Auditory Research publications

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.

Introduction Age-related hearing loss (ARHL) is linked to dementia, with mitochondrial dysfunction playing a key role in its progression. Deficient mitochondrial tRNA modifications impair protein synthesis and energy metabolism, accelerating ARHL. Mitochonic acid 5 (MA-5) has shown promise as a therapeutic candidate by improving mitochondrial function, reducing oxidative stress, and stabilizing membrane potential. Methods In this study, we investigated the effects of MA-5 on ARHL in cyclin-dependent kinase 5 regulatory subunit-associated protein 1 ( Cdk5rap1 ) knockout (KO) mice, which exhibit early-onset ARHL due to abnormalities in mitochondrial transfer RNA (mt-tRNA) modifications. Results MA-5 treatment effectively attenuated ARHL progression in Cdk5rap1 -KO mice by improving auditory brainstem response thresholds and distortion product otoacoustic emissions. It also reduced spiral ganglion and outer hair cell loss, while preserving the cochlear structural integrity by preventing mitochondrial degeneration in spiral ligament fibrocytes. Mechanistically, MA-5 upregulated the expression of silent information regulator sirtuin 1 and promoted the nuclear translocation of yes-associated protein, both of which are involved in regulating mitochondrial function and cellular senescence. Metabolomics analysis further demonstrated that MA-5 restored mitochondrial metabolism, reduced lactate accumulation, and maintained mitochondrial integrity. Conclusion These findings suggest that MA-5 is a viable treatment option for ARHL and other age-related disorders associated with mitochondrial dysfunction.

Auditory learning is supported by long-term changes in the neural processing of sound. We examined these task-depend changes in the auditory cortex by mapping neural sensitivity to timbre, pitch, and location cues in cues in trained ( n = 5) and untrained control female ferrets ( n = 5). Trained animals either identified vowels in a two-alternative forced choice task ( n = 3) or discriminated when a repeating vowel changed in identity or pitch ( n = 2). Neural responses were recorded under anesthesia in two primary auditory cortical fields and two tonotopically organized nonprimary fields. In trained animals, the overall sensitivity to sound timbre was reduced across three cortical fields compared with control animals, but maintained in a nonprimary field (the posterior pseudosylvian field). While training did not increase sensitivity to timbre across the auditory cortex, it did change the way in which neurons integrated spectral information, with neural responses in trained animals increasing their sensitivity to first and second formant frequencies, whereas in control animals cortical sensitivity to spectral timbre depended mostly on the second formant. Animals trained on timbre identification were required to generalize across pitch when discriminating timbre, and their neurons became less modulated by fundamental frequency relative to control animals. Finally, both trained groups showed increased spatial sensitivity and an enhanced response to sound source locations close to the midline, where the loudspeaker was located in the training chamber. These results demonstrate that training elicited widespread alterations in the cortical representation of complex sounds.

Introduction Ibrutinib, widely used in leukemia treatment, has been implicated in sensorineural hearing loss; however, its underlying mechanisms remain unclear. Methods This study investigated the impact of ibrutinib on hearing using HEI-OC1 cells, cochlear explants and C57BL/6 J mice. We used RNA-sequences analysis to investigate the potential mechanisms of ibrutinib-induced ototoxicity. Mice received ibrutinib and auditory thresholds were assessed via auditory brainstem response testing; to assess the potential protective effects, we co-administered the caspase inhibitor Z-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK) and monitored hearing. Results Z-VAD-FMK mitigated ibrutinib-induced hearing loss by inhibiting apoptosis in auditory cells. Ibrutinib exposure resulted in cochlear hair cell (HC) damage and subsequent hearing loss by inhibiting the protein kinase B and G protein-coupled receptor 83 (GPR83) pathways. RNA sequencing suggested that GPR83 protects HCs by modulating autophagy. Z-VAD-FMK application and GPR83 overexpression attenuated ibrutinib-induced cochlear HC apoptosis and auditory decline. Conclusion These findings confirm ibrutinib’s ototoxicity and highlight the protective role of GPR83 in ibrutinib-induced hearing loss, supporting future clinical investigations into Z-VAD-FMK and GPR83 as interventions for ibrutinib or other chemotherapeutic drug-induced ototoxicity.

Perception of rhythm significantly impacts various aspects of daily life, including engaging with music, discerning speech prosody nuances, and coordinating physical activities like walking and sports. Numerous studies in cognitive sciences have highlighted that human rhythmic synchronization is more precise when responding to auditory rhythmic stimuli than to visual ones when the timing cues are identical. However, deaf individuals were shown to display a heightened proficiency in synchronizing their movements with visual timing cues, outperforming hearing controls (HC). Furthermore, it was demonstrated that cochlear implant (CI) users can synchronize their movements with the rhythm of unpitched drum tones. These findings raise an important question: do CI users possess a visual synchronization advantage from their pre-implant deafness, while maintaining auditory synchronization skills comparable to those of HC? Alternatively, does the neural reorganization post-implantation negate the visual synchronization advantage acquired before the implant? This study aims to answer these questions by using a sensorimotor synchronization task to probe multisensory processing abilities in CI users. Specifically, we assessed unimodal and multimodal auditory and visual abilities in CI users compared to HC using a finger tapping synchrony task with four isochronous stimulus conditions: an auditory metronome, a visual metronome, a synchronous presentation of both the auditory and visual metronomes at the same tempo, and an asynchronous presentation of the auditory and visual stimuli at differing tempos. Synchronization to auditory stimuli surpassed synchronization to visual stimuli in both groups. CI users and HC demonstrated similar unisensory synchronization consistency within the visual and auditory conditions. While HC enhanced their consistency in the audio-visual synchronous condition compared to the unisensory visual condition, CI users did not display the same improvement. Furthermore, the interference from incongruent auditory information in the asynchronous condition was comparable in HC and CI users. This study highlights that, although pitch processing is known to be impaired in CI users, our findings suggest that rhythm processing remains relatively spared. As anticipated, CI users demonstrate similar auditory rhythmic synchronization skills to those of HC, in line with existing research. Moreover, we find that, unlike deaf individuals, CI users do not exhibit an advantage in visual rhythmic synchronization, which may be due to the relatively few CI users in the study who had early prolonged pre-implantation deafness. The observed shift in audio-visual integration among CI users suggests that post-deafness or post-implantation reorganization of their auditory cortex may impede the effective integration of temporal auditory stimulation from the implant and visual information.

Exposure to traumatic noise triggers cochlear damage and consequently causes permanent sensorineural hearing loss. However, effective treatment strategies for noise-induced hearing loss (NIHL) are lacking. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that plays a critical role in multiple physiological and pathological events. However, its role in NIHL pathogenesis remains elusive. This study revealed that SIRT1 expression in the cochlea progressively decreases in a mouse model of NIHL. Hair cell-specific knockout of SIRT1 exacerbates the noise-induced loss of outer and inner hair cell synaptic ribbons, retraction of cochlear nerve terminals, and oxidative stress, leading to more severe NIHL. Conversely, adeno-associated virus (AAV)-mediated SIRT1 overexpression effectively attenuated most noise-induced cochlear damage and alleviated NIHL. Transcriptomic analysis revealed that SIRT1 deficiency impairs glucose metabolism and inhibits antioxidant pathways in the cochlea following exposure to noise. Further investigation revealed that SIRT1 exerts an antioxidant effect, at least in part, through AMPK activation in cultured auditory HEI-OC1 cells exposed to oxidative stress. Collectively, these findings indicate that SIRT1 is essential for the maintenance of redox balance and mitochondrial function in the cochlea after traumatic noise exposure, thus providing a promising therapeutic target for NIHL treatment.

Transmembrane protein 135 (TMEM135) is a highly conserved 52 kDa protein with five predicted transmembrane domains that colocalizes with mitochondria and peroxisomes. Previous studies have shown that TMEM135 is involved in mitochondrial dynamics, thermogenesis, and lipid metabolism across multiple tissues and species; however, its role in the inner ear and auditory system remains unknown. We investigated the function of TMEM135 in hearing using wild-type (WT) and Tmem135FUN025/FUN025 (FUN025) mutant mice on a CBA/CaJ background, a normal-hearing mouse strain. Although FUN025 mice displayed normal auditory brainstem response (ABR) thresholds at 1 month, we observed significantly elevated ABR thresholds at 8, 16, and 64 kHz by 3 months, which progressed to profound hearing loss by 12 months. Consistent with our auditory testing results, 13-month-old FUN025 mice exhibited a severe loss of outer hair cells and more modest changes in inner hair cell survival, spiral ganglion neuron density, and stria vascularis integrity in the cochlea. Our results using BaseScope RNA in situ hybridization indicate that TMEM135 is expressed in the inner hair cells, outer hair cells, supporting cells, and stria vascularis. Using Volocity software and Costes colocalization analysis, we found that TMEM135 closely colocalizes with mitochondria in hair cells. Together, these results demonstrate that the FUN025 mutation in Tmem135 causes progressive sensorineural hearing loss, and suggest that TMEM135 is crucial for maintaining key cochlear cell types and normal sensory function in the aging cochlea.

The cochlea is vulnerable to various pathological conditions, with sensory cells typically being the primary targets of damage. However, supporting cells also experience significant impacts. Despite their critical role in maintaining the structural and functional integrity of the sensory epithelium, the supporting cell involvement in cochlear damage remains poorly understood. This study aimed to elucidate the susceptibility of supporting cells in cochlear damage and their role in structural repair, using a mouse model of ototoxicity induced by cyclodextrin-a cyclic oligomer of glucose that is known to preferentially damage outer hair cells at high doses. A morphological examination of the cochlea showed that cyclodextrin exposure caused significant sensory cell loss, particularly affecting outer hair cells across the cochlear spiral, except at the apex. Despite extensive hair cell damage, most supporting cells in the apical and middle cochlear regions survived. In the basal end, where substantial supporting cell loss occurred, certain Deiters' cells survived even after losing their phalangeal processes. Additionally, our observations indicate that Hensen's cells contribute to forming an epithelial layer over the basilar membrane when the organ of Corti collapses. Further quantitative analysis revealed location-dependent susceptibility among supporting cell types. Deiters' cells demonstrated greater resilience than pillar cells. Notably, the three rows of Deiters' cells displayed differential susceptibility: the third row showed a more significant loss in regions with sporadic Deiters' cell loss, while the first row exhibited an increased loss in areas adjacent to regions of complete Deiters' cell depletion. The reduction of Hensen's cells started in the middle section of the cochlea, occurring at a greater level than the reduction observed in Deiters' and pillar cells. However, in the extreme base, where both pillar and Deiters' cells were largely or completely absent, some Hensen's cells were still present. Together, these findings provide new insights into the varying vulnerability of supporting cells to cochlear damage and underscore their essential role in structural repair.

Early and accurate diagnosis of Alzheimer's disease (AD) will be key for effective personalized treatment plans ( Cummings, 2023). Significant difficulties in auditory processing have been frequently reported in many patients with mild cognitive impairment, the prodromal form of AD ( Tarawneh et al., 2022), making it an outstanding candidate as AD diagnostic biomarker. However, the efficiency of diagnosis with this parameter has not been explored. Here we show that when male mice with amyloidosis begin to show memory decline, changes in the auditory brainstem response (ABR) to clicks enable the reliable diagnosis of disease using a machine learning algorithm. Interpretation of the machine learning diagnosis revealed that the upper levels of the auditory pathway, including the inferior colliculus, were the probable sources of the defects. Histological analyses show that in these locations, neuroinflammation and plaque deposition temporally correlate with behavioral changes consistent with memory loss. While these findings are tempered by the caveat that they derive from amyloidosis mice, we propose that ABR measurements be evaluated as an additional rapid, low-cost, noninvasive biomarker to assist the diagnostic testing of early-stage AD.

Aims This study examined the effect of 4,4′‐diisothiocyanostilbene‐2,2′‐disulfonic acid (DIDS), an anion channel blocker of voltage‐dependent anion channel 1 (VDAC1), on noise‐induced hearing loss (NIHL) and its underlying mechanisms. Methods Cochlear explants and House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells were used to assess the effect of DIDS in vitro. Auditory brainstem responses were used to assess auditory functions in mice. Immunofluorescence staining of myosin 7a and CTBP2 were used to examine hair cells and synaptic ribbons. The accumulation of reactive oxygen species (ROS) was measured by 4‐HNE staining. The gene expression changes of cochlea were analyzed using RNA sequencing. Results DIDS reduced the levels of ROS in cochlear explants and attenuated cell death caused by hydrogen peroxide in both cochlear explants and HEI‐OC1 cells. In C57BL/6 mice, DIDS reduced ROS generation and tumor necrosis factor‐α induced by noise exposure, thereby protecting outer hair cells and inner hair cell synaptic ribbons from noise‐induced damage through a mechanism involving the PINK1/Parkin signaling pathway. The preventive effect of DIDS in cochlear explants was eliminated by mitophagy inhibition. Conclusion VDAC1 inhibition enhances mitophagy in cochlear hair cells, playing a critical role in defending against oxidative stress and inflammation. Downregulation of VDAC1 may thus be considered a therapeutic strategy for preventing cochlear hair cell damage and reducing NIHL.

Aminoglycoside antibiotic‐induced sensorineural hearing loss (SNHL) is a common sensory disorder that requires the development of prophylactic and therapeutic interventions. Lycium barbarum glycopeptide (LBGP) is a peptidoglycan isolated and purified from Lycium barbarum polysaccharides that exhibit significant anti‐inflammatory, antioxidant, and neuroprotective effects, but the role of LBGP in aminoglycoside‐induced SNHL has not been well investigated. Here it is shown that LBGP can protect against neomycin‐induced hearing impairment and alleviate oxidative stress in a neomycin‐induced SNHL mouse model. Moreover, it is further found that inhibition of tryptophan hydroxylase (Tph)‐mediated serotonin (5‐HT) biosynthesis plays a key role in the mechanism of action of LBGP in treating neomycin‐induced hearing loss. Systemic delivery of 5‐HT increased neomycin‐induced apoptosis of cochlear hair cells and spiral ganglion neurons, and pharmacological Tph2 inhibition with P‐chlorophenylalanine or Tph2 knock down by AAV‐ie‐ Tph2 effectively attenuated neomycin‐induced hearing dysfunction. Collectively, these results provide a promising strategy for the prevention of SNHL by using natural plant extract which is more available and exhibits lower side effects compared with other otoprotective drugs, and identify Tph2 as a potential pharmacological target for the treatment of aminoglycoside‐induced ototoxicity.

Molecular profiling of inner ear neurons has broadened the classification of the primary afferents that support neural coding for hearing and balance. To extend spatiotemporal characterization of auditory and vestibular neuron diversity, we established a transgenic reporter mouse model (Prphp-mCherry), where elements of the peripherin promoter (Prphp) drive expression of the mCherry fluorescent reporter. Type III intermediate filament protein peripherin expression is a marker for type II spiral ganglion neurons (SGN) that innervate the cochlear outer hair cells, and the small diameter 'bouton' vestibular ganglion neurons (VGN) innervating the type II vestibular hair cells. Using Nanopore genome sequencing, the integration site of the transgene construct was identified within the class III metabotropic glutamate receptor 8 gene (Grm8, chromosome 6). Use of CUBIC / PEGASOS clearing of early postnatal to adult inner ear tissues enabled in situ 3D spatial localization of a dispersed population of cochlear mCherry + ve SGN, with highest expression and density in the hook (high frequency encoding) basal region. Of these mCherry + ve SGN, type II SGN (peripherin-immunopositive) were all co-labeled in the basal region, but the majority of the overall mCherry-delineated SGN auditory subpopulation were type I SGN innervating inner hair cells. In the VGN, mCherry + ve neurons represented ~ 15% of the adult population, dispersed as a small diameter subpopulation throughout both the inferior and superior VGN regions. These findings resolve heterogeneous type I and type II cochlear SGN subpopulations, particularly in the structurally complex hook region, and further differentiate vestibular primary afferents across postnatal development.

Early life stress (ELS) has been shown to disrupt cognitive and limbic functions, yet its impact on sensory systems, particularly the auditory system, remains insufficiently understood. In this study, we investigated the enduring effects of ELS induced by neonatal maternal separation (MS) on behavioral and cortical processing of sound azimuth in adult male rats. We found that MS significantly impairs sound-azimuth discrimination, paralleled by broader azimuth tuning and reduced dendritic branching and spine density in neurons within the primary auditory cortex. Notably, exposure to an enriched acoustic environment during the stress period effectively protects against these MS-induced alterations, restoring behavioral performance, cortical tuning, and dendritic spine density of neurons to levels comparable with controls. Further analyses reveal that epigenetic regulation of cortical brain-derived neurotrophic factor by histone H3 lysine 9 dimethylation may underlie the observed changes in cortical structure and function. These results underscore the profound and lasting impact of MS-induced ELS on auditory processing, particularly within cortical circuits involved in spatial processing. They suggest that sensory enrichment is a potential therapeutic strategy to ameliorate the adverse effects of ELS on sensory processing, with broader implications for understanding and treating sensory deficits in stress-related disorders.

Human cytomegalovirus (HCMV) is the most common viral infection acquired in utero and a leading cause of neurodevelopmental abnormalities, including sensorineural hearing loss (SNHL). In previous studies using a murine model of HCMV induced SNHL, hearing loss was correlated with virus-induced cochlear inflammation but not cochlear viral load. However, these previous findings were determined at the time of auditory testing, a time poiont well past critical periods of auditory development. In the current study, cochlear virus load early in auditory development could be correlated with the magnitude of virus-induced cochlear inflammation, cochlear histopathology and the development of hearing loss. Transcriptional profiling at early times after infection revealed dysregulation of multiple well described deafness-related genes (DRG). Treatment with antiviral antibodies early after infection decreased cochlear virus load, cochlear inflammation, cochlear histopathology, and normalized DRG expression arguing that virus-induced cochlear inflammation can result in pleiotropic effects on the developing auditory system. Finally, this model also demonstrated that sterilizing immunity was unnecessary for prevention of SNHL, thus providing a rationale for inteventions that could limit, but not completely prevent HCMV infection of the developing auditory system.

Purpose: To reduce amplitude variability of auditory evoked potentials (AEPs) we developed a circuit that generates an electric calibration pulse (CalPulse) following each evoking sound presentation. We aim to determine if external CalPulse signals can function as a reliable calibration reference for AEP amplitude measurements. Methods: The CalPulse circuit was integrated with an AEP recording montage. The amplitude and morphology of two CalPulse signals (square wave and sine wave) was first assessed in vitro with electrodes submerged in saline. Repeatability of the two signals was then compared in vivo using five (3 male/2 female) 4-month-old CBA/CAJ mice and four unique auditory brainstem response (ABR) configurations. Sine wave CalPulse amplitudes were subsequently used to adjust raw ABR wave-1 amplitudes in a sample of 38 (19 male/19 female) CBA/CaJ mice. Variability in adjusted wave-1 amplitudes was compared with raw amplitudes. Measurements were repeated every month for 4 months (8 to 11 months old) to evaluate its potential as a tool to detect age-related changes in auditory function. Results: Wave quality examinations indicate that both CalPulse signal types are stable in vitro, with the sine wave signal being more repeatable when recorded in vivo. Sine wave CalPulse amplitudes correlated positively with ABR wave-1 amplitudes. Normalizing wave-1 amplitudes with CalPulse measures significantly reduced within-subject variability. Normalized wave-1 amplitudes showed a significant decrease at 10 months of age consistent with age-related cochlear synaptopathy, while uncalibrated wave-1 amplitudes from the same recordings failed to detect this decrease. Conclusion: Our new calibration circuit can be used to improve diagnostic sensitivity of AEP measures.

Mice and primary fibroblasts derived from mouse embryos completely lacking cytoplasmic β‐actin, because the Actb gene was engineered to instead express γ‐actin protein, have previously been found to be virtually devoid of phenotype. Here, we report the characterization of mice and mouse embryonic fibroblasts homozygous for an Actg1 allele edited to translate β‐actin instead of γ‐actin ( Actg1‐ coding beta; Actg1 c‐b/c‐b ), which resulted in mice and fibroblasts that are devoid of γ‐actin. We demonstrate that these Actg1 c‐b/c‐b mice present with no measurable phenotype in survival, body mass, activity, muscle contractility, or auditory function. Primary fibroblasts derived from Actg1 c‐b/c‐b mouse embryos were still proliferative, with several measured parameters of cell motility not different from wild type. From these and previous data, we conclude that β‐ and γ‐actin proteins are redundant in primary embryonic fibroblasts and during normal mouse development.

A large body of literature has shown that sensory neurons typically exhibit adaptation to repetitive stimulation. However, adaptation alone does not account for the ability of sensory systems to remain vigilant to the environment in spite of repetitive sensory stimulation. Here, we investigated single neuron responses to sequences of sounds repeatedly delivered from a particular spatial location. Instead of inducing adaptation, repetitive stimulation evoked long-lasting and location-specific facilitation (LSF) in firing rate of nearly 90% of recorded neurons. The LSF decreased with decreasing presentation probability and diminished when sounds were randomly delivered from multiple spatial locations. Intracellular recordings showed that repetitive sound stimulation evoked sustained membrane potential depolarization. Computational modeling showed that increased arousal, not decreased inhibition, underlies the LSF. Our findings reveal a novel form of contextual modulation in the marmoset auditory cortex that may play a role in tasks such as auditory streaming and the cocktail party effect.

Transmembrane channel-like protein 1 (TMC1), a pore-forming component of the mechano-electrical transducer (MET) channel in cochlear outer hair cells, is subject to numerous mutations causing deafness and hair cell death. We studied mice harboring semidominant mutations Tmc1 p.T416K, p.M412K, and p.D569N, which all display functional MET channels at postnatal day (P)6 but become deaf by P21. Early signs of concomitant hair cell apoptosis were assayed in neonatal Tmc1 mutants by labeling with Calcein-acetomethyl ester (AM), MitoTracker, and Annexin V, the latter labeling scramblase externalization of phosphatidyl serine. Reduced labeling with Calcein-AM was correlated with reduced MitoTracker, the targeting of mitochondria being confirmed with the uncoupling agent carbonylcyanide p -trifluoromethoxyphenylhydrazone, and use of MitoLight to monitor mitochondrial membrane potential. These markers demonstrated mitochondrial dysfunction in Tmc1 mutants, even at P6 when MET currents were still present. Acoustic brainstem responses established that Tmc1 p.D569N and Tmc1 p.M412K mice were deaf by P15 and Tmc1 p.T416K by P21. Two methods of blocking the stereociliary PMCA2 Ca 2+ pump both elicited scramblase activity, suggesting that apoptosis is promoted by elevation of hair bundle [Ca 2+ ]. Reduced PMCA2 density was found in the stereocilia of Tmc1 mutants and was correlated with a decrease in MET channel Ca 2+ permeability. Cre-Lox excision of the mutant M412K exon at P1 fully preserved hearing across all frequencies by P19 and promoted recovery to wild type of PMCA2 density. These results demonstrate that hair cells in Tmc1 mutants have embarked on apoptosis at P6 and argue for connections between stereociliary PMCA2 density, hair cell apoptosis, and deafness.

To navigate real-world listening conditions, the auditory system relies on the integration of multiple sources of information. However, to avoid inappropriate cross-talk between inputs, highly connected neural systems need to strike a balance between integration and segregation. Here, we develop a novel approach to examine how repeated neurochemical modules in the mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore, we coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal views of the LC to examine neuronal responses with respect to its neurochemical motifs under anesthetized and awake conditions. This approach revealed marked differences in the acoustic response properties of LC and neighboring non-lemniscal portions of the inferior colliculus. In addition, we observed that the module and matrix cellular motifs of the LC displayed distinct somatosensory and auditory responses. Specifically, neurons in modules demonstrated primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of the LC permit functional integration of multimodal inputs while retaining distinct response properties.

The homozygous Cntnap2 knockout (KO) rat is a well-established genetic model for neurodevelopmental disorders, exhibiting core features of autism spectrum disorder (ASD), including impaired sensory processing and sensorimotor gating. Recent findings indicate that the severity of ASD-like phenotypes in Cntnap2 KO offspring is influenced by the parental genotype, with more pronounced impairments observed in KO rats bred from homozygous pairs compared to heterozygous pairs ( Cntnap2 HET). However, it is unclear to what extent this is due to in utero versus postnatal effects. We, therefore, investigated how early postnatal environmental factors, shaped by differences in parental and littermate genotypes, influence auditory processing and sensorimotor gating in Cntnap2 KO rats. To examine this, we cross-fostered Cntnap2 KO pups bred from Cntnap2 KO rats to be reared with litters of Cntnap2 HET dams. Cross-fostering Cntnap2 KO rats reversed or partially reversed delayed hearing sensitivity maturation, heightened acoustic startle responses, and deficits in prepulse inhibition of the acoustic startle response. However, cross-fostering also exacerbated deficits in the neural responsiveness and conductivity in the auditory brainstem, as well as in gap-induced prepulse inhibition of the acoustic startle response. These results emphasize the importance of considering the postnatal environment and breeding strategies in preclinical genetic models of neuropsychiatric disorders. More importantly, they also demonstrate that ASD-like traits, including alterations in brainstem sensory processing, are not strictly determined by genetic factors, but remain malleable by environmental factors during early postnatal development.