Publications using the MF1

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.

The transcription factor ATOH1 is a master regulator of mechanosensory hair-cell (HC) development in the ear. Here, we report that its target gene Casz1 regulates the maturation of outer HCs (OHCs). Genetic deletion of Casz1 during (but not after) cochlear development in the mouse caused: hearing loss; disorganization of mechanosensory stereocilia bundles in OHCs; reduced F-actin density in OHC cuticular plates; progressive OHC loss; and mild morphological alterations in inner HCs. This deletion also altered gene expression, delaying downregulation of genes expressed in immature OHCs, including the actin regulator-encoding gene Coro2a, and accelerating upregulation of genes expressed in mature OHCs. Deleting Coro2a in Casz1 mutant mice restored F-actin density in cuticular plates but increased stereocilia bundle disorganization and hearing thresholds, revealing that CORO2A provides an overall beneficial effect. Our data indicate that CASZ1 regulates transcriptional and morphological maturation of OHCs, and that CASZ1 in maturing HCs is necessary for hearing.

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.

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.

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.

The auditory nerve (AN) glial transition zone (GTZ), where myelination shifts from Schwann cells in the peripheral AN to oligodendrocytes in the central AN, is a unique biological niche housed within the cochlear modiolus. Although age-related hearing loss (ARHL) is associated with AN degeneration, the neuroimmune mechanisms contributing to age-related myelin pathology and altered immune cell function remain poorly defined. We hypothesized that the AN GTZ is especially vulnerable to age-related immune activity which may contribute to AN degeneration and myelin pathology. Using an ARHL mouse model, we combined large-field light sheet microscopy of tissue-cleared mouse temporal bones, three-dimensional high-resolution imaging, and quantitative immunohistochemistry to evaluate the AN GTZ. RNA-sequencing was used to evaluate age-related changes in gene expression of the whole AN. Human temporal bones were also examined to evaluate the AN and its macrophages/microglia. RNA-sequencing revealed age-associated enrichment of neuroinflammation and myelin degeneration-related pathways. Aging was associated with an increase in Iba1 + macrophages/microglia throughout the AN, with prominent accumulation at the AN GTZ. The aged AN GTZ contained Iba1 + subpopulations expressing CD206, Gal3, CD163, and Lamp1, suggesting enhanced phagocytic activity and altered activation state at the AN GTZ. CD68 + cells were also increased at the AN GTZ, as well as the central AN, with aging. Macrophages/microglia contained significantly more internalized myelin debris across all regions of the AN with aging, including myelin localized within Lamp1 + lysosomes of Iba1 + cells. More importantly, normal-appearing myelin was frequently observed within macrophages/microglia at the AN GTZ, but not in the peripheral or central regions of the AN. Myelin debris within Iba1 + cells was also found in the human AN, consistent with our findings in mouse. Together, these findings identify the AN GTZ as a unique microenvironment with age-related alterations in phagocytic activity and immune activation. The immune cell heterogeneity and enhanced myelin phagocytosis observed in the aging AN emphasize the importance of defining how distinct macrophage/microglia populations contribute to AN degeneration and ARHL.

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.

Like mammals, some reptiles possess sensitive and frequency-selective hearing at mid- to high-kilohertz frequencies. Both groups employ a place-frequency map within the inner ear to encode sound stimuli, but the mechanisms by which they achieve tuned nerve activation along the cochlea are believed to be distinct. To investigate the mechanical origins of auditory sensation in the reptiles, we measured sound-evoked displacement responses in the hearing organ of the tokay gecko ( Gekko gecko ), known as the basilar papilla. Using optical coherence tomography, we were able to resolve sub-nanometer-scale vibrations throughout the organ both in vivo and ex vivo . We saw that tuning was not present in the tissue-scale mechanics at any position within the organ; it instead exhibits an untuned rotational motion. We developed a mathematical model which predicted that this motion induces hair-bundle-stimulating fluid displacement, and is due to an anatomical asymmetry seen in many reptile species. These results are consistent with the theory that hair-bundle-level mechanics are primarily responsible for tuning in the tokay gecko cochlea, and we argue that our proposed mechanisms generalize to many other species across the Reptilia class. SIGNIFICANCE We present the most comprehensive picture of tissue-scale mechanics in a reptile hearing organ to-date: sound-evoked displacement responses within the basilar papilla of the tokay gecko ( Gekko gecko ) both ex vivo and in vivo , across the animal’s auditory frequency range, and along all three spatial dimensions. We observed that place-frequency tuning is not present in the mechanics of the tissue as it is in mammals. Instead, this organ relies on an untuned rocking mechanism to stimulate hair bundles. A mathematical model shows that this may be at play in other reptile species, indicating a unifying mechanism of hearing in the class Reptilia in which hair bundle mechanics play the leading role in frequency tuning.

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

Hypercholesterolemia is a recognized risk factor for sensorineural hearing loss. This study investigated the mechanistic link between blood-labyrinth barrier (BLB) disruption and hypercholesterolemia-associated cochlear damage. Low-density lipoprotein receptor knockout (Ldlr -/-) mice fed a high-fat diet for 8 weeks were used as the experimental model. Auditory assessments showed elevated auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs), especially at high frequencies, consistent with hearing loss driven by outer hair cell dysfunction. BLB disruption occurred before hearing impairment, manifest as increased vascular permeability, damaged tight junctions and downregulated junctional protein levels. Cochlear histopathology confirmed outer and inner hair cell loss. These findings demonstrate a sequential and identify BLB as a key therapeutic target for preventing hypercholesterolemia-associated hearing impairment.

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3 -/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3 -/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3 -/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3 -/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract Highlights SCMAS accumulates across the auditory thalamocortical circuit in Cln3 -/- mice Accumulation shows distinct age- and sex-dependent regional trajectories Cln3 -/- mice exhibit progressive alterations in auditory evoked potentials Thalamic pathology is strongly associated with the early auditory N1 response Histology–EEG integration links circuit pathology to auditory dysfunction

Auditory brainstem response (ABR) recordings are widely used in neuroscience as a cross-species translational tool to evaluate hearing sensitivity and auditory processing. In animal models, ABR recordings typically require the use of anesthesia to minimize myogenic artifacts, necessitating the development of anesthetic regimens that balance safety, adequate immobilization, and preservation of neural responses. Using a within-subject design in male and female Long-Evans rats, this study systematically evaluated the safety and auditory signal fidelity of five anesthetic regimens -ketamine/xylazine (K/X), ketamine/dexmedetomidine (K/D), dexmedetomidine alone (DEX), dexmedetomidine plus low dose (0.5%) isoflurane (D/I), and high dose (2%) isoflurane (ISO). Anesthetic safety and efficacy were assessed by induction time, recovery time, blood oxygen saturation (SpO₂), and survival rate. ABR signal quality was quantified by threshold, signal strength, wave amplitude, wave latency, and inter-trial phase coherence. K/X anesthesia produced ABRs with low thresholds and well-defined waveforms, but also exhibited the least favorable safety profile, with prolonged recovery times and reduced survival rates. Conversely, isoflurane regimens (ISO and D/I) had a favorable safety profile but significantly elevated thresholds and degraded ABR signal quality, even at low doses. K/D and DEX achieved survival and recovery outcomes equal to or better than conventional anesthetics (K/X and ISO) while also preserving ABR waveform morphology and trial-to-trial reliability. Together, these results highlight dexmedetomidine, particularly when combined with ketamine, as a safe and effective anesthetic for ABR recordings that preserves key metrics of auditory sensitivity and signal integrity.

The neural response of the brainstem to brief sounds, known as the auditory brainstem response (ABR), is widely employed in the laboratory and the clinic to diagnose hearing loss. Current ABR approaches are limited to analyzing the average ABR to hundreds of stimulus trials. Historically, trial-by-trial ABR analysis has not been possible owing to each trial's small signal-to-noise ratio. Here we overcome this limitation and show how to score individual ABR trials. We use the distribution of individual-trial ABR scores to define thresholds, which we call auditory brainstem detection (ABD) thresholds, and to assess suprathreshold hearing. Scores based on individual-trial amplitude and similarity produce lower ABD thresholds than scores based on individual-trial amplitude alone. Our method enables us to rank the suprathreshold hearing of individual subjects. Despite having normal ABR thresholds, some subjects appear to have suprathreshold hearing deficits.

Hereditary hearing loss, the most prevalent genetic sensory disorder, lacks approved pharmacological therapies and represents a compelling target for gene correction. Pathogenic variants in KCNQ4 account for ~9.5% of autosomal dominant nonsyndromic cases. Prior gene-editing strategies disrupting mutant alleles have failed to achieve durable auditory rescue. Here we employed a knock-in mouse model harboring the human KCNQ4 c.961 G > A (p.G321S) mutation to evaluate precise base editing. Dual-AAV delivery of the adenine base editor ABE8e achieved 21.4–28.9% correction in the organ of Corti—the highest efficiency reported for genetic hearing loss. A dose-dependent therapeutic window emerged: higher doses promoted rapid recovery, whereas optimized lower doses minimized long-term toxicity and sustained functional benefit for at least 32 weeks. Treatment reduced auditory brainstem response thresholds by up to 49.09 dB SPL at optimal frequencies, mitigated degeneration of hair cells, spiral ganglion neurons, and auditory nerve fibers, and partially restored outer hair cell electrophysiology. These findings demonstrate the durability of precise mutation correction over allele-disruptive approaches and support clinical translation for KCNQ4 -associated hearing loss.

Objective Traumatic brain injury (TBI) significantly reduces the quality of life for millions of survivors worldwide, causing persistent brain tissue damage and cognitive impairments, with no established therapeutic interventions currently available. Slow‐wave activity, a hallmark of deep sleep, has been implicated in recovery after TBI, but pharmacological approaches to enhance it lack specificity and scalability, complicating efforts to identify slow‐wave activity as a direct mechanistic contributor and severely limiting clinical translation. Methods To overcome these limitations, we developed a preclinical closed‐loop auditory stimulation (CLAS) paradigm that targets sleep's slow waves, enabling highly specific and temporally precise enhancement of slow‐wave activity. Therefore, we delivered 30‐ms sound triggers targeting the up‐phase of real‐time detected slow‐waves (upCLAS: TBI n = 8), or no sound stimulation (mockCLAS: non‐TBI n = 8, TBI n = 7) during sleep to healthy controls (non‐TBI) or brain injured (TBI) rats. Concomitantly, we assessed the ability of upCLAS‐enhanced sleep to counteract brain tissue damage (primary outcome) and symptomatic sequelae (secondary outcome) of TBI. Results Bayesian analysis revealed that sound‐mediated slow‐wave activity enhancement: (1) reduces diffuse axonal injury, with TBI mockCLAS posterior estimates falling outside the 95% confidence intervals of both other groups, whereas the posterior distributions of TBI upCLAS and non‐TBI groups largely overlapped (~13% posterior differences >0), consistent with a negligible effect size between groups; (2) decreases demyelination, with approximately 97% posterior differences >0 between TBI mockCLAS and TBI upCLAS groups, compared to approximately 60% between non‐TBI and TBI upCLAS groups; and (3) preserves cognitive ability, with recognition indexes in the novel object recognition test significantly above chance level in non‐TBI (* p = 0.031) and TBI upCLAS (* p = 0.026) groups, in contrast to mockCLAS‐treated TBI rats ( p = 0.156), presenting pronounced cognitive deficit. Furthermore, microglial response to brain injury was increased by deep sleep enhancement, with reduced ionized calcium‐binding adaptor molecule 1+ area coverage in TBI upCLAS rats (* p = 0.0445) compared to non‐TBI ones. Interpretation These results unambiguously demonstrate slow‐wave activity enhancement confers robust disease modification following TBI while overcoming major limitations of other preclinical approaches. Our findings constitute proof‐of‐concept that boosted sleep intensity mitigates histopathological and cognitive sequelae of brain trauma, suggesting that a clinically relevant, nonobtrusive, sleep‐based therapy may represent a novel therapeutic intervention for TBI survivors. ANN NEUROL 2026;100:242–254

Hearing is the largest modifiable mid-life risk factor for Alzheimer's disease (AD), yet its link to dementia remains unclear. We identified a neurophysiological biomarker of AD risk using the non-invasive, rapidly acquired, and clinically translatable auditory brainstem response (ABR) in normal hearing knock-in rats (Swedish familial AD risk variant to Amyloid precursor protein, AppS; male and female). Human ABRs have been proposed as a biomarker for AD and related dementias. The novel metric reported here is derived from multidimensional parametric feature extraction on the distribution statistics of repeated single-trial ABR traces. We report accurate prediction of genetic risk for AD risk in young and aged rats: AppS separate clearly from healthy humanized (AppH) in sex- and age-dependent manners. Notably, auditory learning during young adulthood shifted the AppS ABR signature towards a healthy AppH-like state that maintained over time into older age. Altogether the findings support the utility of the ABR to track disease state, progression, and effects of intervention, and point to a central neural generator of auditory dysfunction related to AD risk. ABRs could provide a very early biomarker for detection of AD risk and used to test the synergy of auditory and cognitive functions in human dementia.

Stimulus-specific adaptation is a key feature of sensory systems, where the repeated presentation of a stimulus results in diminishing neuronal responses specifically to that stimulus, but not to a different stimulus. Cortical neurons display varying degrees of stimulus-specific adaptation, with cortical circuits shaping the dynamics of these responses. Here, we use calcium imaging and optogenetic approaches to assess the contributions of SOM and PV neurons to stimulus-specific adaptation in the mouse auditory cortex. We find opposing and complementary effects of SOM and PV neurons on the adaptation of principal neurons which manifest as context-dependent SOM neuron-mediated enhancement and PV-neuron mediated suppression of responses that depend on the temporal repetition rate of the sounds. Our results suggest that SOM and PV neurons can engage in multiple operating regimes that exist in a continuum during sensory processing.

Oncomodulin (OCM) is the most abundant Ca2+ buffering protein found in mature outer hair cells (OHCs). Cadherin 23 (CDH23) is a crucial component of the tip-links in hair cell stereocilia. The absence or dysfunction of these two proteins contributes to the early onset of age-related hearing loss (AHL). In this study, we investigated the effects of the Cdh23753G→A mutation on OHC function using new Ocm-knockout (KO) mouse models (Ocmtm1a/tm1a) with or without the Cdh23753G→A mutation. Despite having the same genetic background, Ocm-KO mice carrying the Cdh23753G→A mutation displayed a notable decline in OHC function across all measured frequencies as early as three months of age. In contrast, Ocm-KO mice without the Cdh23753G→A mutation did not exhibit comparable hearing loss until they reached twelve months of age. Additionally, we examined the role of OCM in preserving OHC function under ototoxic stress induced by HPβCD (2-hydroxypropyl-β-cyclodextrin). The distortion product otoacoustic emission data show that the administration of HPβCD resulted in a more pronounced decline in OHC function in Ocm-KO mice compared to wild-type (WT) mice. Time-lapse recording also shows that HPβCD treatment led to greater structural deterioration and more rapid rupture events in OHCs from Ocm-KO mice than in those from WT mice. These findings suggest that the Cdh23753G→A mutation, rather than other potential strain-specific genetic factors associated with AHL, significantly exacerbates the early onset of AHL phenotypes in Ocm-KO mice. Furthermore, our data indicates that the OCM protein in OHCs enhances their ability to withstand ototoxic stimuli.

Our ability to generalize abstract rules to new situations is a cognitive hallmark, yet its neural basis is unclear. We identified a thalamocortical circuit essential for this process in mice. During a cross-modal rule transfer task, medial prefrontal cortex (mPFC) neurons encoded task rules across sensory modalities to enable generalization. Crucially, mediodorsal thalamus (MD) projections to mPFC were causally required: Inhibiting this pathway destabilized mPFC representations and impaired rule transfer, whereas enhancing it improved performance. Without MD input, mPFC recruited distinct populations for each task, losing cross-context stability. Direct mPFC excitation impaired generalization, underscoring the specificity of thalamic regulation. Thus, the MD stabilizes mPFC activity for flexible rule transfer—a mechanism with implications for cognitive disorders and artificial intelligence.

Activity-dependent modulation of presynaptic voltage-gated Ca 2+ channels (Ca V 2) regulates Ca 2+ influx to control neuronal circuit output. Although Ca V 2.1 can undergo robust Ca 2+ dependent facilitation (CDF), whether it occurs in native central nervous system neuronal circuits is disputed. Accurate auditory information processing requires precise and reliable synaptic transmission at high activity rates in the auditory brainstem. To determine if Ca V 2.1 CDF is a key regulator of high-fidelity synaptic transmission, we expressed Ca V 2.1 splice variants capable (Ca V 2.1 37a) or incapable (Ca V 2.1 37b) of CDF at the calyx of Held presynaptic terminal in the auditory brainstem. We found no difference in basal Ca V 2.1 currents or synaptic transmission. However, Ca V 2.1 37b terminals lacked CDF, synaptic facilitation and had a decreased reliability and precision of postsynaptic action-potential firing. Additionally, the Wave III amplitude of the auditory brainstem responses was reduced. We propose that Ca V 2.1 CDF is essential for accurate auditory information processing.