Biology subjects

Szczot, I.

Publications and source records attributed to Szczot, I..

4 recordsLinked to original sources

bioRxiv2026

Rapid peripheral reprogramming of myelinated afferents drives human hyperalgesia

A small burn can render a large area of skin painfully tender. This widespread hyperalgesia protects injured tissue and is typically attributed to altered spinal cord mechanisms. Whether peripheral sensory afferents directly interact to contribute to hyperalgesia remains unclear. Using single-unit microneurography, we recorded cutaneous afferents before and after inducing localized TRPV1-mediated inflammatory flare. This triggered minutes-scale reweighting of transcriptomically defined TRPV1- afferents, with divergent effects among myelinated (A{beta}-range) classes: tactile receptors showed reduced responsiveness, whereas mechano-nociceptors underwent sensitization. These changes paralleled diminished tactile sensitivity and intensified mechanical pain. Recruitment of mechanically silent branches in A{beta}-range mechano-nociceptors produced wide-field amplification of peripheral nociceptive signaling beyond the inflamed site. These findings suggest that rapid peripheral crosstalk from TRPV1+ afferents reprograms TRPV1- A{beta}-afferents and drives human hyperalgesia.

neuroscience↗

bioRxiv2025

Hierarchical organization of mechano-nociceptive pathways revealed by activity labeling

Noxious mechanical stimuli give rise to distinct percepts, from sharp cutaneous pain to diffuse visceral discomfort, yet the nociceptor ensembles that underlie these differences remain poorly defined. We mapped the peripheral architecture of nociceptive signaling by combining in vivo activity labeling of pelvic nerve afferents with single-cell RNA sequencing. Noxious stimuli recruited diverse classes of mechano-nociceptors, but stimulus type exerted modest influence on the composition of activated ensembles. Instead, tissue identity imposed the dominant organizational structure: stimulation of cutaneous and deep pelvic tissues engaged distinct subsets of both myelinated and unmyelinated neurons, revealing a clear domain-level division. Within this architecture, we identified a bladder-innervating myelinated nociceptor subtype with distinctive molecular features, illustrating an additional layer of refinement. Functional imaging and anatomical tracing corroborated this multilevel organization. These findings reveal a hierarchical organization of peripheral mechanical pain encoding, in which mechano-nociceptor populations are differentially engaged according to tissue domain and organ context.

neuroscience↗

bioRxiv2025

Tactile Illusion Reveals Central Neural Basis for Touch Pleasantness

C-low threshold mechanoreceptors (C-LTMRs) have been highlighted in mediating the pleasantness of slow, caressing touch. This has given rise to the "Affective Touch Hypothesis," which posits that velocity tuning of C-LTMRs underpins pleasantness perception. The known activation preferences of C-LTMRs have been used as a proxy for pleasant touch, yet recent findings have raised questions about the necessity of this peripheral mechanism. This project explored the peripheral and central mechanisms in affective touch through comparing two motion-conditions: gentle brushing-like motion and apparent motion, an illusory perception of movement produced by successive touches along the skin. We used this illusion to examine whether previously established velocity tuning of true lateral motion is observed in apparent motion, when local information provided to individual peripheral afferents is held constant. The sole dependence on peripheral modulation predicts that the characteristic inverted-U-shaped relationship between velocity and pleasantness, regularly associated with C-LTMRs, would only be observed for brushing-like motion. Central modulation would instead predict a more similar relationship between the motion-conditions. To investigate this, pleasantness-ratings and velocity-ratings were collected across different velocities (0.1-30cm/s, N=23) for both conditions. Linear and quadratic regression analyses were performed and for both conditions adding a quadratic term improved the overall model fit, reaching significance (p<0.001). The quadratic term coefficients were negative for both conditions, displaying an inverted-U-shape. Further analyses revealed that motion-condition did not significantly alter the relationship between stimulus-velocity and pleasantness. These findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs. Key pointsO_LIC-low threshold mechanoreceptors (C-LTMRs) have been shown to display a unique inverted-U-shaped relationship between firing frequencies and stroking velocity, which is not seen with any other cutaneous afferents C_LIO_LIAn inverted-U-shaped relationship is also observed between perceived touch pleasantness and stroking velocity, giving rise to a hypothesis which posits that the velocity tuning of C-LTMRs underpins the perception of pleasant touch C_LIO_LIWe compared traditional stroking (brushing-like motion) to an illusory perception of movement produced by successive touches along the skin (apparent motion) to examine if similar velocity-dependent pleasantness patterns would be observed when information provided to individual peripheral afferents is held constant C_LIO_LIIn our experiment, the type of motion did not significantly alter the relationship between perceived pleasantness and stimulus-velocity C_LIO_LIThese findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs C_LI

neuroscience↗

bioRxiv2023

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare A{beta} deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on A{beta} input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

neuroscience↗