Biology subjects

Smith, S. S.

Publications and source records attributed to Smith, S. S..

8 recordsLinked to original sources

bioRxiv2026

Neural and autonomic predictors of future listening errors

Some of the most demanding perceptual tasks require sustained vigilance to detect and classify infrequent, unpredictable targets within continuous sensory streams. Here, we designed a sustained listening task to ask whether cardinal classes of perceptual errors (misclassifications, miss, and false alarms) were associated with variability in event-related processing, ongoing cortical state, and autonomic arousal. We recorded 64-channel scalp EEG and pupil diameter in 39 adults while they monitored streams of random tone pips for occasional target sequences of repeating tones. A target-evoked negativity varied systematically with listening outcome: it was largest for correct reports, reduced for misclassifications, and nearly absent for misses. Notably, these differences emerged within the first 500 ms of the target sequence, before the information needed to classify its length was available. Related negativities also accompanied false alarms despite the absence of a target. By contrast, neural synchronization to acoustic cues in individual tone pips did not differ across perceptual outcomes. We then looked further back in time, to the 1 s period preceding target onset, and identified additional signatures of forthcoming misclassifications and false alarms in pupil diameter and EEG aperiodic slopes. Models evaluated with leave-one-subject-out cross-validation showed that baseline state measures and event-related negativity amplitude provided complementary information about the probability and type of forthcoming errors. These findings link perceptual errors during sustained listening to higher-order cortical and arousal-state dynamics rather than fluctuant encoding of bottom-up acoustic cues.

neuroscience↗

bioRxiv2025

Arousal state fluctuations are a source of internal noise underlying age-related declines in speech intelligibility

Understanding speech in noisy, multi-talker environments is crucial for social communication but becomes increasingly challenging and frustrating as we age. Here, we simulated the acoustic challenges of multi-talker listening and found that adults over 50 years old (N = 76) recognized speech more slowly, less accurately, and less consistently than younger adults (N = 107). While peripheral hearing status accounted for average differences in speech intelligibility by age, it did not account for moment-to-moment variability in speed and accuracy - fluctuations central to the frustration experienced by older listeners in challenging environments. We hypothesized that age-related changes in brain arousal systems might account for the fluctuant "noise" in speech processing observed in older listeners. To isolate the contribution of arousal state independent of hearing status and cognitive load, we measured the pre-stimulus pupil-indexed arousal state (PPAS) immediately prior to speech onset. Older - but not younger - adults exhibited a striking inverted-U relationship between PPAS and speech recognition accuracy. Notably, pupil-indexed listening effort measured seconds later during speech encoding was not associated with trial-to-trial performance. Moreover, older adults exhibited altered arousal regulation, occupying a lower PPAS extremum not observed in younger listeners that was specifically associated with performance deficits and subjective listening difficulties reported in hearing health questionnaires. These findings show that age-related changes in central arousal states interact with peripheral hearing status to offer a more complete explanation for why older adults find speech processing in social setting so challenging. Significance StatementAs we age, following a conversation in crowded environments becomes more difficult and frustrating, even when hearing tests appear normal. This study shows that variations in arousal level (measured through pre-stimulus pupil size) are tightly linked to fluctuations in the speed and accuracy of speech processing in adults over 50 years of age. Changes in arousal state regulation uniquely accounted for the moment-to-moment variations in speech intelligibility and were more closely associated with self-reported listening challenges than other conventional measures. These findings highlight the contribution of brain-wide arousal systems to real-world listening challenges and identify a straightforward measure that could be used to more comprehensively assess and potentially improve speech understanding in social settings.

neuroscience↗

bioRxiv2025

G-Quadruplexes Act as an On/Off Switch While i-Motifs Regulate Insulin Expression in Reporter Gene Assays

The insulin-linked polymorphic region (ILPR) is a variable number tandem repeat located in the promoter of the human insulin gene. This G-rich sequence can fold into four-stranded G-quadruplex DNA structures, while its complementary C-rich strand forms i-motifs. The ILPR varies in repeat number and sequence composition, but the relationship between sequence diversity, DNA structure, and insulin gene regulation remains poorly understood. Although both G-quadruplexes and i-motifs have been implicated in transcriptional control, their relative contributions, particularly when formed on complementary strands of the same locus, are unclear. Here, we characterised the structure and stability of nine ILPR-based sequences using biophysical techniques and luciferase reporter assays. We demonstrate that transcriptional activation in response to high glucose occurs only when both G-quadruplex and i-motif structures can form. Other combinations of structures do not induce transcription. Moreover, promoter activity correlated positively with i-motif stability, but not with G-quadruplex stability. These results suggest a model in which G-quadruplexes function as an on/off switch, while i-motifs act as modulators of gene expression. Our findings underscore the importance of treating G-quadruplexes and i-motifs as a dynamic, interdependent system in both the regulation of gene expression and also the potential of these structures as therapeutic targets. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/651924v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@16ae322org.highwire.dtl.DTLVardef@65e893org.highwire.dtl.DTLVardef@884ab3org.highwire.dtl.DTLVardef@1e0311e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

The human pupil and face encode sound affect and provide objective signatures of tinnitus and auditory hypersensitivity disorders

Sound is jointly processed along acoustic and emotional dimensions. These dimensions can become distorted and entangled in persons with sensory disorders, producing a spectrum of loudness hypersensitivity, phantom percepts, and - in some cases - debilitating sound aversion. Here, we looked for objective signatures of disordered hearing (DH) in the human face. Pupil dilations and micro facial movement amplitudes scaled with sound valence in neurotypical listeners but not DH participants with chronic tinnitus (phantom ringing) and sound sensitivity. In DH participants, emotionally evocative sounds elicited abnormally large pupil dilations but blunted and invariant facial reactions that jointly provided an accurate prediction of individual tinnitus and hyperacusis questionnaire handicap scores. By contrast, EEG measures of central auditory gain identified steeper neural response growth functions but no association with symptom severity. These findings highlight dysregulated affective sound processing in persons with bothersome tinnitus and sound sensitivity disorders and introduce approaches for their objective measurement.

neuroscience↗

bioRxiv2021

Species-specific deployment of Runx2 isoforms and differential regulation of target genes during avian jaw development and evolution

Developmental regulation of bone formation in the jaw skeleton is essential to species-specific adaptation. The jaws are derived from neural crest mesenchyme (NCM), a progenitor population that directs skeletal patterning by exerting temporal and spatial control over molecular and cellular programs for osteogenesis. One important NCM-mediated gene is Runx2, which is a transcription factor required for osteoblast differentiation. RUNX2 protein binds many target genes involved in the deposition and resorption of bone. To determine the extent to which changes in Runx2 structure, function, and expression underlie the evolution of the jaw skeleton, we compare Runx2 across vertebrates and within birds. Runx2 contains two alternative promoters, tandem repeats of glutamine and alanine with variable lengths in different species, a conserved DNA-binding domain, an exon that is alternatively spliced, as well as two possible C-termini. Such alternative splicing produces eight potential isoforms that show distinct stage- and species-specific patterns in the jaw primordia of chick, quail and duck embryos. We also find that certain isoforms are strongly induced by TGF{beta} signaling whereas others are not. Overexpressing Runx2 isoforms in NCM reveals that some are transcriptionally activating, while others are repressive. But context appears to be relevant since species-specific polymorphisms in the promoter of target genes like Mmp13, can modulate the effects of different isoforms. Overall, our study indicates that the structure and species-specific deployment of Runx2 isoforms affect the transcriptional activity of target genes in ways that may have played a generative and regulatory role in the evolution of the avian jaw skeleton.

developmental biology↗

bioRxiv2021

Inferring the Neural Basis of Binaural Detection Using Deep Learning

The binaural system utilizes interaural timing cues to improve the detection of auditory signals presented in noise. In humans, the binaural mechanisms underlying this phenomenon cannot be directly measured - and hence remain contentious. As an alternative, we trained modified autoencoder networks to mimic human-like behavior in a binaural detection task. The autoencoder architecture emphasizes interpretability and, hence, we "opened it up" to see if it could infer latent mechanisms underlying binaural detection. We found that the optimal network automatically developed artificial neurons with sensitivity to timing cues and with dynamics consistent with a cross-correlation mechanism. These computations were similar to neural dynamics reported in animal models. That these computations emerged to account for human hearing attests to their generality as a solution for binaural signal detection. Methodologically, the study examines the utility of explanatory-driven neural networks and how they may be used to infer mechanisms of audition.

neuroscience↗

bioRxiv2020

Species-specific sensitivity to TGFβ signaling and changes to the Mmp13 promoter underlie avian jaw development and evolution

Developmental control of jaw length is critical for survival. The jaw skeleton arises from neural crest mesenchyme and previously we demonstrated that these progenitors upregulate bone-resorbing enzymes including Matrix metalloproteinase 13 (Mmp13) when generating short quail beaks versus long duck bills. Inhibiting bone resorption or Mmp13 increases jaw length. Here, we uncover mechanisms establishing species-specific levels of Mmp13 and bone resorption. Quail show greater activation of, and sensitivity to Transforming Growth Factor-Beta (TGF{beta}) signaling than duck; where mediators like SMADs and targets like Runx2, which bind Mmp13, become elevated. Inhibiting TGF{beta} signaling decreases bone resorption. We discover a SMAD binding element in the quail Mmp13 promoter not found in duck and single nucleotide polymorphisms (SNPs) near a RUNX2 binding element that affect expression. Switching the SNPs and SMAD site abolishes TGF{beta}-sensitivity in the quail Mmp13 promoter but makes duck responsive. Thus, differential regulation of TGF{beta} signaling and Mmp13 promoter structure underlie avian jaw development and evolution.

developmental biology↗

bioRxiv2020

Stable integration of an optimized inducible promoter system enables spatiotemporal control of gene expression throughout avian development

Precisely altering gene expression is critical for understanding molecular processes of embryogenesis. Although some tools exist for transgene misexpression in developing chick embryos, we have refined and advanced them by simplifying and optimizing constructs for spatiotemporal control. To maintain expression over the entire course of embryonic development we use an enhanced piggyBac transposon system that efficiently integrates sequences into the host genome. We also incorporate a DNA targeting sequence to direct plasmid translocation into the nucleus and a D4Z4 insulator sequence to prevent epigenetic silencing. We designed these constructs to minimize their size and maximize cellular uptake, and to simplify usage by placing all of the integrating sequences on a single plasmid. Following electroporation of stage HH8.5 embryos, our tetracycline-inducible promoter construct produces robust transgene expression in the presence of doxycycline at any point during embryonic development in ovo or in culture. Moreover, expression levels can be modulated by titrating doxycycline concentrations and spatial control can be achieved using beads or gels. Thus, we have generated a novel, sensitive, tunable, and stable inducible-promoter system for high-resolution gene manipulation in vivo.View Full Text

developmental biology↗