Publications using TDT

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.

Cisplatin-induced ototoxicity leads to irreversible hearing loss in approximately 50% of treated patients, largely due to the cochlea's exceptionally poor cisplatin clearance compared with other organs. Although sodium thiosulfate (STS), a hydrophilic small molecule, is an established otoprotectant, achieving therapeutically sufficient cochlear concentrations remains challenging because systemic administration is limited by the blood-labyrinth barrier. Here, we report a viscosity-tunable microgel-in-sol system based on hyaluronic acid (HA) that enables sustained, localized delivery of STS to the inner ear via intratympanic injection. The STS-loaded microgel was readily injectable through 31 G needles and provided a six-fold extension in drug release duration compared with free STS solution. However, direct microgel injection caused significant occlusion of the middle ear cavity due to swelling and poor clearance. To overcome this limitation, we developed a microgel-in-sol formulation composed of an HA solution and microgel at a 3:1 volumetric ratio. This formulation exhibited concentration-dependent, lubricant-like viscosity while maintaining effective drug delivery and preserving auditory function, as confirmed by in vivo auditory brainstem response (ABR) measurements. Overall, this microgel-in-sol strategy represents a biocompatible, minimally invasive approach for localized inner-ear drug delivery.

CDC42 is involved in multiple signaling pathways, including actin organization and polarity. We previously reported progressive sensorineural hearing loss (SNHL) in inner ear hair cell (HC)-specific Cdc42-knockout (Atoh1-Cre+/-;Cdc42flox/flox) mice. However, the phenotype was milder than expected, suggesting possible redundancy with other Rho-family GTPases. Thereafter, Takenouchi-Kosaki syndrome (TKS), caused by de novo CDC42 mutations and manifesting as SNHL, was reported, in which the p.Y64C mutation was speculated to be constitutively active. However, the relationship between CDC42 status and hearing phenotypes in TKS remains unclear. Using cell models, mouse models, and patient data, we propose that impaired and/or dysregulated cycling between GDP/inactive and GTP/active forms, through either loss-of-function or constitutive activation, can lead to SNHL. Furthermore, to test redundancy, we generated HC-specific Cdc42;RhoQ double-knockout (Atoh1-Cre+/-;Cdc42flox/flox;RhoQflox/flox) mice, which revealed synergistic roles of CDC42 and RHOQ in cochlear HCs. Supporting this synergy, MDCK cells with CDC42 and RHOQ double knockdown showed greater phospho-cofilin, a key regulator of actin turnover, elevation than single knockdowns.

The limitations of electrical neuromodulation are driving the development of neuroprosthetic systems enhanced with complementary modalities. A key technological challenge however remains the integration of the necessary hardware components (optical, thermal, fluidic, electrical) into miniaturized implants. Here we present a design framework, inspired by fast prototyping, that promises to reduce the complexity, fabrication time, and device bulk of multimodal neural interface systems. By combining extrusion‐based 3D printing of silicones and discrete electronic components, we integrated thermal neuromodulation and electrical recording capabilities in soft packages suitable for placement on the cortical surface of rodents. When linked to an autonomous auxiliary driver unit, these packages establish rapid, stable and localized hypothermia together with ElectroCorticoGraphy (ECoG) recording. In a rodent model of epilepsy (4‐aminopyridine), we demonstrate hypothermia‐induced suppression of seizure‐like activity. Our approach may advance the clinical translation of focal hypothermia as an alternative therapy for drug‐resistant focal epilepsies.

Aging has profound effects on sensory systems, such that older adults can report problems in hearing despite having normal audiometric thresholds. While it is known that older listeners have poorer temporal processing than younger listeners, there is limited understanding of how these deficits interact with effects of sound level, in particular when they are above conversational level (e.g., > 65 dB SPL). Here we wanted to investigate the link between temporal processing and sound level as a function of age in normal-hearing listeners. Using a forward-masking paradigm, auditory brainstem responses (ABRs) and behavioral detection thresholds were measured at different masker levels. It was found that with increasing age and masker sound level, older listeners’ Wave V amplitudes decreased and directly correlated with behavioral detection thresholds of the probe stimulus in the forward-masking paradigm. These results elucidate the fundamental effects of aging on temporal processing and its interactions with sound level in the central auditory system. The results of this study have clinical implications for the concept of “normal hearing” in the aging population and how older listeners may struggle in different listening environments that are not captured by simple audiometry. Further delineating the important effects of aging will pave the way for earlier clinical diagnosis of hearing disorders and personalized treatments for different forms of age-related hearing loss.

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.

Energy homeostasis and motivated behaviours are tightly interconnected processes coordinated by peripheral metabolic signals and central reward circuits. Among these signals, circulating triglycerides (TG) have emerged as neuromodulators of mesolimbic dopamine functions and reward processing. However, whether TG directly regulate the activity of defined neuronal populations within the nucleus accumbens (NAc) during appetitive behaviours remains unknown. Here, we investigated how central TG availability shapes the in vivo activity of NAc dopamine D2 receptor-expressing spiny projection neurons (D2R-SPNs) across distinct nutritional and metabolic states. Using in vivo fiber photometry in Drd2 -Cre mice, we monitored D2R-SPN Ca 2+ dynamics during appetitive Pavlovian conditioning and refeeding. D2R-SPNs progressively developed robust responses to a reward-predictive conditioned stimulus (CS + ) over the course of learning, while their activity during reward consumption remained stable. Acute elevation of central TG levels through carotid infusion did not alter D2R-SPN activity or behavioural performance in lean chow-fed mice, irrespective of whether they were fed or food-restricted. In contrast, in mice exposed to a high-fat diet (HFD), central TG delivery suppressed cue-evoked D2R-SPN activity in food-restricted animals without affecting reward consumption or behavioural outputs. Likewise, TG significantly reduced refeeding-evoked D2R-SPN activation in fasted HFD-mice, while leaving novelty-induced neuronal responses unchanged. Together, these findings demonstrate that obesogenic conditions reveal a metabolic state-dependent sensitivity of accumbal D2R-SPNs to circulating lipids. This work identifies TG as context-dependent modulators of D2R-SPN function and uncovers a mechanism through which dietary history interacts with current metabolic state to reshape the neural encoding of reward-predictive cues and food-directed behaviours.

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.

Animals frequently move their sensory organs relative to dynamic environmental stimuli to maximize information acquisition, a behaviour known as active sensing. Recent studies show that insects adjust antennal movements according to the temporal structure and salience of olfactory signals, suggesting that antennae participate in active sensing. However, how these movements affect central olfactory processing remains unclear. To address this question, we trained honey bee foragers using a proboscis extension response (PER) protocol in which one odour (CS+) was paired with sucrose and another (CS−) with salt water. This training produces distinct antennal movements toward the two odours. Bees were subsequently tested with a series of concentrations of both CS+ and CS− odours. Antennae were either fixed or allowed to move freely during training and testing, while electrophysiological recordings were made from the antennae and from the antennal lobes. Peripheral antennal responses across odour concentrations were not affected by whether the antennae were fixed or free. In contrast, antennal lobe projection neurons and local interneurons showed learning-related increases in responses to the CS+ odour, consistent with previous studies, and these increases were stronger in bees with freely moving antennae. Neural responses were also more variable, particularly at lower odour concentrations, when antennae could move, suggesting that response variability may contribute to plasticity. These results support the hypothesis that active antennal movements influence central processing of odour representations. Future studies comparing restrained bees with freely walking bees will help clarify the natural behavioural contexts in which antennal movements enhance olfactory sensing. SUMMARY STATEMENT This study shows that allowing honey bees to move their antennae enhances learning-related neural plasticity, linking active sensing behaviour to central olfactory processing.

Background/Objectives: Children’s perception of phonemes differs from that of adults. Our purpose was to examine whether children’s perception of vowels differs from that of adults because of differential emphasis on vowel segments (steady-state or transition), degree of coarticulation, or amount of information to make a perceptual judgment of the vowel. Methods: A, between-group cross-sectional design was employed. Twenty-four children aged four to nine years and 17 adults (aged 18 to 53) participated. Stimuli were three naturally produced syllables (/bɑ/, /bi/ and /bu/), presented in the sound field in entirety or segmented to isolate the formant transition or the vowel static formant center. Participants selected the vowel presented by choosing from corresponding pictures on a computer screen. Results: The data from children showed consistently less accuracy for vowel identification than adults for whole syllable and all segments except full transitions. Conclusions: Children were more attuned to acoustic change or contrast to enable vowel perception than adults, yet needed more extensive change before reaching adult performance.

With practice, rapid early gains in performance are followed by a slower phase marked by kinematic refinement, automaticity and enhanced cortical and striatal interactions. While sleep is known to support early learning, its causal role in the slow phase of learning is not known. Here we recorded neuronal activity in primary motor cortex (M1) and the dorsolateral striatum (DLS) during long-term skill acquisition and interleaved sleep. Surprisingly, the slow phase of learning was marked by the emergence of a previously unrecognized 5–10 Hz oscillatory activity during NREM sleep that was coherent across M1 and DLS. This oscillation resulted in repeated joint reactivation of task-specific information in cortex and striatum. Strikingly, during later stages of training, such joint reactivation of task activity increased over the course of NREM sleep, suggesting that sleep-dependent processing strengthens cortico-striatal interactions. The strength of M1–DLS coherence was predictive of next-day performance gains and increased cortico-striatal coupling during task performance. Targeted closed-loop disruption of this oscillation during NREM sleep abolished performance gains, whereas switching to a dose-matched random stimulation paradigm enabled performance improvements in the same animals. Importantly, the same cortico-striatal 5–10 Hz rhythm was also found in sleeping non-human primates, where it was selectively enhanced following learning. Together, we identify, across species, a novel NREM sleep oscillation that is important for sleep-dependent performance gains which depend on cortico-striatal processing.

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.

Individuals with fetal alcohol spectrum disorders exhibit impaired auditory processing and atypical auditory behaviors across the disorder's spectrum. Although low to moderate prenatal alcohol exposure (PAE) is a prevalent type of exposure, the developmental trajectory of auditory processing deficits resulting from this level of exposure remains unknown. To examine the effects of PAE in the auditory system, we utilized the maternal voluntary alcohol consumption paradigm to model chronic low to moderate PAE throughout gestation. We measured auditory brainstem responses (ABRs) in juvenile mice (postnatal day 16–19) and longitudinally across early adolescence (4–5 weeks), late adolescence (7–8 weeks), and young adulthood (12–14 weeks). ABR abnormalities were first observed in juvenile PAE mice. The effects of PAE on brainstem auditory processing were most prominent in early adolescence, largely dissipated in late adolescence, and showed a reemergence in early adulthood. PAE mice showed elevated ABR thresholds, prolonged wave latencies, and reduced wave amplitudes. Ratios of ABR peak 3 relative to the first ABR peak indicated that the auditory brainstem pathways were hyperactive in PAE mice. The amplitude ratio was found to be elevated from early adolescence to early adulthood, suggesting that PAE has a persistent effect on auditory processing. We found a significant correlation between the amplitude ratios in early adolescent PAE mice and dam ethanol consumption, which point toward dose‐dependent brainstem gain dysregulation. Our study shows multilevel auditory alterations highlighting the vulnerability of central auditory pathways to PAE and fills an important gap in understanding auditory processing deficits in a clinically relevant exposure model.

Acoustic communication signals often contain a complex temporal structure, yet how this temporal structure contributes to signal recognition is poorly understood, particularly in eavesdropping receivers. The parasitoid fly Ormia ochracea localises host crickets by eavesdropping on their calling songs. In Florida, preferred host songs consist of sound pulses repeated at ∼50 pulses s−1, and flies exhibit matching preferences. However, it is unclear whether this preference reflects sensitivity to individual temporal parameters or to derived temporal relationships that emerge from their combination. We independently varied pulse duration and interpulse interval across a broad stimulus space and quantified tethered-walking phonotaxis using a switch-following paradigm. Behavioural responses formed a structured tuning surface, with elevated responses for pulse durations of ∼5–15 ms across a broad range of interpulse intervals, together with high performance along a diagonal corresponding to 50 pulses s−1. Responses failed to collapse across stimuli sharing the same pulse rate or pulse period, indicating that these parameters alone do not determine recognition. Models allowing behavioural responses to vary jointly across combinations of temporal parameters substantially outperformed models based on single parameters. Although pulse duration strongly constrained recognition, behavioural responses also varied systematically with interpulse interval and could not be explained by pulse duration, interpulse interval, pulse rate, pulse period or duty cycle alone. The apparent preference of O. ochracea for ∼50 pulses s−1 therefore represents one component of a broader temporal recognition landscape rather than recognition based on pulse rate alone.

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.

Cisplatin–induced ototoxicity is a significant clinical issue linked to ferroptosis and mitophagy dysfunction. This study investigated how mitophagy regulates ferroptosis in cisplatin–induced hearing loss using cultured primary rat cochlear marginal cells in vitro and a C57BL/6J mouse model of cisplatin–induced ototoxicity in vivo. Cisplatin suppressed the PTEN–induced putative kinase 1 (PINK1) pathway, impaired mitophagy, and triggered ferroptosis characterized by iron overload, lipid peroxidation, increased acyl–CoA synthetase long–chain family member 4 (ACSL4), and decreased glutathione peroxidase 4. Pharmacological activation of mitophagy or PINK1 overexpression alleviated ferroptosis in vitro, while deferoxamine treatment reduced cisplatin–induced hearing loss and blood–labyrinth barrier damage in vivo. Mechanistically, restoration of mitophagy was associated with increased mitochondrial targeting and reduced cytosolic accumulation of ACSL4, potentially through mitophagic clearance, thereby suppressing ferroptosis. These findings support a model in which impaired PINK1–associated mitophagy contributes to cytosolic ACSL4 accumulation and ferroptotic injury. Modulating mitophagy and ACSL4 subcellular distribution may represent a potential strategy for mitigating cisplatin–induced ototoxicity.

The brain's complex network relies on electrical and chemical signaling to support its normal functions. Understanding brain circuits requires simultaneously monitoring neurotransmitters and electrophysiological signals. The striatal dopamine circuits are integral to neurological processes such as reward and circadian rhythm regulation, making it highly desirable to monitor both neural activity and dopamine (DA) levels in freely behaving animals. One promising approach involves the implantation of multimodal microelectrode arrays (MEAs). However, chronic electrochemical sensing of DA in freely moving animals faces significant challenges, including biofouling of sensing electrodes and the instability of the Ag/AgCl reference. In this study, we developed two complementary strategies to coat the implanted Ag/AgCl reference and MEA with zwitterionic poly(sulfobetaine methacrylate) (PSB). The PSB coating effectively inhibits protein fouling and inflammatory responses to the MEA, while the PSB hydrogel protects the Ag/AgCl electrodes from delamination in vivo. We achieved stable DA detection and electrophysiological recordings in freely moving mice over four weeks. Weekly electrochemical impedance spectroscopy confirmed the long‐term stability of the implanted electrodes. Our method enables multidimensional analysis of behavioral patterns, electrophysiological activity, and DA dynamics. This work advances neurochemical and electrophysiological methodologies by offering reliable tools for longitudinal investigations of brain function in freely behaving animals.

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.