Auditory Research publications

Brain asymmetry in the sensitivity to spectrotemporal modulation is an established functional feature that underlies the perception of speech and music. Recent studies in humans suggest separable neural mechanisms must underlie these cognitively complex functions. The left Auditory Cortex (ACx) is believed to specialize in processing fast temporal components of speech sounds, and the right ACx slower components. However, the circuit features and neural computations behind these lateralized spectrotemporal processes are poorly understood. To answer these mechanistic questions we use mice, an animal model that captures some relevant features of human communication systems. In this study, we screened for circuit features that could subserve temporal integration differences between the left and right ACx. We mapped excitatory input to principal neurons in all cortical layers and found significantly stronger recurrent connections in the superficial layers of the right ACx compared to the left. We hypothesized that the underlying recurrent neural dynamics would exhibit differential characteristic timescales corresponding to their hemispheric specialization. To investigate, we recorded spike trains from awake mice and estimated the network time constants using a quasi-Bayesian method to combine evidence from multiple weak signal-to-noise ratio neurons. We found longer temporal integration windows in the right ACx compared to the left as predicted by stronger recurrent excitation. Our study shows direct evidence that stronger recurrent synaptic connections lead to longer network time scales. These findings support speech processing theories that purport asymmetric integration time constants is a crucial feature of lateralization in auditory processing.

Development is a time of great opportunity. A heightened period of neural plasticity contributes to dramatic improvements in perceptual, motor, and cognitive skills. However, developmental plasticity poses a risk: greater malleability of neural circuits exposes them to environmental factors that may impede behavioral maturation. While these risks are well-established prior to sexual maturity (i.e., critical periods), the degree of neural vulnerability during adolescence remains uncertain. To address this question, we induced a transient period of hearing loss (HL) spanning adolescence in the gerbil, confirmed by assessment of circulating sex hormones, and asked whether behavioral and neural deficits are diminished. Wireless recordings were obtained from auditory cortex neurons during perceptual task performance, and within-session behavioral and neural sensitivity were compared. We found that a transient period of adolescent HL caused a significant perceptual deficit (i.e., amplitude modulation detection thresholds) that could be attributed to degraded auditory cortex processing, as confirmed with both single neuron and population-level analyses. In contrast, perceptual deficits did not occur when HL of the same duration was induced in adulthood. To determine whether degraded auditory cortex encoding was attributable to an intrinsic change, we obtained auditory cortex brain slices from adolescent HL animals, and recorded synaptic and discharge properties from auditory cortex pyramidal neurons. There was a clear and novel phenotype, distinct from critical period HL: excitatory postsynaptic potential amplitudes were elevated in adolescent HL animals, whereas inhibitory postsynaptic potentials were unchanged. This is in contrast to critical period deprivation, where there are large changes to synaptic inhibition. Taken together, these results show that diminished adolescent sensory experience can cause long-lasting behavioral deficits that originate, in part, from a dysfunctional cortical circuit. Abstract Figure Summary of experimental design and main findings.

Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6 , encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the COL4A6 mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated Col4a6 knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner’s membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of Col4a6 KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of Col4a6 KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the COL4A6 missense mutation c.1771G>A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in COL4A6 are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.

Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3-dependent SNHL remains unclear and warrants further investigation. We generated Nox3-Cre knock-in mice, in which Nox3 was replaced with Cre recombinase ( Cre ). Using Nox3-Cre;tdTomato mice of either sex, in which tdTomato is expressed under the control of the Nox3 promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3-expressing cells in the cochlea included various types of supporting cells, outer hair cells, inner hair cells, and spiral ganglion neurons. Nox3 expression increased with cisplatin, age, and noise insults. Moreover, increased Nox3 expression in supporting cells and outer hair cells, especially at the basal turn of the cochlea, played essential roles in ROS-related SNHL. The extent of Nox3 involvement in SNHL follows the following order: cisplatin-induced hearing loss > age-related hearing loss > noise-induced hearing loss. Here, on the basis of Nox3-Cre;tdTomato , which can be used as a reporter system ( Nox3-Cre +/− ;tdTomato +/+ and Nox3-Cre +/+ ;tdTomato +/+ ), and Nox3 -KO ( Nox3-Cre +/+ ;tdTomato +/+ ) mice, we demonstrate that Nox3 inhibition in the cochlea is a promising strategy for ROS-related SNHL, such as cisplatin-induced HL, age-related HL, and noise-induced HL. SIGNIFICANCE STATEMENT We found Nox3-expressing regions and cell types in the inner ear, especially in the cochlea, using Nox3-Cre;tdTomato mice, a reporter system generated in this study. Nox3 expression increased with cisplatin, age, and noise insults in specific cell types in the cochlea and resulted in the loss (apoptosis) of outer hair cells. Thus, Nox3 might serve as a molecular target for the development of therapeutics for sensorineural hearing loss, particularly cisplatin-induced, age-related, and noise-induced hearing loss.

Spiral ganglion neurons (SGNs) are auditory neurons that relay sound signals from the inner ear to the brainstem. The ototoxic drug cisplatin can damage SGNs and thus lead to sensorineural hearing loss (SNHL), and there are currently no methods for preventing or treating this. Macroautophagy/autophagy plays a critical role in SGN development, but the effect of autophagy on cisplatin-induced SGN injury is unclear. Here, we first found that autophagic flux was activated in SGNs after cisplatin damage. The SGN apoptosis and related hearing loss induced by cisplatin were alleviated after co-treatment with the autophagy activator rapamycin, whereas these were exacerbated by the autophagy inhibitor 3-methyladenine, indicating that instead of inducing SGN death, autophagy played a neuroprotective role in SGNs treated with cisplatin both in vitro and in vivo. We further demonstrated that autophagy attenuated reactive oxygen species (ROS) accumulation and alleviated cisplatin-induced oxidative stress in SGNs to mediate its protective effects. Notably, the role of the antioxidant enzyme PRDX1 (peroxiredoxin 1) in modulating autophagy in SGNs was first identified. Deficiency in PRDX1 suppressed autophagy and increased SGN loss after cisplatin exposure, while upregulating PRDX1 pharmacologically or by adeno-associated virus activated autophagy and thus inhibited ROS accumulation and apoptosis and attenuated SGN loss induced by cisplatin. Finally, we showed that the underlying mechanism through which PRDX1 triggers autophagy in SGNs was, at least partially, through activation of the PTEN-AKT signaling pathway. These findings suggest potential therapeutic targets for the amelioration of drug-induced SNHL through autophagy activation. Abbreviations: 3-MA: 3-methyladenine; AAV : adeno-associated virus; ABR: auditory brainstem responses; AKT/protein kinase B: thymoma viral proto-oncogene; Baf: bafilomycin A1; CAP: compound action potential; COX4I1: cytochrome c oxidase subunit 4I1; Cys: cysteine; ER: endoplasmic reticulum; H2O2: hydrogen peroxide; HC: hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; NAC: N-acetylcysteine; PRDX1: peroxiredoxin 1; PTEN: phosphatase and tensin homolog; RAP: rapamycin; ROS: reactive oxygen species; SGNs: spiral ganglion neurons; SNHL: sensorineural hearing loss; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling; WT: wild type.

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin ( Nptn ) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice ( Nptn −/− ) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn −/− mice. Adult Nptn −/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn −/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn −/− mice. Conditional ablation of neuroplastin in Nptn lox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult Nptn Δlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca 2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

Variation in the acoustic structure of vocal signals is important to communicate social information. However, relatively little is known about the features that receivers extract to decipher relevant social information. Here, we took an expansive, bottom-up approach to delineate the feature space that could be important for processing social information in zebra finch song. Using operant techniques, we discovered that female zebra finches can consistently discriminate brief song phrases (“motifs”) from different social contexts. We then applied machine learning algorithms to classify motifs based on thousands of time-series features and to uncover acoustic features for motif discrimination. In addition to highlighting classic acoustic features, the resulting algorithm revealed novel features for song discrimination, for example, measures of time irreversibility (i.e., the degree to which the statistical properties of the actual and time-reversed signal differ). Moreover, the algorithm accurately predicted female performance on individual motif exemplars. These data underscore and expand the promise of broad time-series phenotyping to acoustic analyses and social decision-making.

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics, 10,240 compounds were initially screened in zebrafish larvae, selecting for those that protected lateral-line hair cells against neomycin and gentamicin. When the 64 hits from this screen were retested in mouse cochlear cultures, 8 protected outer hair cells (OHCs) from gentamicin in vitro without causing hair-bundle damage. These 8 hits shared structural features and blocked, to varying degrees, the OHC’s mechano-electrical transducer (MET) channel, a route of aminoglycoside entry into hair cells. Further characterization of one of the strongest MET channel blockers, UoS-7692, revealed it additionally protected against kanamycin and tobramycin and did not abrogate the bactericidal activity of gentamicin. UoS-7692 behaved, like the aminoglycosides, as a permeant blocker of the MET channel; significantly reduced gentamicin–Texas red loading into OHCs; and preserved lateral-line function in neomycin-treated zebrafish. Transtympanic injection of UoS-7692 protected mouse OHCs from furosemide/kanamycin exposure in vivo and partially preserved hearing. The results confirmed the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides and provide a series of hit compounds that will inform the design of future otoprotectants.

Non-native listeners deal with adverse listening conditions in their daily life much harder than native listeners. However, previous work in our laboratories found that native Chinese listeners with native English exposure may improve the use of temporal fluctuations of noise for English vowel identification. The purpose of this study was to investigate whether Chinese listeners can generalize the use of temporal cues for the English sentence recognition in noise. Institute of Electrical and Electronics Engineers (IEEE) sentence recognition in quiet condition, stationary noise, and temporally-modulated noise were measured for native American English listeners (EN), native Chinese listeners in the United States (CNU), and native Chinese listeners in China (CNC). Results showed that in general, EN listeners outperformed the two groups of CN listeners in quiet and noise, while CNU listeners had better scores of sentence recognition than CNC listeners. Moreover, the native English exposure helped CNU listeners use high-level linguistic cues more effectively and take more advantage of temporal fluctuations of noise to process English sentence in severely degraded listening conditions [i.e., the signal-to-noise ratio (SNR) of −12 dB] than CNC listeners. These results suggest a significant effect of language experience on the auditory processing of both speech and noise.

Our previous study demonstrated rapamycin added to diet at 4 months of age had significantly less age-related outer hair cell loss in the basal half of the cochlea at 22 months of age compared to mice without rapamycin. The present study tested adding rapamycin to diet later in life, at 14 months of age, and added a longitudinal assessment of auditory brain stem response (ABR). The present study used UMHET4 mice, a 4 way cross in which all grandparental strains lack the Cdh23 753A allele that predisposes to early onset, progressive hearing loss. UMHET4 mice typically have normal hearing until 16–17 months, then exhibit threshold shifts at low frequencies/apical cochlea and later in more basal high frequency regions. ABR thresholds at 4, 12, 24, and 48 kHz were assessed at 12, 18, and 24 months of age and compared to baseline ABR thresholds acquired at 5 months of age to determine threshold shifts (TS). There was no TS at 12 months of age at any frequency tested. At 18 months of age mice with rapamycin added to diet at 14 months had a significantly lower mean TS at 4 and 12 kHz compared to mice on control diet with no significant difference at 24 and 48 kHz. At 24 months of age, the mean 4 kHz TS in rapamycin diet group was no longer significantly lower than the control diet group, while the 12 kHz mean remained significantly lower. Mean TS at 24 and 48 kHz in the rapamycin diet group became significantly lower than in the control diet group at 24 months. Hair cell counts at 24 months showed large loss in the apical half of most rapamycin and control diet mice cochleae with no significant difference between groups. There was only mild outer hair cell loss in the basal half of rapamycin and control diet mice cochleae with no significant difference between groups. The results show that a later life addition of rapamycin can decrease age-related hearing loss in the mouse model, however, it also suggests that this decrease is a delay/deceleration rather than a complete prevention.

Age-related hearing loss (ARHL) is the most common form of hearing loss and the predominant neurodegenerative disease associated with aging. Sirtuin 1 (SIRT1) is associated with the most complex physiological processes, including metabolism, cancer onset, and aging. SIRT1 protein levels are enhanced by the conversion of nicotinamide to N 1 -methylnicotinamide (MNAM), independent of its mRNA levels. Moreover, MNAM has implications in increased longevity achieved through its mitohormetic effects. Nicotinamide N-methyltransferase (Nnmt) is an enzyme involved in MNAM metabolism, and its level increases under caloric restriction (CR) conditions. The CR condition has implications in delaying ARHL onset. In this study, we aimed to determine the relationship between diet, hearing function, SIRT1 and SIRT3 expression levels in the inner ear, and cochlear morphology. Mice fed with a high-fat diet (HFD), HFD + 1% MNAM, and low-fat diet (LFD) were monitored for age-related auditory-evoked brainstem responses, and changes in cochlear histology, metabolism, and protein and mRNA expressions were analyzed. Our results revealed that the HFD- and aging-mediated downregulated expression of SIRT1 and SIRT3 promoted hearing loss that was obfuscated by MNAM supplementation-induced upregulated expression of cochlear SIRT1 and SIRT3. Thus, our results suggest that MNAM can be used as a therapeutic agent for preventing ARHL.

Transmembrane channel-like protein isoform 1 (TMC1) is a major component of the mechano-electrical transducer (MET) channel in cochlear hair cells and is subject to numerous mutations causing deafness. We report a new dominant human deafness mutation, TMC1 p.T422K, and have characterized the homologous mouse mutant, Tmc1 p.T416K, which caused deafness and outer hair cell (OHC) loss by the fourth postnatal week. MET channels showed decreased Ca 2+ permeability and resting open probability, but no change in single-channel conductance or expression. Three adjacent deafness mutations are TMC1 p.L416R, p.G417R, and p.M418K, the last homologous to the mouse Beethoven that exhibits similar channel effects. All substitute a positive for a neutral residue, which could produce charge screening in the channel pore or influence binding of an accessory subunit. Channel properties were compared in mice of both sexes between dominant ( Tmc1 p.T416K, Tmc1 p.D569N) and recessive ( Tmc1 p.W554L, Tmc1 p.D528N) mutations of residues near the putative pore of the channel. Tmc1 p.W554L and p.D569N exhibit reduced maximum current with no effect on single-channel conductance, implying a smaller number of channels transported to the stereociliary tips; this may stem from impaired TMC1 binding to LHFPL5. Tmc1 p.D528N, located in the pore's narrowest region, uniquely caused large reductions in MET channel conductance and block by dihydrostreptomycin (DHS). For Tmc1 p.T416K and Tmc1 p.D528N, transduction loss occurred between P15 and P20. We propose two mechanisms linking channel mutations and deafness: decreased Ca 2+ permeability, common to all mutants, and decreased resting open probability in low Ca 2+ , confined to dominant mutations. SIGNIFICANCE STATEMENT Transmembrane channel-like protein isoform 1 (TMC1) is thought to be a major component of the mechanotransducer channel in auditory hair cells, but the protein organization and channel structure are still uncertain. We made four mouse lines harboring Tmc1 point mutations that alter channel properties, causing hair cell degeneration and deafness. These include a mouse homolog of a new human deafness mutation pT416K that decreased channel Ca 2+ permeability by introducing a positively-charged amino acid in the putative pore. All mutations are consistent with the channel structure predicted from modeling, but only one, p.D528N near the external face of the pore, substantially reduced channel conductance and Ca 2+ permeability and virtually abolished block by dihydrostreptomycin (DHS), strongly endorsing its siting within the pore.

Striatin-interacting protein 1 ( Strip1 ) is a core component of the striatin interacting phosphatase and kinase (STRIPAK) complex, which is involved in embryogenesis and development, circadian rhythms, type 2 diabetes, and cancer progression. However, the expression and role of Strip1 in the mammalian cochlea remains unclear. Here we studied the expression and function of Strip1 in the mouse cochlea by using Strip1 knockout mice. We first found that the mRNA and protein expression of Strip1 increases as mice age starting from postnatal day (P) 3 and reaches its highest expression level at P30 and that the expression of Strip1 can be detected by immunofluorescent staining starting from P14 only in cochlear HCs, and not in supporting cells (SCs). Next, we crossed Strip1 heterozygous knockout ( Strip +/−) mice to obtain Strip1 homozygous knockout ( Strip1 −/−) mice for studying the role of Strip1 in cochlear HCs. However, no Strip1 −/− mice were obtained and the ratio of Strip +/− to Strip1 +/+ mice per litter was about 2:1, which suggested that homozygous Strip1 knockout is embryonic lethal. We measured hearing function and counted the HC number in P30 and P60 Strip +/− mice and found that they had normal hearing ability and HC numbers compared to Strip1 +/+ mice. Our study suggested that Strip1 probably play important roles in HC development and maturation, which needs further study in the future.

Noise-induced hearing loss (NIHL) is a common inner ear disease but has complex pathological mechanisms, one of which is increased oxidative stress in the cochlea. The high-mobility group box 1 (HMGB1) protein acts as an inflammatory mediator and shows different activities with redox modifications linked to the generation of reactive oxygen species (ROS). We aimed to investigate whether manipulation of cochlear HMGB1 during noise exposure could prevent noise-induced oxidative stress and hearing loss. Sixty CBA/CaJ mice were divided into two groups. An intraperitoneal injection of anti-HMGB1 antibodies was administered to the experimental group; the control group was injected with saline. Thirty minutes later, all mice were subjected to white noise exposure. Subsequent cochlear damage, including auditory threshold shifts, hair cell loss, expression of cochlear HMGB1, and free radical activity, was then evaluated. The levels of HMGB1 and 4-hydroxynonenal (4-HNE), as respective markers of reactive nitrogen species (RNS) and ROS formation, showed slight increases on post-exposure day 1 and achieved their highest levels on post-exposure day 4. After noise exposure, the antibody-treated mice showed markedly less ROS formation and lower expression of NADPH oxidase 4 (NOX4), nitrotyrosine, inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1) than the saline-treated control mice. A significant amelioration was also observed in the threshold shifts of the auditory brainstem response and the loss of outer hair cells in the antibody-treated versus the saline-treated mice. Our results suggest that inhibition of HMGB1 by neutralization with anti-HMGB1 antibodies prior to noise exposure effectively attenuated oxidative stress and subsequent inflammation. This procedure could therefore have potential as a therapy for NIHL.

Cognition depends on integrating sensory percepts with the memory of recent stimuli. However, the distributed nature of neural coding can lead to interference between sensory and memory representations. Here, we show that the brain mitigates such interference by rotating sensory representations into orthogonal memory representations over time. To study how sensory inputs and memories are represented, we recorded neurons from the auditory cortex of mice as they implicitly learned sequences of sounds. We found that the neural population represented sensory inputs and the memory of recent stimuli in two orthogonal dimensions. The transformation of sensory information into a memory was facilitated by a combination of 'stable' neurons, which maintained their selectivity over time, and 'switching' neurons, which inverted their selectivity over time. Together, these neural responses rotated the population representation, transforming sensory inputs into memory. Theoretical modeling showed that this rotational dynamic is an efficient mechanism for generating orthogonal representations, thereby protecting memories from sensory interference.

In sensory systems, representational features of increasing complexity emerge at successive stages of processing. In the mammalian auditory pathway, the clearest change from brainstem to cortex is defined by what is lost, not by what is gained, in that high-fidelity temporal coding becomes increasingly restricted to slower acoustic modulation rates.1,2 Here, we explore the idea that sluggish temporal processing is more than just an inability for fast processing, but instead reflects an emergent specialization for encoding sound features that unfold on very slow timescales.3,4 We performed simultaneous single unit ensemble recordings from three hierarchical stages of auditory processing in awake mice - the inferior colliculus (IC), medial geniculate body of the thalamus (MGB) and primary auditory cortex (A1). As expected, temporal coding of brief local intervals (0.001 - 0.1 s) separating consecutive noise bursts was robust in the IC and declined across MGB and A1. By contrast, slowly developing (∼1 s period) global rhythmic patterns of inter-burst interval sequences strongly modulated A1 spiking, were weakly captured by MGB neurons, and not at all by IC neurons. Shifts in stimulus regularity were not represented by changes in A1 spike rates, but rather in how the spikes were arranged in time. These findings show that low-level auditory neurons with fast timescales encode isolated sound features but not the longer gestalt, while the extended timescales in higher-level areas can facilitate sensitivity to slower contextual changes in the sensory environment.

Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model. We administered TAK-063, a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor, to Fmr1 KO mice, and examined its effects on MEA EEG biomarkers. We demonstrate significant dose-related amelioration of inter-trial phase coherence (ITPC) to temporally modulated auditory stimuli by TAK-063 in Fmr1 KO mice. Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development.

Blast trauma is a common acoustic/physical insult occurring in modern warfare. Twenty percent of active duty military come into close proximity to explosions and experience mild to severe sensory deficits. The prevalence of such injuries is high but correlating auditory sensitivity changes with the initial insult is difficult because injury and evaluations are often separated by long time periods. Here, auditory sensitivity was measured before and after a traumatic blast in adult CBA/CaJ mice using auditory brainstem responses, distortion production otoacoustic emissions, and behavioral detection of pure tones. These measurements included baseline auditory sensitivity prior to injury in all mice, and again at 3, 30, and 90 days after the blast in the two physiological groups, and daily for up to 90 days in the behavioral group. Mice in all groups experienced an initial deterioration in auditory sensitivity, though physiological measurements showed evidence of recovery that behavioral measurements did not. Amplitudes and latencies of ABR waves may reflect additional changes beyond the peripheral damage shown by the threshold changes and should be explored further. The present work addresses a major gap in the current acoustic trauma literature both in terms of comparing physiological and behavioral methods, as well as measuring the time course of recovery.

Across sensory systems, temporal frequency information is progressively transformed along ascending central pathways. Despite considerable effort to elucidate the mechanistic basis of these transformations, they remain poorly understood. Here we used a novel constellation of approaches, including whole-cell recordings and focal pharmacological manipulation, in vivo, and new computational algorithms that identify conductances resulting from excitation, inhibition and active membrane properties, to elucidate the mechanisms underlying the selectivity of midbrain auditory neurons for long temporal intervals. Surprisingly, we found that stimulus-driven excitation can be increased and its selectivity decreased following attenuation of inhibition with gabazine or intracellular delivery of fluoride. We propose that this nonlinear interaction is due to shunting inhibition. The rate-dependence of this inhibition results in the illusion that excitation to a cell shows greater temporal selectivity than is actually the case. We also show that rate-dependent depression of excitation, an important component of long-interval selectivity, can be decreased after attenuating inhibition. These novel findings indicate that nonlinear shunting inhibition plays a key role in shaping the amplitude and interval selectivity of excitation. Our findings provide a major advance in understanding how the brain decodes intervals and may explain paradoxical temporal selectivity of excitation to midbrain neurons reported previously.

Hearing loss affects ∼10% of adults worldwide. Most sensorineural hearing loss is caused by the progressive loss of mechanosensitive hair cells (HCs) in the cochlea. The molecular mechanisms underlying HC maintenance and loss remain poorly understood. LBH, a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role in HCs. Surprisingly, Lbh deletion did not affect differentiation and the early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia. The stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. RNA-seq analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy in Lbh-null OHCs. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival in adult mice.