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Verhulst, S.

Publications and source records attributed to Verhulst, S..

At least 19 recordsLinked to original sources

Growing despite ectoparasite infection: sex-specific effects on telomere shortening in a free-living corvid

Ectoparasite infections during development are known to impact fitness-related traits, but their physiological costs in relation to sex or growth trade-offs are understudied. In birds, previous studies at the brood level have found costs of infection by blood-sucking ectoparasites in molecular biomarkers (i.e., increased telomere shortening). However, infection probability also varies with age, sex, or within broods. Whether such costs are age or sex-dependent is not well known, and disentangling these effects is of interest, because telomeres potentially reveal the long-term impact of infection. Here, we used 6-year-data from jackdaw nestlings (Coloeus monedula) to investigate individual level associations of infection by the fly (Carnus hemapterus) at two intermediate time points during development, with telomere dynamics over the nestling period. We evaluated (i), Carnus presence in relation to sex, brood size manipulation, body mass, and size, and (ii), how telomere shortening varied in relation to parasite presence and achieved growth. Early in development (day 10), flies were more prevalent on heavier nestlings, while later in development (day 20), they were more prevalent on smaller and lighter nestlings, suggesting different ectoparasite preference. Telomere loss was higher in female nestlings when exposed to parasites only on day 20, and in males, when they were heavy earlier in development. In conclusion, infection is a dynamic process, and ectoparasite effects may depend on the timing of infection and reveal sex-specific growth vs. self-maintenance trade-offs. Our study indicates a need to sample at multiple developmental stages when assessing host-parasite interactions and the physiological costs of infection.

evolutionary biology↗

DNA methylation correlates with lifespan and predicts remaining lifespan in the zebra finch

Biomarkers that correlate with age are essential tools for understanding aging and lifespan variation. DNA methylation (DNAm) changes predictably with age in parts of the genome. In humans, epigenetically 'old' individuals relative to their chronological age also have a reduced life expectancy but whether the link between epigenetic age and lifespan is a general feature remains an open question. We explored age-related changes in DNAm in the zebra finch (Taeniopygia castanotis), a key avian model species, using 100 longitudinal whole genome methylomes from 50 captive adults monitored until their natural death. We found genome-wide hypomethylation with age, with DNAm decreasing faster in individuals with shorter lifespans and identified 29 CpG sites where DNAm changed significantly with age. We developed an epigenetic aging clock based on 119 CpG sites, that predicted chronological age with high accuracy (median absolute deviation=0.68 years, 8.2% of maximum lifespan in our dataset). Females raised in large broods, which have shorter lifespans, showed increased epigenetic age acceleration, consistent with faster biological aging. However, epigenetic age acceleration did not predict lifespan or remaining lifespan. In contrast, the within-individual rate of change in epigenetic age significantly predicted lifespan: faster epigenetic aging was associated with a shorter lifespan. Moreover, a 'doom' clock, trained to predict post-sampling lifespan, successfully predicted remaining lifespan. Our findings provide the first evidence that DNAm provides a window into biological aging in birds, showing how early-life environments shape the aging trajectory via the epigenome and underscore the value of longitudinal data in aging studies.

molecular biology↗

Auditory Profiles in Tinnitus are Age-Dependent: Electrophysiological and Behavioral Evidence

Tinnitus is commonly associated with hearing loss, yet it can also occur in individuals with clinically normal audiometric thresholds. This dissociation has led to the hypothesis that hidden sensorineural hearing loss underlies tinnitus in audiometrically normal-hearing individuals. However, identifying such subclinical deficits non-invasively is challenging because audiometric measures are influenced by age-related changes and interactions among sensorineural processes. In this study, we disentangled the contributions of tinnitus, age, and hearing status to sensorineural encoding and speech perception. We included 113 participants, divided into age- and hearing-status-matched groups with and without tinnitus, and assessed them using otoacoustic emissions, auditory evoked potentials, auditory reflex measurements, and behavioral tasks of speech perception. This design enabled a rigorous evaluation of whether hidden sensorineural deficits underlie tinnitus. Age and hearing status had substantial effects on objective measures of sensorineural function, whereas tinnitus-related effects were subtle and age specific. Young adults with tinnitus and normal audiometric thresholds exhibited enhanced auditory brainstem responses, elevated envelope following responses, and better vowel discrimination. In contrast, middle-aged adults with tinnitus showed no such enhancements and demonstrated poorer speech-in-noise performance. Correlation analyses revealed a tinnitus-related shift toward greater reliance on central auditory processing, compared with the predominantly peripheral associations observed in controls. The middle ear muscle reflex was unaffected by tinnitus but was correlated with hyperacusis-related parameters. Together, these findings suggest distinct tinnitus-related auditory profiles across the lifespan: neural enhancement and improved vowel discrimination in young adults, versus degraded sensorineural encoding and reduced speech intelligibility in middle-aged adults. Significance StatementTinnitus affects a significant portion of the population, yet its underlying origins are still unclear. While hearing loss is a common cause, individuals with tinnitus may also have normal hearing thresholds. This suggests that subtle sensorineural damage may also play a role. This study critically investigates tinnitus-, age-, and hearing-related sensorineural encoding using non-invasive electrophysiological measures, auditory reflexes, and speech perception tasks in carefully matched participant groups. The study reveals distinct tinnitus-related auditory profiles throughout the lifespan; including enhanced sensorineural processing in young adults and degraded encoding with impaired speech perception in middle-aged adults. These findings provide critical insight into the mechanisms underlying tinnitus and offer objective markers for future research on tinnitus diagnosis and treatment

neuroscience↗

Extended high frequency hearing influences cortical response amplitudes to speech

Since young adults hear sounds up to 20 kHz, the loss of extended high-frequency hearing (EHF; above 8 kHz) is a hallmark of age-related hearing loss, often progressing from early lifetime. However, this deficit frequently goes undetected because routine clinical hearing tests and most hearing aids are currently limited mostly up to 8 kHz. EHF hearing has been linked to deficits in speech perception in noise and to self-reported hearing. However, it remains elusive how EHF hearing influences speech intelligibility. Here we recorded neuromagnetic brain responses using magnetoencephalography (MEG) within a frequency-tagging speech paradigm designed to probe hierarchical levels of attention and memory-dependent speech processing and recognition. Auditory evoked cortical magnetic field (AEF) responses were significantly reduced in both left and right brain hemispheres in individuals with impaired EHF hearing compared to those subjects with rather preserved EHF hearing. A gradual reinforcement of left-hemispheric AEF seen over age was not observed in young adults (19-29 y) with preserved EHF hearing. This was linked to stronger auditory brainstem responses (ABR), reflecting better neural synchronized auditory responses at stimulus onset. The reinforced left hemispheric dominance in young adults with impaired EHF hearing, in contrast, was linked to lower ABRs. Our findings suggest that sound energy above 8 kHz contributes through its impact on stimulus-onset synchrony to phase locking of oscillations in the auditory cortex to intelligible speech. Together, the results highlight the need to reconsider the neglect of EHF hearing in both audiological assessment and hearing aid design. SignificanceWe show here that deficits in extended high-frequency (EHF) hearing, up to now neglected in routine clinical audiometry and hearing aid technology, lead to reduced cortical evoked auditory field (AEF) response amplitudes to attended and unattended speech, even at a young age. A gradual increase in reinforced left-hemispheric AEF responses during attended speech does not occur in young people with good EHF hearing; this is linked to better synchronization of neural responses at the onset of sound. This suggests a crucial role of sounds containing energy above 8kHz in minimizing the need for cognitive resources during active listening. Collectively, our results challenge current clinical practices and underscore the need to incorporate EHF hearing into audiological assessment and hearing aid design.

neuroscience↗

Increases in BCL2L1 and ID1 dosage synergistically drive fate bias and competitive advantage in human pluripotent stem cells

BackgroundGains of chromosome 20q11.21 are among the most common culture-acquired abnormalities in human pluripotent stem cells (hPSC), conferring a well-defined survival advantage while altering differentiation capacity. However, it remains unclear whether this advantage persists during differentiation, how the aneuploidy alters ectodermal and retinal pigment epithelium (RPE) lineage specification, and which genes within the minimal amplicon drive these effects. MethodsWe used three isogenic human embryonic stem cell line pairs (wild-type and 20q11.21 gain) and assessed their behaviour in two neuroectoderm differentiation systems: directed neuroectoderm induction (dual SMAD inhibition) and long-term spontaneous RPE differentiation. Competitive dynamics were measured in mixed cultures, and lineage outcomes were analysed using immunostaining, gene expression profiling and single-cell RNA sequencing. To identify driver genes, we generated BCL2L1 and ID1 overexpression lines and tested their effects under both directed and spontaneous differentiation conditions. ResultsAcross all lines and conditions, 20q cells expanded from a minor fraction to dominate mixed cultures, indicating that their competitive advantage persists beyond the undifferentiated state. Despite this dominance, pure 20q cells failed to specify to neuroectoderm or RPE. Single-cell transcriptomics revealed consistent diversion toward non-neural ectodermal and extraembryonic fates. Mechanistically, overexpression of BCL2L1 and ID1 alone or in combination impaired neuroectoderm specification, while synergistic effect of both genes promoted non-neural ectodermal outcomes under directed differentiation conditions. In spontaneous differentiation, both genes could disrupt differentiation. ConclusionsThe 20q11.21 gain couples a persistent survival advantage with a disruption of neural and RPE lineage competence, redirecting cells toward alternative ectodermal and extraembryonic fates. These effects arise from the combined action of two dosage-sensitive genes BCL2L1 and ID1 within the amplicon, illustrating how regional gene dosage can reshape developmental signalling responses in hPSC.

developmental biology↗

Peripheral phoneme encoding and discrimination in aging and hearing impairment

HighlightsO_LISpeech EEG shows age- and OHC-related vulnerability of high-CF envelope coding. C_LIO_LISpeech EEG shows low-CF envelope encoding stays intact with age. C_LIO_LIFine-structure contrast discrimination worsens with OHC loss in quiet. C_LIO_LIFine-structure contrast discrimination worsens with age in contralateral noise. C_LIO_LIPhoneme discrimination involving high-frequency contrasts remains robust with age. C_LIO_LIPeripheral coding strength is not directly reflected at behavioral level. C_LI Speech perception difficulties in noise are common among older adults and individuals with hearing impairment, but also occur among younger adults whose audiometric thresholds are within the clinically-normal range. We examined how aging, cochlear synaptopathy (CS), and outer hair cell (OHC) damage affect speech encoding and phoneme discrimination. Envelope-following responses (EFRs) to rectangular amplitude-modulated (RAM) tones and speech-like phoneme pairs were recorded in quiet using EEG, and behavioral discrimination was assessed in quiet, and with ipsilateral and contralateral noise. Stimuli were designed to target temporal envelope (TENV) or temporal fine structure (TFS) encoding. Results showed that RAM-EFR amplitudes decreased gradually with increasing age, consistent with emerging CS, while magnitudes of high-frequency TENV-based EFRs in quiet were most reduced in older hearing-impaired subjects with combined CS and OHC damage. In contrast, EFRs targeting low-frequency TENV encoding in quiet remained preserved. Behaviorally, discrimination of predominantly TFS-based phoneme contrasts worsened with OHC loss and age in quiet and contralateral noise, respectively, whereas discrimination of predominantly TENV-based contrasts showed no significant age effect. Considering that high-frequency contrasts are discriminated via place-based spectral cues, low-frequency contrasts rely on TFS, and the EFR reflects primarily TENV, this framework explains why EFRs decline for high-frequency cues without perceptual loss, while EFRs remain stable for low-frequency cues even as TFS-based discrimination deteriorates. These findings highlight the need to investigate how neural coding deficits relate to perception. Combining electrophysiological and behavioral measures might provide a framework for detecting subclinical auditory deficits to earlier diagnose age-related and hidden hearing loss.

neuroscience↗

Inferences from epigenetic information in an ecological context: a case study of early-life environmental effects on DNA methylation in zebra finches

DNA methylation (DNAm) plays a key role in mediating phenotypic responses to environmental variation. Various approaches exist to link DNAm variation to phenotypes, ranging from single nucleotide resolution to the development of composite indexes ( epigenetic clocks). We here discuss the conceptual differences between these approaches through a case study using whole genome, longitudinal DNAm data from adult zebra finches raised in experimentally created small or large broods. Specifically, we (i) identified sex and age-specific CpG sites where DNAm was affected by brood size, and (ii) developed two DNAm-based indexes of the early-life environment (DMSi: based on differentially methylated sites with respect to rearing brood size; SMLmi: supervised machine learning-derived index optimized to predict brood size). We also compared results obtained by either merging or analyzing longitudinal DNAm samples separately and discussed how the permanence or transience of DNAm changes shapes responses to environmental variation through life. Our findings confirm that early-life environment leaves lasting DNAm signatures detectible in adulthood, and this effect is stronger later in life. Importantly, both indexes predicted early-life growth rates, demonstrating that DNAm-based indexes can be leveraged to retroactively quantify aspects of early-life conditions, providing a powerful novel tool in the study of wild populations.

evolutionary biology↗

Long-term effects of early-life adversity on DNA methylation in zebra finches

Early-life experiences can have profound and long-lasting effects on adult phenotype and thereby Darwinian fitness, though the mechanisms driving these effects remain poorly understood. Epigenetic alterations, especially DNA methylation which affects gene expression, potentially mediate developmental condition effects on adult phenotype. We tested for such effects using captive zebra finches that were reared in either small or large broods, a manipulation that is known to have pleiotropic phenotypic effects. Analyzing whole genome DNA methylation patterns in erythrocytes from 50 individuals sampled in adulthood, we found 0.8% of all CpG sites after filtering to be differentially methylated after correction for multiple testing. We identified 149 non-transiently differentially methylated sites (DMSs) where the DNA methylation difference between treatments was larger than 25%. These DMSs were located in 19 autosomal chromosomes, in or near genes involved in critical biological processes such as cell growth, division, and differentiation, regulation of immune response, muscle contraction, and neuronal signaling. These findings suggest that epigenetic modifications such as DNA methylation potentially mediate long-term effects of early-life adversity via differential gene expression, but follow-up studies are needed to identify the extent to which the observed DMSs are functionally related to the previously observed phenotypic effects.

ecology↗

Begging costs rather than food received cause brood size effect on growth in zebra finches

Altricial species rely on parental provisioning for early-life sustenance, and a larger brood size leads to higher levels of competition between siblings for parental resources. Early-life stress can have severe and lifelong effects on Darwinian fitness. Indeed, it is well established that being reared in a larger brood impairs growth and fitness prospects of birds, but the mechanistic underpinnings of this effect are still largely unknown. Specifically, it is not well known to what extent the reduced growth and fitness prospects of nestlings reared in large broods is due to increased resource allocation to competition versus a per capita reduction in parental provisioning rate, or a combination of the two. We cross-fostered zebra finch (Taeniopygia castanotis) chicks into small and large broods, and recorded their growth as well as the behavior of parents and offspring throughout the nestling period. As in previous experiments, growth rate was higher in small broods. In large broods, chicks begged more and parents invested more time feeding which more than compensated for the difference in brood size. We therefore conclude that the lower growth rate for nestlings raised in large broods must be atleast in part-attributed to increased energy expenditure on begging rather than a reduction in the amount of food received. These results suggest significant energetic costs associated with begging and raise the interesting possibility that brood size would not have negatively affected growth in large broods if chicks had not increased their begging effort due to increased levels of competition in nest.

animal behavior and cognition↗

Age-related decline in neural phase-locking to envelope and temporal fine structure revealed by frequency following responses: A potential signature of cochlear synaptopathy impairing speech intelligibility

Assessing the contribution of cochlear synaptopathy (CS) to the variability in speech-in-noise intelligibility among individuals remains a challenge. While several studies have proposed biomarkers for CS based on neural phase-locking to the temporal envelope (ENV), fewer have investigated how CS affects the coding of temporal fine structure (TFS), despite its crucial role in speech-in-noise perception. In this study, we specifically examined whether TFS-based markers of CS could be derived from electrophysiological responses and psychophysical detection thresholds of spectral modulation (SM) in a complex tone, which serves as a parametric model of speech. We employed an integrated approach, combining psychophysical testing with frequency-following response (FFR) measurements in three groups of participants: young normal-hearing (yNH), older normal-hearing (oNH), and older hearing-impaired (oHI) individuals. We expanded on previous work by assessing phase-locking to both ENV, using a 4 kHz rectangular amplitude-modulated (RAM) tone, and TFS, using a low-frequency (<1.5 kHz) SM complex tone. Overall, FFR results showed significant reductions in neural phase-locking to both ENV and TFS components with age and hearing loss. Specifically, the strength of TFS-related FFRs, particularly the component corresponding to the harmonic closest to the peak of the spectral envelope ([~]500 Hz), was negatively correlated with age, even after adjusting for audiometric thresholds. This TFS marker also correlated with ENV-related FFRs derived from the RAM tone, suggesting a shared decline in phase-locking capacity across low and high cochlear frequencies. Computational simulations of the auditory periphery indicated that the observed FFR strength reduction with age is consistent with approximately 50% loss of auditory nerve fibers, aligning with histopathological data. However, the TFS-based FFR marker did not account for variability in speech intelligibility observed in the same participants. Psychophysical measurements showed no age-related effects and were unrelated to the TFS-based FFR marker, highlighting the need for further psychophysical research to establish a behavioral counterpart. Altogether, our results demonstrate that FFRs to vowel-like stimuli can serve as a complementary electrophysiological marker for assessing neural coding fidelity to stimulus TFS. This approach could provide a valuable tool for better understanding the impact of CS on an important coding dimension for speech-in-noise perception.

neuroscience↗

Dosage compensation and sexual conflict in female heterogametic methylomes

DNA methylation (DNAm) suppresses gene expression and contributes to dosage compensation in mammals but whether DNAm plays a similar role in female ZW chromosome heterogametic species remains unresolved. We assessed chromosome-level DNAm using whole genome bisulphite sequencing in two avian species, zebra finches and jackdaws. Dosage compensation by DNAm would result in higher and more variable DNAm level in males relative to females on the Z chromosome. However, we found that the level of DNAm and its variance on the Z chromosome was lower in males. Moreover, male Z chromosome-based gene promoters were more frequently hypomethylated compared to females, indicating absence of upregulation on a gene-by-gene basis across the female Z chromosome. We suggest our findings reveal mitigation of an intra-genomic sexual conflict, with females suppressing expression of Z chromosome-based genes that benefit male but not female fitness. W was the most methylated chromosome, but hypermethylation on the W chromosome was mostly confined to intergenic regions, presumably resulting in the downregulation of transposable elements known to comprise a large part of the W chromosome. Thus, DNAm is involved in the development of sex-dependent phenotypes, but dosage compensation is achieved through other mechanisms.

evolutionary biology↗

Sex-chromosome-dependent aging in female heterogametic methylomes

Recent research in humans and both model and non-model animals has shown that DNA methylation (DNAm), an epigenetic modification, is one of the mechanisms underlying the aging process. DNAm-based indices predict mortality and provide valuable insights into biological aging mechanisms. Although sex-dependent differences in lifespan are ubiquitous and sex chromosomes are thought to play an important role in sex-specific aging, they have been largely ignored in epigenetic aging studies. We characterized the genome-wide distribution of age-related CpG sites from longitudinal samples in two avian species (zebra finch and jackdaw), including for the first time the avian sex chromosomes (Z and the female-specific, haploid W). In both species, we find a small fraction of the CpG sites to show age-related changes in DNAm with the majority of them being located on the haploid, female-specific W chromosome where DNAm levels predominantly decrease with age. Age-related CpG sites were overrepresented on the zebra finch but underrepresented on the jackdaw Z chromosome. Our results highlight distinct age-related changes in sex chromosome DNAm compared to the rest of the genome in two avian species, suggesting this previously understudied feature of sex chromosomes may be instrumental in sex-dependent aging. Moreover, studying the DNAm of sex chromosomes might be particularly useful in aging research, facilitating the identification of shared (sex-dependent) age-related pathways and processes between phylogenetically diverse organisms.

evolutionary biology↗

Conditional deletion of CEACAM1 causes hepatic stellate cell activation

ObjectivesHepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with MASH. Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPAR{gamma} on CEACAM1 transcriptoin and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. MethodsWe examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre+Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. ResultsLratCre+Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HDCs. This was inhibited by nicotinic acid treatment which stemmed the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-{kappa}B/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. ConclusionsLoss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.

physiology↗

The role of hidden hearing loss in tinnitus: insights from early markers of peripheral hearing damage

Since the presence of tinnitus is not always associated with audiometric hearing loss, it has been hypothesized that hidden hearing loss may act as a potential trigger for increased central gain along the neural pathway leading to tinnitus perception. In recent years, the study of hidden hearing loss has improved with the discovery of cochlear synaptopathy and several objective diagnostic markers. This study investigated three potential markers of peripheral hidden hearing loss in subjects with tinnitus: extended high-frequency audiometric thresholds, the auditory brainstem response, and the envelope following response. In addition, speech intelligibility was measured as a functional outcome measurement of hidden hearing loss. To account for age-related hidden hearing loss, participants were grouped according to age, presence of tinnitus, and audiometric thresholds. Group comparisons were conducted to differentiate between age- and tinnitus-related effects of hidden hearing loss. All three markers revealed age-related differences, whereas no differences were observed between the tinnitus and non-tinnitus groups. However, the older tinnitus group showed improved performance on low-pass filtered speech in noise tests compared to the older non-tinnitus group. These low-pass speech in noise scores were significantly correlated with tinnitus distress, as indicated using questionnaires, and could be related to the presence of hyperacusis. Based on our observations, cochlear synaptopathy does not appear to be the underlying cause of tinnitus. The improvement in low-pass speech-in-noise could be explained by enhanced temporal fine structure encoding or hyperacusis. Therefore, we recommend that future tinnitus research takes into account age-related factors, explores low-frequency encoding, and thoroughly assesses hyperacusis.

neuroscience↗

Phase coding in phoneme processing slows with age

The comprehension of phonemes is a fundamental component of speech processing which relies on both, temporal fine structure (TFS) and temporal envelope (TE) coding. EEG amplitude in response to phonemes has been identified as indicator of speech performance in hearing aid users. Presbyacusis may also alter neuro-electric responses to phonemes, even with minimally or unaffected hearing thresholds. Elevated speech reception thresholds (SRT) in absence of pure-tone threshold (PTT) elevation suggest central processing deficits. We therefore collected audiometric data (PTT, SRT) and EEG during passive listening in 80 subjects, ranging in age from 18 to 76 years. We confirm phoneme-evoked EEG response amplitude (PEA) as indicator of speech comprehension. Specifically, PEA decreased with elevated SRT, PTT and increased age. As novel observation, we report the temporal delay of phoneme-evoked EEG responses (PED) to increase with age and PTT. The absolute duration of PED, its age-correlation, and the lack of PEA-lateralization combined with the frequency of phoneme stimuli used here suggest a predominantly thalamic generator of phoneme-evoked EEG responses. Hearing loss in extended high-frequencies affects PED more than PEA. In our sample, neural compensation for increased PTT came at the cost of decreased temporal processing speed. Most importantly, PED correlates with SRT and explains SRT-variance in quiet and in ipsilateral noise that PTT cannot. PED was a better predictor of TFS coding in quiet and of TE coding in ipsilateral noise. As PED reflects both TFS and TE coding, thalamic activity may provide integrated information at the gate of neocortex. Significance StatementIntact speech comprehension is essential for social participation which protects against depression and dementia. Age-related hearing loss is a growing problem in aging societies, as hearing deficits constitute the third most important modifiable risk factor for cognitive decline. This work uses electrical brain responses to phonemes in a cohort covering age 18 to 76 years. As the temporal delay of phoneme responses showed the most significant correlations with age and high-frequency thresholds, we demonstrated that speed of neural processing seems essential for speech comprehension. The observed neural signals likely originate from thalamus which receives feedback from neocortex and is embedded in cognitive processing. Developing objective markers for speech processing is key for ensuring cognitive fitness in aging.

systems biology↗

Neural adaptation at stimulus onset and speed of neural processing as critical contributors to speech comprehension independent of hearing threshold or age

Loss of afferent auditory fiber function (cochlear synaptopathy) has been suggested to occur before a clinically measurable deterioration of subjective hearing threshold. This so-called "hidden" hearing loss is characterized by speech comprehension difficulties. We examined young, middle-aged, and older individuals with and without hearing loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (DPOAE), auditory brainstem responses (ABR), auditory steady state responses (ASSR), speech comprehension (OLSA), and syllable discrimination in quiet and noise. After normalizing OLSA thresholds for PT thresholds ("PNOT"), differences in speech comprehension still remained and showed no significant dependence on age, allowing us to categorize participants into groups with good, standard, and poor speech comprehension. Listeners with poor speech comprehension in quiet exhibited smaller firing rate adaptions at stimulus onset (as measured by the difference between DPOAE threshold and pure-tone threshold) and delayed supra-threshold ABR waves I-V, suggesting high spontaneous rate low threshold fiber cochlear synaptopathy. In contrast, when speech comprehension was tested in noise, listeners with poor speech comprehension had larger DPOAEs acceptance rate, putatively resulting from altered basilar membrane compression (recruitment). This was linked with higher uncomfortable loudness levels and larger ASSR amplitudes. Moreover, performance in phoneme discrimination was significantly different below (/o/-/u/) and above the phase-locking limit (/i/-/y/), depending on whether vowels were presented in quiet or ipsilateral noise. This suggests that neural firing rate adaptation at stimulus onset is critical for speech comprehension, independent of hearing threshold and age, whereas the recruitment phenomenon counterbalances the loss in speech-in-noise discrimination due to impaired threshold. Significance StatementAge-related hearing loss is the third largest modifiable risk factor for cognitive decline. It has been suggested that the link between hearing loss and cognitive decline is not fully explained by hearing threshold loss. We here suggest that language comprehension deficits may be used as an early indication of future hearing loss and therefore cognitive decline. We found that, independent of age and pure-tone thresholds, speech comprehension in quiet and ipsilateral noise depend on different onset firing-rate adaptations of inner hair cells (measured by DPOAE threshold), along with cochlear synaptopathy of high spontaneous rate auditory nerve fibers and neural spiking synchronicity. These measures may be used as possible future indicators of risk for cognitive decline.

neuroscience↗

Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity

Gains of 1q are a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains of 1q impact the differentiation capacity to derivates of the three germ layers, leading to miss-specification to cranial placode and non-neural ectoderm during neuroectoderm differentiation and by poorer expression of lineage specific markers in hepatoblasts and cardiac progenitors. Competition assays show that the cells retain their selective advantage during differentiation, which is mediated by a higher expression of MDM4, a gene located in the common region of gain. MDM4 drives the winner phenotype of the mutant cells in both the undifferentiated and differentiating state by reducing the cells sensitivity to DNA-damage through decreased p53-mediated apoptosis. Finally, we find that cell density in culture plays a key role in promoting the competitive advantage of the cells by increasing DNA damage.

cell biology↗

Do glucocorticoids indicate stress? Meta-analysis reveals a tight association between glucocorticoids and metabolic rate

Glucocorticoid (GC) variation has long been thought to reflect variation in organismal stress, but associations between GCs and Darwinian fitness components are diverse in magnitude, direction, and highly context-dependent. This paradox reveals our poor understanding of the causes of GC variation, contrasting with the detailed knowledge of the functional consequences of GC variation. Amongst an array of effects in many physiological systems, GCs orchestrate energy availability to anticipate and recover from predictable and unpredictable environmental fluctuations and challenges. Although this is mechanistically well-known, the extent to which GC levels are quantitatively explained by energy metabolism is unresolved. We investigated this association through meta-analysis, selecting studies of endotherms in which (1) an experiment was performed that affected metabolic rate and (2) metabolic rate and GC-levels were measured simultaneously. We found that an increase in metabolic rate was associated with an increase in GC levels in 20 out of 21 studies (32 out of 35 effect sizes). More importantly, there was a strong positive correlation between the increases in metabolic rate and GCs (p=0.003). This pattern was similar in birds and mammals, and independent of the nature of the experimental treatment. We conclude that metabolic rate is a major driver of GC variation within individuals. Stressors often affect metabolic rate, leading us to question whether GC levels provide information on stress beyond the stressors effect on metabolic rate.

ecology↗