Auditory Neurophysiology publications

Background: Neonatal hypoxia-ischemia (HI) disrupts brain development and can impair sensory circuit maturation. However, how HI vulnerability is modified within developing auditory pathways remains poorly defined. Purpose: Metformin is used during pregnancy in select cases and modulates cellular energy signaling. Here, we tested whether maternal metformin administration during gestation alters functional and cellular outcomes in offspring brain after neonatal HI. Methods: Pregnant rat dams received metformin in drinking water, and offspring rat pups underwent HI during early postnatal life. Auditory pathway function was assessed in vivo using auditory brainstem responses (ABRs), and cellular pathology within the medial nucleus of the trapezoid body (MNTB) was evaluated by immunohistochemistry across postinjury developmental time points. Results: HI significantly elevated click-evoked ABR thresholds and reduced wave II and III amplitudes, whereas maternal metformin exposure prevented the HI-induced click-threshold elevation and preserved wave II and III amplitudes without altering peripheral or central conduction times. Histologically, HI produced an age-dependent decline in MAP2-positive neuronal density in the MNTB, culminating in marked neuronal loss at later postnatal stages. Notably, maternal metformin partially rescued HI-associated reductions in MNTB neurons, with a parallel trend toward preservation of oligodendrocyte lineage cells. Conclusion: Together, these findings indicate that maternal metformin administration during pregnancy enhances metabolic signaling and mitigates HI-related auditory brainstem dysfunction and cellular pathology in offspring, supporting maternal metabolic modulation as a determinant of neonatal sensory brain injury outcomes.

Optogenetic stimulation is widely used to establish causal links between neural activity, behavior, and sensory perception, yet animals may also perceive the neural stimulation itself, a phenomenon termed “optoception.” We hypothesized that cortical optogenetic stimulation would generate an artificial percept that could be distinguished from externally evoked sensations and characterized psychometrically in an operant task. We tested this hypothesis using mesoscale cortical photostimulation delivered by a 3 mm, 459 nm LED implanted over auditory cortex. Four mice expressing Channelrhodopsin-2 (ChR2) in excitatory neurons learned a head-fixed go/no-go task in which 20 Hz cortical photostimulation served as the target. ChR2-positive mice detected cortical photostimulation relative to LED-off catch trials, distinguished it from both an external LED matched in wavelength and pulse rate and from an acoustic noise matched in amplitude-modulation rate, and discriminated between 20- and 10-Hz cortical photostimulation. Reducing implanted-LED optical power initially lowered rate-discrimination sensitivity, which then increased across training sessions, demonstrating perceptual learning. In two mice tested with 11 randomly interleaved rates spanning 10-20 Hz, lick probability followed a saturating rate-dependent function. Two ChR2-negative littermates failed to acquire photostimulation-locked behavioral responding. Together, these findings show that mesoscale cortical optogenetic stimulation generates a graded, learnable artificial percept whose behavioral readout depends on photostimulation rate and optical power. This single-LED preparation provides a cost-efficient and wavelength-extensible platform for psychometric analysis of optoception. SIGNIFICANCE STATEMENT Optogenetic stimulation can alter sensory processing, but the neural perturbation itself may also become a perceptual cue. We show that mice detect mesoscale cortical photostimulation delivered by a 3 mm implanted LED, distinguish it from matched external light and sound, and discriminate differences in photostimulation rate. When implanted-LED optical power was reduced, discrimination sensitivity initially declined and then increased across training sessions, revealing perceptual learning of optoception. Thus, mesoscale cortical photostimulation generates a graded internal signal whose behavioral readout depends on stimulation rate, optical power, and experience. A single implanted LED provides a cost- efficient and wavelength-extensible assay for measuring optogenetic perception.

Objective Cisplatin, a life-saving chemotherapeutic drug, causes ototoxicity. Although sodium thiosulfate is used to prevent ototoxicity in pediatric patients, no other intervention has been approved for clinical use against cisplatin-induced hearing loss. Hence, there is an urgent need to identify drugs that prevent cisplatin ototoxicity. Methods CBA/J mice were treated with cisplatin (3 mg/kg, i.p., daily for 5 days), and MnTBAP (10 mg/kg, i.p., daily for 8 days) was used to inhibit cisplatin-induced ototoxicity. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were recorded before and after treatment to assess hearing loss, while immunohistochemistry with anti-Myosin-VIIa was conducted to examine hair cell loss, with phalloidin to examine spiral ganglion neuron (SGN) loss, and with anti-nitrotyrosine to assess nitrotyrosine levels. Results Cisplatin treatment elevated the nitrotyrosine levels in hair cells and SGNs and increased the loss of these cells in the middle and basal cochlear regions. A negative correlation was observed between cisplatin-induced changes in the hair cell count or SGN density and nitrotyrosine levels. Cisplatin treatment elevated the hearing thresholds, as indicated by the ABRs, and lowered the DPOAE amplitudes, suggesting cisplatin-induced hearing loss. However, MnTBAP cotreatment prevented the cisplatin-induced changes in hearing sensitivity and reversed the morphological changes. Conclusion The otoprotection observed with MnTBAP cotreatment along with the attenuation of cisplatin-induced increase in nitrotyrosine levels in the cochlea indicates its potential as an inhibitor of cochlear nitrative stress and its utility in mitigating cisplatin-induced ototoxicity.

Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism spectrum disorder. Previous studies in the Fmr1 knockout (KO) mouse model of FXS and affected individuals have identified common electroencephalographic (EEG) abnormalities, which constitute biomarkers of cortical dysfunction for drug treatments. Methods We evaluated the effects of three different doses of oral blarcamesine, a Sigma-1 receptor agonist (S1R), on FXS-relevant EEG biomarkers in Fmr1 KO mice utilizing a multielectrode array (MEA) on resting-state power (from delta to gamma frequencies) and network synchronization (inter-trial phase coherence [ITPC]) using three auditory stimulation paradigms (chirp, auditory steady-state response [ASSR] at 40 Hz and at 80 Hz). Results Blarcamesine-treated Fmr1 KO mice showed dose-dependent modulation of EEG biomarkers across cortical regions. Resting-state EEG power was reduced across multiple frequency bands, including suppression of the FXS-distinctive elevation in the gamma band. Significant improvements in ITPC were observed in all cortical regions for chirp stimulation and 40 Hz ASSR, while modest improvements were seen for 80 Hz ASSR. Conclusion Altogether, these data demonstrate that blarcamesine modulates multiple EEG biomarkers of cortical dysfunction in Fmr1 KO mice. Given that these biomarkers are associated with fundamental neurophysiological mechanisms underlying cognitive and behavioral abnormalities, and are shared between FXS mouse models and affected individuals, these findings are consistent with previously characterized S1R-mediated pharmacological effects of blarcamesine. These data support further investigation of blarcamesine’s clinical potential in FXS and other neurodevelopmental disorders.

Focused ultrasound (FUS) is a promising noninvasive neuromodulation approach, but whether it can directly activate central auditory neurons in vivo remains unresolved. We applied high-frequency FUS (20 MHz) to the central nucleus of the inferior colliculus (CNIC) in anesthetized guinea pigs while recording electrophysiological responses from the auditory pathway and cochlea. FUS evoked cortical activity through indirect cochlear activation, possibly via skull-mediated mechanical coupling, rather than direct inferior colliculus activation, with ultrasound-evoked compound action potentials predominating in the ipsilateral cochlea. More interestingly, FUS stimulation of the CNIC induced activation of neurons and glial cells in the CNIC and auditory cortex as demonstrated by c-Fos expression, suggesting that FUS stimulation activated the afferent pathway. We also show that FUS engaged the auditory efferent system, likely via medial olivocochlear neurons, producing reduced compound action potential amplitudes, enhanced cochlear microphonics, and persistent effects lasting at least two hours, consistent with long-lasting efferent plasticity. Strikingly, FUS administered before acoustic trauma almost completely prevented noise-induced hearing loss, limiting auditory brainstem response threshold shifts to <10 dB versus ∼60 dB in controls. Gentamicin abolished these physiological and protective effects, implicating medial olivocochlear activation. These findings identify FUS as a potent noninvasive strategy for engaging auditory efferent circuits and protecting against acoustic injury.

The inferior colliculus (IC) is a major midbrain convergence site critical for processing complex sounds and undergoes fundamental changes with age-related hearing loss (ARHL). Local field potentials (LFPs) represent pre-synaptic integration of excitatory and inhibitory signals in local neural populations. Here, we assessed age-related changes in sound-evoked IC LFPs in the CBA/CaJ mouse model of ARHL across the tonotopic axis. We recorded from 495 sites across four age groups (young: 4-6 months; middle: 8-14 months; old: 24-25 months; “oldest old”: 27-31 months), examining LFP responses from dorsal (low-frequency), medial (mid-frequency), and ventral (high-frequency) IC regions. Analysis of the onset depolarization (N1 component) in response to broadband noise bursts revealed significant age-related hyperexcitability in medial and dorsal regions, with oldest old animals showing enhanced responses while ventral regions were unaffected. Amplitude-intensity functions demonstrated significant age × level interactions across all regions, with oldest old animals exhibiting level-dependent hyperexcitability most pronounced at suprathreshold intensities. Time-frequency analysis of LFP spectral content (30-100 Hz) revealed a crossover pattern across medial and dorsal regions, with oldest old animals showing reduced power at low-to-moderate stimulus levels but enhanced power at high stimulus levels. Ventral regions showed a low-level reduction without suprathreshold enhancement. These findings reveal paradoxical enhancement of neural activity in the aging IC, with the most pronounced changes in dorsal and medial regions rather than ventral regions most affected by peripheral hearing loss, suggesting that central hyperexcitability depends on residual afferent drive and implicating region-specific alterations in excitatory-inhibitory balance underlying central presbycusis.

Auditory hypersensitivity or decreased sound tolerance is a common phenotype of Fragile X Syndrome (FXS). Impairments in adaptation, defined as the reduction in the neuronal responsiveness to repeating sounds, can contribute to this prevalent phenotype. Previous studies on event-related potential observed impairments in mismatch negativity (MMN) in both FXS individuals and in the FMR1 -knockout (KO) mouse model of FXS. Therefore, in the present study we characterized stimulus-specific adaptation (SSA), a neural correlate of MMN, at the auditory cortex (AC) of anesthetized (with ketamine/xylazine) female and male postnatal day 20 (P20) wild-type (WT) and FMR1 -KO mice, using the oddball paradigm with either 4 Hz or 1 Hz repetition rate. We observed robust SSA at the 4 Hz repetition rate of the oddball paradigm in the AC neurons of all four groups of animals. We also noted that the strength of SSA diminished between 4 to 1 Hz repetition rate. In addition, at both the 4 Hz and 1 Hz repetition rate, reduced SSA was observed particularly in the male FMR1 -KO mice compared to their WT counterparts, while female WT and FMR1 -KO mice displayed similar SSA. In terms of sex differences, male FMR1 -KO mice had lower SSA than female FMR1 -KO mice, while SSA was similar in male and female WT mice. Overall, our observation of reduced SSA in the male FMR1 -KO mice suggests that impairments in neuronal adaptation potentially contribute to the auditory hypersensitivity phenotype particularly within the male population.

A key feature of vowels in spoken language is that their fundamental frequency ( f 0 ), which underlies perceived pitch, can change dynamically over time. However, it remains elusive how such prosodic glides shape the neural response in the auditory cortex. The current magnetoencephalography (MEG) experiment was designed to study the transient and sustained neuromagnetic correlates of prosodic contour information in vowels, with a particular focus on the P2 component. Twenty-four normal-hearing participants passively listened to vowel sequences in which both vowel type and prosodic contour were either unchanged or varied between successive vowels. At the level of single vowels, the results showed that falling contours elicit larger and earlier P2 responses than rising and flat prosodic contours. At the level of vowel triplets, the P2 was larger in response to stimulus sequences in which prosodic contour was varied across stimuli. The data indicate that the P2 might be a neural correlate of the early processing of prosodic contour information; moreover, they suggest that the P2 might be particularly sensitive to pitch glides, possibly due to longer time constants that are encompassed within the P2.

The inferior colliculus (IC) is a critical auditory processing center. IC neurons exhibit diverse responses to different sound features, but how IC neurons encode co-varying sound features—such as both the direction and intensity of a frequency-modulated (FM) sweep—is poorly understood. Here, we show that individual IC neurons and neuronal populations multiplex information about FM sweep direction, frequency range, and speed through distinct coding strategies, including both spike timing patterns and overall firing rate.

Aging and noise over-exposure lead to complex mixtures of cochlear degradation that impair the structure and function of outer hair cells (OHCs), inner hair cells (IHCs), and the cochlear nerve. However, IHC damage and cochlear synaptopathy (CS) remain pathologies "hidden" from the audiogram. This study aimed to compare and contrast the physiological signatures of these two popular and distinct exposure paradigms using promising non-invasive assays: Envelope Following Responses (EFRs), Auditory Brainstem Response (ABRs), Wideband Middle-Ear Muscle Reflexes (WB-MEMRs), and Distortion Product Otoacoustic Emissions (DPOAEs). We utilized chinchilla models of carboplatin exposure (CA) (N = 4) and temporary threshold shift (TTS) noise-induced CS (N = 4) to compare the physiological signatures of each type of exposure. While both groups showed unchanged ABR thresholds two weeks after exposure, EFRs, ABR Wave 5/1 ratios, and MEMRs showed distinct effects of exposure. CA and TTS exposures showed differences in the pattern and degree of decreased EFR "peakiness" across different stimulus modulation types (e.g., sinusoidal vs. rectangular). Significant elevations in ABR Wave 5/1 ratios were less-pronounced in the TTS-exposed animals. Reduced WB-MEMR amplitudes and increased WB-MEMR thresholds occurred in both groups, although this effect was more pronounced for TTS. Opposite trends in DPOAE amplitudes suggest that effects on OHC integrity and auditory efferent physiology may differ between the two exposure types and their induced pathologies. Overall, these results suggest a combination of EFR "peakiness", ABR Wave 5/1 ratio, and WB-MEMR may be useful for profiling IHC dysfunction and CS as potentially distinct forms of hidden hearing loss.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male Fmr1 knockout (KO) mouse, FXS model. Following intracerebroventricular (i.c.v.) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human FMR1 isoform 7 ameliorates cortical dysfunction and behavioral deficits in a murine FXS model and suggests that widespread cortical biodistribution is required for therapeutic benefit.

Objectives. Spatial mapping of sound frequencies along the auditory pathway is refined through sound-evoked activity during early development. However, how neonatal auditory deprivation alters this organization remains unclear. This study examined frequency-specific spatial representations in the inferior colliculus (IC) using targeted low-frequency (apical) and high-frequency (basal) cochlear stimulation, enabling direct evaluation of low-frequency pathway integrity after neonatal deafness.Methods. Sixteen Sprague-Dawley rats (8 normal-hearing [NH] and 8 neonatally deafened [ND]) were studied. Neonatal deafness was induced by daily kanamycin injections from postnatal days 4 to 17. At 8–10 weeks of age, all animals underwent unilateral cochlear implantation with bipolar electrode pairs positioned in apical and basal cochlear regions to activate low- and high-frequency pathways. Multiunit responses were recorded from the contralateral IC using a multichannel linear electrode array. Spatial tuning curves (STCs) based on cumulative discriminability were used to assess thresholds, spread of excitation, and tonotopic precision. Spiral ganglion neuron (SGN) density was quantified histologically.Results. Despite 48%–67% SGN loss across cochlear turns, electrically evoked auditory brainstem response thresholds and IC thresholds were comparable between groups, indicating preserved peripheral excitability. However, ND rats exhibited significantly broader STCs (P=0.002) and reduced dorsoventral separation of apical and basal best sites (1.18± 0.67 mm vs. 1.80±0.40 mm, P=0.039), reflecting degraded central tonotopic precision. The effects were most pronounced for apical (low-frequency) stimulation, consistent with the selective vulnerability of low-frequency pathways to early auditory deprivation.Conclusion. These findings provide direct physiological evidence that early auditory experience is critical for refining frequency-organized connectivity in the auditory midbrain. The preferential degradation of apical (low-frequency) spatial tuning offers translational insights for optimizing stimulation strategies in early-onset deafness.

Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood–labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin–proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in spiral ganglion neurons as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.

Difficulties understanding speech in noise remain a common complaint even among listeners with normal hearing sensitivity, highlighting the need for objective, more effective measures of real-world listening. The goal of this study was to validate the use of a novel, chirped-speech (Cheech) stimulus—continuous, naturally-spoken speech fused with chirps designed to elicit robust auditory evoked potentials—to characterize relationships between speech recognition, listening effort, and auditory neural encoding. Twenty-five normal-hearing adults completed a sentence-recognition task using both original (unmodified) and Cheech-modified AzBio sentence lists in quiet, +3 dB, and −3 dB signal-to-noise ratio (SNR) conditions while neural responses from the brainstem through cortex were recorded simultaneously. Speech recognition remained near ceiling in quiet but declined with decreasing SNR for both original and Cheech stimuli. Compared with clean speech, Cheech-modified speech showed slightly poorer recognition performance as SNR decreased and somewhat higher perceived effort overall. Yet, Cheech was highly effective at evoking auditory responses from the brainstem (auditory brainstem response, ABR) through the cortex (including middle- and late-latency responses, MLR and LLR) even with <5 minutes listening time per condition. Neural responses showed reduced amplitudes and prolonged latencies as SNR decreased. In general, ABR latencies and wave I amplitudes were associated with speech-in-noise recognition performance, whereas cortical responses (MLR Na, Nb, and LLR P1) were associated with subjective workload. These findings show that Cheech-modified speech preserves intelligibility while yielding robust, multilevel neural recordings during sentence perception, offering a promising approach to examine hierarchical auditory processing under ecologically relevant speech-in-noise conditions.

Mammalian cochlear hair cells convert acoustic stimuli into electrical signals, which are relayed to the central auditory pathway via auditory neurons. Progressive loss of hair cells and their synapses is a characteristic of age‐related hearing loss (ARHL), but the underlying mechanisms remain poorly understood. In this study, we tested the hypothesis that hair cell physiological properties change with age in CBA/CaJ mice, a strain known for its slow ARHL progression. We found that hair cell size began to decrease from 10 months of age, well before detectable increase in hearing thresholds from auditory brainstem responses. This structural change was associated with a significant decrease in the size of the basolateral membrane current, in particular that carried by the large conductance calcium‐activated potassium (BK) channel currents ( I K,f ) in the apical inner hair cells (IHCs). However, the size of the mechanoelectrical transducer (MET) current measured in the IHCs remained unaffected at least up to 22 months of age. Our results provide clear evidence of an early change in the physiological properties of apical IHCs with age, which precedes measurable hearing loss, suggesting that these cellular deficits might define a distinct pathological route in the CBA/CaJ mice.

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.

Cochlear damage triggers compensatory primary auditory cortex (A1) plasticity that amplifies responses to residual sensory inputs, thereby contributing to the restoration of both cortical responsiveness to sound and perceptual sound detection threshold. However, this adaptation can become maladaptive, producing neuronal hyperactivity that contributes to tinnitus and hyperacusis. The neuromodulatory mechanisms governing these adaptive and maladaptive changes remain unknown. Here, we demonstrate that noise-induced cochlear injury triggers bidirectional synaptic zinc signaling plasticity that potentiates activity in excitatory principal neurons and parvalbumin-expressing interneurons, while suppressing activity in somatostatin-expressing interneurons. These cell-type-specific effects of synaptic zinc plasticity contribute to restoring A1 responsiveness to sound and perceptual detection thresholds, while being necessary for neural hyperactivity. Together, our findings establish synaptic zinc as a pivotal neuromodulator that shapes both adaptive and maladaptive cortical plasticity and identify a promising therapeutic target for improving perceptual recovery after cochlear damage and mitigating tinnitus and hyperacusis.

Introduction Sensory processing depends on interactions between neural circuits that convey and regulate information across cortical and subcortical networks. Classical frameworks distinguish driving inputs, which transmit sensory content via suprathreshold activation, from modulatory inputs, which alter neuronal excitability without directly eliciting spiking. However, physiological signatures of these circuit types that generalize widely across distributed brain regions remain unclear. Methods We functionally differentiated driving and modulatory circuits in the awake macaque brain by jointly quantifying suprathreshold multiunit activity (MUA) and oscillatory phase coherence (inter-trial coherence, ITC) across eight cortical and thalamic structures during auditory, visual, and eye-movement conditions. Results Preferred sensory stimuli elicited broadband ITC increases accompanied by robust MUA, yielding relatively uniform spectral distributions across adjacent frequency bands, consistent with driving inputs. In contrast, non-preferred sensory and eye-movement related events produced narrowband, frequency-specific ITC modulation without concurrent firing, characterized by dominant peaks at stimulation or event rates, consistent with modulatory inputs. These two response types were observed within individual regions, revealing two separable modes of neural activity. Discussion This narrowband ITC modulation is indicative of coordinated phase alignment, capable of dynamically regulating information transfer mediated by driving inputs across thalamocortical circuits. These findings identify distinct spectrotemporal signatures of driving and modulatory circuit properties across cortical and thalamic levels and demonstrate that subthreshold oscillatory modulation is a widespread phenomenon reflecting cross-modal and saccadic-related influences on neural excitability.

In nature, animals learn to replace predisposed behaviors with new strategies, yet the neural constraints on these transitions are unclear. Using an ethological search task in mice, we reveal medial prefrontal cortical (mPFC) neural correlates of a predisposed win-stay strategy that decays as animals learn to follow a more reliable auditory cue. Auditory cortex (ACx) activity predicts correct trial-by-trial sound-guided search, even on day one of training. This prognostic coding strengthens with learning and emerges from suppressed spiking, most pronounced in neurons tuned laterally to the cue’s spectrum. Chemogenetic disruption reveals ACx contributions to improving performance. Unexpectedly, the global silencing of mPFC accelerates successful usage of sound-tracking, contrary to its canonical role in flexible or stimulus-dependent behavior. Instead, a decentralized multiexpert competition model best predicts behavior and causal perturbations. These findings suggest that mPFC implements a default strategy based on prior knowledge, which actively hinders the expression of more efficient strategies.

Aminoglycoside antibiotics such as kanamycin induce sensorineural hearing loss by killing hair cells, resulting in secondary degeneration of spiral ganglion neurons (SGNs). Previous studies show that anti-inflammatory agents reduce SGN death, implicating a causal role of the immune response. This is consistent with observations of increased numbers of macrophages and lymphocytes, including T and NK cells, in the spiral ganglion after exposure to aminoglycosides. Here, we directly test the role of T cells and other lymphocytes in SGN degeneration in kanamycin-deafened rats. Homozygous RNU nude rats that lack T cells – but retain NK and B cells– show neurodegeneration similar to rats with a normal T cell complement, indicating that T cells are not necessary for neurodegeneration. Homozygous SRG rats lacking all lymphocytes (i.e., T, B, and NK cell-deficient), exhibit remarkable regional variation in the pattern of spiral ganglion degeneration post-deafening. In the basal half of the ganglion, SGN degeneration is significantly reduced in deafened SRG rats, implying a role for lymphocytes, presumably NK cells of the innate immune system, in SGN death. In the apical half of the deafened ganglion, SGN degeneration is not significantly affected by the lack of all lymphocytes, implying a role for other cellular mechanisms.