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Molecular Pain 2024We recently used Nav1.8-ChR2 mice in which Nav1.8-expressing afferents were optogenetically tagged to classify mechanosensitive afferents into Nav1.8-ChR2-positive and...
We recently used Nav1.8-ChR2 mice in which Nav1.8-expressing afferents were optogenetically tagged to classify mechanosensitive afferents into Nav1.8-ChR2-positive and Nav1.8-ChR2-negative mechanoreceptors. We found that the former were mainly high threshold mechanoreceptors (HTMRs), while the latter were low threshold mechanoreceptors (LTMRs). In the present study, we further investigated whether the properties of these mechanoreceptors were altered following tissue inflammation. Nav1.8-ChR2 mice received a subcutaneous injection of saline or Complete Freund's Adjuvant (CFA) in the hindpaws. Using the hind paw glabrous skin-tibial nerve preparation and the pressure-clamped single-fiber recordings, we found that CFA-induced hind paw inflammation lowered the mechanical threshold of many Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors but heightened the mechanical threshold of many Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors. Spontaneous action potential impulses were not observed in Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors but occurred in Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors with a lower mechanical threshold in the saline goup, and a higher mechanical threshold in the CFA group. No significant change was observed in the mechanical sensitivity of Nav1.8-ChR2-positive and Nav1.8-ChR2-negative Aδ-fiber mechanoreceptors and Nav1.8-ChR2-positive C-fiber mechanoreceptors following hind paw inflammation. Collectively, inflammation significantly altered the functional properties of both Nav1.8-ChR2-positive and Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors, which may contribute to mechanical allodynia during inflammation.
Topics: Mice; Animals; Mechanoreceptors; Skin; Hyperalgesia; Nerve Fibers, Unmyelinated; Inflammation
PubMed: 38438192
DOI: 10.1177/17448069241240452 -
Cell Reports Mar 2024Hearing starts, at the cellular level, with mechanoelectrical transduction by sensory hair cells. Sound information is then transmitted via afferent synaptic connections...
Hearing starts, at the cellular level, with mechanoelectrical transduction by sensory hair cells. Sound information is then transmitted via afferent synaptic connections with auditory neurons. Frequency information is encoded by the location of hair cells along the cochlear duct. Loss of hair cells, synapses, or auditory neurons leads to permanent hearing loss in mammals. Birds, in contrast, regenerate auditory hair cells and functionally recover from hearing loss. Here, we characterized regeneration and reinnervation in sisomicin-deafened chickens and found that afferent neurons contact regenerated hair cells at the tips of basal projections. In contrast to development, synaptic specializations are established at these locations distant from the hair cells' bodies. The protrusions then contracted as regenerated hair cells matured and became functional 2 weeks post-deafening. We found that auditory thresholds recovered after 4-5 weeks. We interpret the regeneration-specific synaptic reestablishment as a location-preserving process that might be needed to maintain tonotopic fidelity.
Topics: Animals; Chickens; Hair Cells, Auditory; Hearing; Hearing Loss; Sound; Mammals
PubMed: 38393948
DOI: 10.1016/j.celrep.2024.113822 -
Biomimetics (Basel, Switzerland) Jan 2024For people who have experienced a spinal cord injury or an amputation, the recovery of sensation and motor control could be incomplete despite noteworthy advances with...
For people who have experienced a spinal cord injury or an amputation, the recovery of sensation and motor control could be incomplete despite noteworthy advances with invasive neural interfaces. Our objective is to explore the feasibility of a novel biohybrid robotic hand model to investigate aspects of tactile sensation and sensorimotor integration with a pre-clinical research platform. Our new biohybrid model couples an artificial hand with biological neural networks (BNN) cultured in a multichannel microelectrode array (MEA). We decoded neural activity to control a finger of the artificial hand that was outfitted with a tactile sensor. The fingertip sensations were encoded into rapidly adapting (RA) or slowly adapting (SA) mechanoreceptor firing patterns that were used to electrically stimulate the BNN. We classified the coherence between afferent and efferent electrodes in the MEA with a convolutional neural network (CNN) using a transfer learning approach. The BNN exhibited the capacity for functional specialization with the RA and SA patterns, represented by significantly different robotic behavior of the biohybrid hand with respect to the tactile encoding method. Furthermore, the CNN was able to distinguish between RA and SA encoding methods with 97.84% ± 0.65% accuracy when the BNN was provided tactile feedback, averaged across three days in vitro (DIV). This novel biohybrid research platform demonstrates that BNNs are sensitive to tactile encoding methods and can integrate robotic tactile sensations with the motor control of an artificial hand. This opens the possibility of using biohybrid research platforms in the future to study aspects of neural interfaces with minimal human risk.
PubMed: 38392124
DOI: 10.3390/biomimetics9020078 -
Audiology Research Feb 2024Soft tissue conduction is a mode of hearing which differs from air and bone conduction since the soft tissues of the body convey the audio-frequency vibrations to the...
Soft tissue conduction is a mode of hearing which differs from air and bone conduction since the soft tissues of the body convey the audio-frequency vibrations to the ear. It is elicited by inducing soft tissue vibrations with an external vibrator applied to sites on the body or by intrinsic vibrations resulting from vocalization or the heartbeat. However, the same external vibrator applied to the skin sites also excites cutaneous mechanoreceptors, and attempts have been made to assist patients with hearing loss by audio-tactile substitution. The present study was conducted to assess the contribution of the auditory nerve and brainstem pathways to soft tissue conduction hearing. The study involved 20 normal hearing students, equipped with ear plugs to reduce the possibility of their response to air-conducted sounds produced by the external vibrator. Pure tone audiograms and speech reception (recognition) thresholds were determined in response to the delivery of the stimuli by a clinical bone vibrator applied to the cheek, neck and shoulder. Pure tone and speech recognition thresholds were obtained; the participants were able to repeat the words they heard by soft tissue conduction, confirming that the auditory pathways in the brain had been stimulated, with minimal involvement of the somatosensory pathways.
PubMed: 38391775
DOI: 10.3390/audiolres14010018 -
ELife Feb 2024Touch sensation is primarily encoded by mechanoreceptors, called low-threshold mechanoreceptors (LTMRs), with their cell bodies in the dorsal root ganglia. Because of...
Touch sensation is primarily encoded by mechanoreceptors, called low-threshold mechanoreceptors (LTMRs), with their cell bodies in the dorsal root ganglia. Because of their great diversity in terms of molecular signature, terminal endings morphology, and electrophysiological properties, mirroring the complexity of tactile experience, LTMRs are a model of choice to study the molecular cues differentially controlling neuronal diversification. While the transcriptional codes that define different LTMR subtypes have been extensively studied, the molecular players that participate in their late maturation and in particular in the striking diversity of their end-organ morphological specialization are largely unknown. Here we identified the TALE homeodomain transcription factor Meis2 as a key regulator of LTMRs target-field innervation in mice. is specifically expressed in cutaneous LTMRs, and its expression depends on target-derived signals. While LTMRs lacking survived and are normally specified, their end-organ innervations, electrophysiological properties, and transcriptome are differentially and markedly affected, resulting in impaired sensory-evoked behavioral responses. These data establish as a major transcriptional regulator controlling the orderly formation of sensory neurons innervating peripheral end organs required for light touch.
Topics: Animals; Mice; Gene Expression Regulation; Mechanoreceptors; Nervous System Physiological Phenomena; Sensory Receptor Cells; Transcription Factors; Homeodomain Proteins
PubMed: 38386003
DOI: 10.7554/eLife.89287 -
Nature Communications Feb 2024Artificial communication with the brain through peripheral nerve stimulation shows promising results in individuals with sensorimotor deficits. However, these efforts...
Artificial communication with the brain through peripheral nerve stimulation shows promising results in individuals with sensorimotor deficits. However, these efforts lack an intuitive and natural sensory experience. In this study, we design and test a biomimetic neurostimulation framework inspired by nature, capable of "writing" physiologically plausible information back into the peripheral nervous system. Starting from an in-silico model of mechanoreceptors, we develop biomimetic stimulation policies. We then experimentally assess them alongside mechanical touch and common linear neuromodulations. Neural responses resulting from biomimetic neuromodulation are consistently transmitted towards dorsal root ganglion and spinal cord of cats, and their spatio-temporal neural dynamics resemble those naturally induced. We implement these paradigms within the bionic device and test it with patients (ClinicalTrials.gov identifier NCT03350061). He we report that biomimetic neurostimulation improves mobility (primary outcome) and reduces mental effort (secondary outcome) compared to traditional approaches. The outcomes of this neuroscience-driven technology, inspired by the human body, may serve as a model for advancing assistive neurotechnologies.
Topics: Male; Humans; Touch; Biomimetics; Ganglia, Spinal; Brain; Computers
PubMed: 38378671
DOI: 10.1038/s41467-024-45190-6 -
Physics of Life Reviews Mar 2024In primary or idiopathic osteoarthritis (OA), it is unclear which factors trigger the shift of articular chondrocyte activity from pro-anabolic to pro-catabolic. In... (Review)
Review
In primary or idiopathic osteoarthritis (OA), it is unclear which factors trigger the shift of articular chondrocyte activity from pro-anabolic to pro-catabolic. In fact, there is a controversy about the aetiology of primary OA, either mechanical or inflammatory. Chondrocytes are mechanosensitive cells, that integrate mechanical stimuli into cellular responses in a process known as mechanotransduction. Mechanotransduction occurs thanks to the activation of mechanosensors, a set of specialized proteins that convert physical cues into intracellular signalling cascades. Moderate levels of mechanical loads maintain normal tissue function and have anti-inflammatory effects. In contrast, mechanical over- or under-loading might lead to cartilage destruction and increased expression of pro-inflammatory cytokines. Simultaneously, mechanotransduction processes can regulate and be regulated by pro- and anti-inflammatory soluble mediators, both local (cells of the same joint, i.e., the chondrocytes themselves, infiltrating macrophages, fibroblasts or osteoclasts) and systemic (from other tissues, e.g., adipokines). Thus, the complex process of mechanotransduction might be altered in OA, so that cartilage-preserving chondrocytes adopt a different sensitivity to mechanical signals, and mechanic stimuli positively transduced in the healthy cartilage may become deleterious under OA conditions. This review aims to provide an overview of how the biochemical exposome of chondrocytes can alter important mechanotransduction processes in these cells. Four principal mechanosensors, i.e., integrins, Ca channels, primary cilium and Wnt signalling (canonical and non-canonical) were targeted. For each of these mechanosensors, a brief summary of the response to mechanical loads under healthy or OA conditions is followed by a concise overview of published works that focus on the further regulation of the mechanotransduction pathways by biochemical factors. In conclusion, this paper discusses and explores how biological mediators influence the differential behaviour of chondrocytes under mechanical loads in healthy and primary OA.
Topics: Humans; Osteoarthritis, Knee; Chondrocytes; Mechanotransduction, Cellular; Cytokines; Anti-Inflammatory Agents
PubMed: 38377727
DOI: 10.1016/j.plrev.2024.02.003 -
International Journal of Molecular... Jan 2024TRPV4 channels, which respond to mechanical activation by permeating Ca into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study...
TRPV4 channels, which respond to mechanical activation by permeating Ca into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study aimed to investigate TRPV4 involvement in pathological and physiological remodeling through Ca-dependent signaling. TRPV4 expression was assessed in heart failure (HF) models, induced by isoproterenol infusion or transverse aortic constriction, and in exercise-induced adaptive remodeling models. The impact of genetic TRPV4 inhibition on HF was studied by echocardiography, histology, gene and protein analysis, arrhythmia inducibility, Ca dynamics, calcineurin (CN) activity, and NFAT nuclear translocation. TRPV4 expression exclusively increased in HF models, strongly correlating with fibrosis. Isoproterenol-administered transgenic TRPV4-/- mice did not exhibit HF features. Cardiac fibroblasts (CFb) from TRPV4+/+ animals, compared to TRPV4-/-, displayed significant TRPV4 overexpression, elevated Ca influx, and enhanced CN/NFATc3 pathway activation. TRPC6 expression paralleled that of TRPV4 in all models, with no increase in TRPV4-/- mice. In cultured CFb, the activation of TRPV4 by GSK1016790A increased TRPC6 expression, which led to enhanced CN/NFATc3 activation through synergistic action of both channels. In conclusion, TRPV4 channels contribute to pathological remodeling by promoting fibrosis and inducing TRPC6 upregulation through the activation of Ca-dependent CN/NFATc3 signaling. These results pose TRPV4 as a primary mediator of the pathological response.
Topics: Animals; Mice; Calcineurin; Cells, Cultured; Fibrosis; Heart Failure; Isoproterenol; Mice, Transgenic; Myocytes, Cardiac; NFATC Transcription Factors; TRPC6 Cation Channel; TRPV Cation Channels; Ventricular Remodeling
PubMed: 38338818
DOI: 10.3390/ijms25031541 -
Journal of the Mechanical Behavior of... Apr 2024Our daily lives are constantly surrounded by dynamic stimuli, and our skin is deformed in a time-dependent manner. Although skin plays an important role in transmitting...
Our daily lives are constantly surrounded by dynamic stimuli, and our skin is deformed in a time-dependent manner. Although skin plays an important role in transmitting stimuli received at the surface to mechanoreceptors, few studies have investigated how differences in skin viscoelasticity affect the mechanical stimuli propagation in the skin. Therefore, using a finite element model, we evaluated the effects and trends of changes in the stiffness and viscoelasticity of the skin on the propagation of mechanical quantities between skin layers where mechanoreceptors are present when subjected to periodic stimuli. First, we constructed a new, sophisticated mathematical model of skin viscoelasticity based on the history-dependent deformation behavior of human skin obtained experimentally. We were able to construct a skin model that thoroughly reproduced the actual human skin deformation behavior at oscillations as fast as 10 Hz by setting viscoelastic parameters with a short time constant (0.001-0.006 s). Then, we calculated how skin material parameters affect the propagation of the mechanical quantities in the skin during the history-dependent skin deformation response to periodic stimuli. The finite element analysis showed that not only stiffness but also viscoelasticity markedly affected the mechanical stimuli propagation in the skin, and the effect differed depending on the layer. In particular, greater immediate responsiveness of the dermis contributed to greater propagation of the mechanical stimulus. Our results indicate that more attention needs to be given to the differences in the time-dependent intradermal mechanical stimuli propagation caused by individual's skin viscoelasticity.
Topics: Humans; Skin; Finite Element Analysis
PubMed: 38335646
DOI: 10.1016/j.jmbbm.2024.106416 -
ELife Feb 2024Two calcium-binding proteins, CaBP1 and CaBP2, cooperate to keep calcium channels in the hair cells of the inner ear open.
Two calcium-binding proteins, CaBP1 and CaBP2, cooperate to keep calcium channels in the hair cells of the inner ear open.
Topics: Calcium; Hair Cells, Auditory; Calcium Channels; Calcium, Dietary; Hair Cells, Auditory, Inner; Calcium-Binding Proteins
PubMed: 38334748
DOI: 10.7554/eLife.96139