that layer 6 (L6) CTs may be activated by extra-sensory inputs prior to anticipated sounds, we performed optogenetically targeted single-unit recordings and two-photon imaging of Ntsr1-Cre+ L6 CT neurons in the primary auditory cortex (A1) while mice were engaged in an active listening task. We found that L6 CTs and other L6 units began spiking hundreds of milliseconds prior to orofacial movements linked to sound presentation and reward, but not to other movements such as locomotion, which were not linked to an explicit behavioral task. Rabies tracing of monosynaptic inputs to A1 L6 CT neurons revealed a narrow strip of cholinergic and non-cholinergic projection neurons in the external globus pallidus, suggesting a potential source of motor-related input. These findings identify new pathways and local circuits for motor modulation of sound processing and suggest a new role for CT neurons in active sensing.

Neurotransmission of acoustic signals from the hair cells to the auditory nerve relies on a tightly controlled communication between pre-synaptic ribbons and post-synaptic glutamatergic terminals. After noise overexposure, de-afferentation occurs as a consequence of excessive glutamate release. What maintains synaptic integrity in the cochlea is poorly understood. The objective of this study is to evaluate the role of GLAST in maintaining synaptic integrity in the cochlea in absence or presence of noise, and its impact on sound-evoked brain activity using manganese-enhanced MRI (MeMRI). The glutamate aspartate transporter GLAST is present in supporting cells near the afferent synapse and its genetic deletion leads to greater synaptic swelling after noise overexposure. At baseline, GLAST knockout (GLAST KO) mice displayed two-fold lower wave 1 amplitude of the auditory brainstem response (ABR) when compared to their wild-type littermates in spite of similar ABR and distortion product otoacoustic emissions (DPOAE) thresholds. While the abundance of ribbons was not affected by the loss of GLAST function, the number of paired synapses was halved in GLAST KO mice, suggestive of a pre-existing auditory synaptopathy. Immediately after the noise exposure ABR thresholds rose by 41-62dB to a similar degree in GLAST WT and KO mice and DPOAE remained unaffected. In the acute phase following noise exposure, GLAST KO mice showed near complete de-afferentation unlike WT mice which maintained four to seven paired synapses per IHC. Brain activity using MeMRI found noise exposure to cause greater activity in the inferior colliculus in GLAST KO but not in WT mice. No changes in brain activity was found in GLAST KO mice at baseline in spite of affected afferent synapses, suggesting that auditory synaptopathy may not be sufficient to alter brain activity in the absence of noise exposure.

Elucidating changes in sensory processing across attentional and arousal states is a major focus in neuroscience. The local/global deviant (LGD) stimulus paradigm engages auditory predictive coding over short (local deviance, LD) and long (global deviance, GD) time scales, and has been used to assay disruption of auditory predictive coding upon loss of consciousness. Our previous work (Nourski et al., 2018, J Neurosci 38:8441-52) examined effects of general anesthesia on short- and long-term novelty detection. GD effects were suppressed at subhypnotic doses of propofol, suggesting that they may be more related to task engagement than consciousness per se. The present study addressed this hypothesis by comparing cortical responses to auditory novelty during passive versus active listening conditions in awake listeners. Subjects were seven adult neurosurgical patients undergoing chronic invasive monitoring for medically intractable epilepsy. LGD stimuli were sequences of four identical vowels followed by a fifth identical or different vowel. In the passive condition, the stimuli were presented to subjects as they watched a silent TV program and were instructed to attend to its content. In the active condition, stimuli were presented in the absence of a TV program, and subjects were instructed to press a button in response to GD target stimuli. Intracranial recordings were made from multiple brain regions, including core and non-core auditory, auditory-related, prefrontal and sensorimotor cortex. Metrics of task performance included hit rate, sensitivity index, and reaction times. Cortical activity was measured as averaged auditory evoked potentials (AEPs) and event-related band power in high gamma (70-150 Hz) and alpha (8-14 Hz) frequency bands. The vowel stimuli and LD elicited robust AEPs in all studied brain areas in both passive and active conditions. High gamma responses to stimulus onset and LD were localized predominantly to the auditory cortex in the superior temporal plane and had a comparable prevalence and spatial extent between the two conditions. In contrast, GD effects (AEPs, high gamma and alpha suppression) were greatly enhanced during the active condition in all studied brain areas. The prevalence of high gamma GD effects was positively correlated with individual subjects' task performance. The data demonstrate distinct task engagement-related effects on responses to auditory novelty across the auditory cortical processing hierarchy. The results motivate a closer examination of effective connectivity underlying attentional modulation of cortical sensory responses, and serve as a foundation for examining changes in sensory processing associated with general anesthesia, sleep and disorders of consciousness.

Predictive coding is an influential theory of neural processing underlying perceptual inference. However, it is unknown to what extent prediction violations of different sensory features are mediated in different regions in auditory cortex, with different dynamics, and by different mechanisms. This study investigates the neural responses to synthesized acoustic syllables, which could be expected or unexpected, along several features. By using electrocorticography (ECoG) in rat auditory cortex (subjects: adult female Wistar rats with normal hearing), we aimed at mapping regional differences in mismatch responses to different stimulus features. Continuous streams of morphed syllables formed roving oddball sequences in which each stimulus was repeated several times (thereby forming a standard) and subsequently replaced with a deviant stimulus which differed from the standard along one of several acoustic features: duration, pitch, interaural level differences (ILD), or consonant identity. Each of these features could assume one of several different levels, and the resulting change from standard to deviant could be larger or smaller. The deviant stimuli were then repeated to form new standards. We analyzed responses to the first repetition of a new stimulus (deviant) and its last repetition in a stimulus train (standard). For the ECoG recording, we implanted urethane-anaesthetized rats with 8 × 8 surface electrode arrays covering a 3 × 3 mm cortical patch encompassing primary and higher-order auditory cortex. We identified the response topographies and latencies of population activity evoked by acoustic stimuli in the rat auditory regions, and mapped their sensitivity to expectation violations along different acoustic features. For all features, the responses to deviant stimuli increased in amplitude relative to responses to standard stimuli. Deviance magnitude did not further modulate these mismatch responses. Mismatch responses to different feature violations showed a heterogeneous distribution across cortical areas, with no evidence for systematic topographic gradients for any of the tested features. However, within rats, the spatial distribution of mismatch responses varied more between features than the spatial distribution of tone-evoked responses. This result supports the notion that prediction error signaling along different stimulus features is subserved by different cortical populations, albeit with substantial heterogeneity across individuals.

Continuous acoustic streams, such as speech signals, can be chunked into segments containing reoccurring patterns (e.g., words). Noninvasive recordings of neural activity in humans suggest that chunking is underpinned by low-frequency cortical entrainment to the segment presentation rate, and modulated by prior segment experience (e.g., words belonging to a familiar language). Interestingly, previous studies suggest that also primates and rodents may be able to chunk acoustic streams. Here, we test whether neural activity in the rat auditory cortex is modulated by previous segment experience. We recorded subdural responses using electrocorticography (ECoG) from the auditory cortex of 11 anesthetized rats. Prior to recording, four rats were trained to detect familiar triplets of acoustic stimuli (artificial syllables), three were passively exposed to the triplets, while another four rats had no training experience. While low-frequency neural activity peaks were observed at the syllable level, no triplet-rate peaks were observed. Notably, in trained rats (but not in passively exposed and naïve rats), familiar triplets could be decoded more accurately than unfamiliar triplets based on neural activity in the auditory cortex. These results suggest that rats process acoustic sequences, and that their cortical activity is modulated by the training experience even under subsequent anesthesia.

Hearing loss is a sensory deprivation that can affect the quality of life. Currently, only rehabilitation devices such as hearing aids and cochlear implants are used, without a definitive cure. However, in chronic hearing‐deprived patients, in whom secondary auditory neural degeneration is expected, a relatively poor rehabilitation prognosis is projected. Stem cell therapy for cochlear neural structures would be an easier and feasible strategy compared with cochlear sensory cells. Considering the highly developed cochlear implantation technology, improving cochlear neural health has significant medical and social effects. Stem cell delivery to Rosenthal’s canal in an acutely damaged mouse model has been performed and showed cell survival and the possibility of differentiation. The results of stem cell transplantation in chronic auditory neural hearing loss should be evaluated because neural stem cell replacement therapy for chronic (long‐term) sensorineural hearing loss is a major target in clinics. In the present study, we established a mouse model that mimicked chronic auditory neural hearing loss (secondary degeneration of auditory neurons after loss of sensory input). Then, mouse embryonic stem cells (mESCs) were transplanted into the scala tympani and survival and distribution of transplanted cells were compared between the acute and chronic auditory neural hearing loss models induced by ouabain or kanamycin (KM), respectively. The mESC survival was similar to the acute model, and perilymphatic distribution of cell aggregates was more predominant in the chronic model. Lastly, the effects of mESC transplantation on neural signal transduction observed in the cochlear nucleus (CN) were compared and a statistical increase was observed in the chronic model compared with other models. These results indicated that after transplantation, mESCs survived in the cochlea and increased the neural signaling toward the central auditory pathway, even in the chronic (secondary) hearing loss mouse model.

There is considerable interest in understanding cortical processing and the function of top-down and bottom-up human neural circuits that control speech production. Research efforts to investigate these circuits are aided by analysis of spectro-temporal response characteristics of neural activity recorded by electrocorticography (ECoG). Further, cortical processing may be altered in the case of hearing-impaired cochlear implant (CI) users, as electric excitation of the auditory nerve creates a markedly different neural code for speech compared with that of the functionally intact hearing system. Studies of cortical activity in CI users typically record scalp potentials and are hampered by stimulus artifact contamination and by spatiotemporal filtering imposed by the skull. We present a unique case of a CI user who required direct recordings from the cortical surface using subdural electrodes implanted for epilepsy assessment. Using experimental conditions where the subject vocalized in the presence (CIs ON) or absence (CIs OFF) of auditory feedback, or listened to playback of self-vocalizations without production, we observed ECoG activity primarily in γ (32-70 Hz) and high γ (70-150 Hz) bands at focal regions on the lateral surface of the superior temporal gyrus (STG). High γ band responses differed in their amplitudes across conditions and cortical sites, possibly reflecting different rates of stimulus presentation and differing levels of neural adaptation. STG γ responses to playback and vocalization with auditory feedback were not different from responses to vocalization without feedback, indicating this activity reflects not only auditory, but also attentional, efference-copy, and sensorimotor processing during speech production.

Polychlorinated biphenyls (PCBs) are enduring environmental toxicants and exposure is associated with neurodevelopmental deficits. The auditory system appears particularly sensitive, as previous work has shown that developmental PCB exposure causes both hearing loss and gross disruptions in the organization of the rat auditory cortex. However, the mechanisms underlying PCB-induced changes are not known, nor is it known whether the central effects of PCBs are a consequence of peripheral hearing loss. Here, we study changes in both peripheral and central auditory function in rats with developmental PCB exposure using a combination of optical and electrophysiological approaches. Female rats were exposed to an environmental PCB mixture in utero and until weaning. At adulthood, auditory brainstem responses (ABRs) were measured, and synaptic currents were recorded in slices from auditory cortex layer 2/3 neurons. Spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) were more frequent in PCB-exposed rats compared with controls and the normal relationship between IPSC parameters and peripheral hearing was eliminated in PCB-exposed rats. No changes in spontaneous EPSCs were found. Conversely, when synaptic currents were evoked by laser photostimulation of caged-glutamate, PCB exposure did not affect evoked inhibitory transmission, but increased the total excitatory charge, the number and distance of sites that evoke a significant response. Together, these findings indicate that early developmental exposure to PCBs causes long-lasting changes in both inhibitory and excitatory neurotransmission in the auditory cortex that are independent of peripheral hearing changes, suggesting the effects are because of the direct impact of PCBs on the developing auditory cortex.

The sound-field auditory steady-state response (ASSR) is a promising measure for the objective validation of hearing-aid fitting in patients who are unable to respond to behavioral testing reliably. To record the sound-field ASSR, the stimulus is reproduced through a loudspeaker placed in front of the patient. However, the reverberation and background noise of the measurement room could reduce the stimulus modulation used for eliciting the ASSR. As the ASSR level is heavily dependent on the stimulus modulation, any reduction due to room acoustics could affect the clinical viability of sound-field ASSR testing. This study investigated the effect of room acoustics on the level and detection rate of sound-field ASSR. The study also analyzed whether early decay time and an auditory-inspired relative modulation power model could be used to predict the changes in the recorded ASSR in rooms. A monaural auralization approach was used to measure sound-field ASSR via insert earphones. ASSR was measured for 15 normal-hearing adult subjects using narrow-band CE-Chirps® centered at the octave bands of 500, 1000, 2000, and 4000 Hz. These stimuli were convolved with simulated impulse responses of three rooms inspired by audiological testing rooms. The results showed a significant reduction of the ASSR level for the room conditions compared with the reference anechoic condition. Despite this reduction, the detection rates for the first harmonics of the ASSR were unaffected when sufficiently long recordings (up to 6 min) were made. Furthermore, the early decay time and relative modulation power appear to be useful predictors of the ASSR level in the measurement rooms.

We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.

The cochlea encodes sound pressures varying over six orders of magnitude by collective operation of functionally diverse spiral ganglion neurons (SGNs). The mechanisms enabling this functional diversity remain elusive. Here, we asked whether the sound intensity information, contained in the receptor potential of the presynaptic inner hair cell (IHC), is fractionated via heterogeneous synapses. We studied the transfer function of individual IHC synapses by combining patch‐clamp recordings with dual‐color Rhod‐FF and iGluSnFR imaging of presynaptic Ca 2+ signals and glutamate release. Synapses differed in the voltage dependence of release: Those residing at the IHC' pillar side activated at more hyperpolarized potentials and typically showed tight control of release by few Ca 2+ channels. We conclude that heterogeneity of voltage dependence and release site coupling of Ca 2+ channels among the synapses varies synaptic transfer within individual IHCs and, thereby, likely contributes to the functional diversity of SGNs. The mechanism reported here might serve sensory cells and neurons more generally to diversify signaling even in close‐by synapses.

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with “no-repetition” controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection.

Little is known about the functions of Group II metabotropic glutamate receptors (mGluRs2/3) in the inferior colliculus (IC), a midbrain structure that is a major integration region of the central auditory system. We investigated how these receptors modulate sound-evoked and spontaneous firing in the mouse IC in vivo We first performed immunostaining and tested hearing thresholds to validate vesicular GABA transporter (VGAT)-ChR2 transgenic mice on a mixed CBA/CaJ x C57BL/6J genetic background. Transgenic animals allowed for optogenetic cell-type identification. Extracellular single neuron recordings were obtained before and after pharmacological mGluR2/3 activation. We observed increased sound-evoked firing, as assessed by the rate-level functions (RLFs), in a subset of both GABAergic and non-GABAergic IC neurons following mGluR2/3 pharmacological activation. These neurons also displayed elevated spontaneous excitability and were distributed throughout the IC area tested, suggesting a widespread mGluR2/3 distribution in the mouse IC.