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1.
Nat Commun ; 10(1): 4019, 2019 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-31488820

RESUMEN

Biological cellular structures have inspired many scientific disciplines to design synthetic structures that can mimic their functions. Here, we closely emulate biological cellular structures in a rationally designed synthetic multicellular hybrid ion pump, composed of hydrogen-bonded [EMIM+][TFSI-] ion pairs on the surface of silica microstructures (artificial mechanoreceptor cells) embedded into thermoplastic polyurethane elastomeric matrix (artificial extracellular matrix), to fabricate ionic mechanoreceptor skins. Ionic mechanoreceptors engage in hydrogen bond-triggered reversible pumping of ions under external stimulus. Our ionic mechanoreceptor skin is ultrasensitive (48.1-5.77 kPa-1) over a wide spectrum of pressures (0-135 kPa) at an ultra-low voltage (1 mV) and demonstrates the ability to surpass pressure-sensing capabilities of various natural skin mechanoreceptors (i.e., Merkel cells, Meissner's corpuscles, Pacinian corpuscles). We demonstrate a wearable drone microcontroller by integrating our ionic skin sensor array and flexible printed circuit board, which can control directions and speed simultaneously and selectively in aerial drone flight.


Asunto(s)
Técnicas Biosensibles/instrumentación , Electroquímica/instrumentación , Enlaces de Hidrógeno , Mecanorreceptores/fisiología , Mecanotransducción Celular/fisiología , Fenómenos Fisiológicos de la Piel , Adulto , Biomimética/instrumentación , Técnicas Biosensibles/métodos , Humanos , Mecanorreceptores/química , Mecanorreceptores/citología , Células de Merkel/metabolismo , Estimulación Física , Poliuretanos , Presión , Gel de Sílice , Piel/citología , Tacto/fisiología
2.
Nat Neurosci ; 22(9): 1438-1449, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31332375

RESUMEN

How the somatosensory cortex (S1) encodes complex patterns of touch, such as those that occur during tactile exploration, is poorly understood. In the mouse whisker S1, temporally dense stimulation of local whisker pairs revealed that most neurons are not classical single-whisker feature detectors, but instead are strongly tuned to two-whisker sequences that involve the columnar whisker (CW) and one specific surround whisker (SW), usually in a SW-leading-CW order. Tuning was spatiotemporally precise and diverse across cells, generating a rate code for local motion vectors defined by SW-CW combinations. Spatially asymmetric, sublinear suppression for suboptimal combinations and near-linearity for preferred combinations sharpened combination tuning relative to linearly predicted tuning. This resembles computation of motion direction selectivity in vision. SW-tuned neurons, misplaced in the classical whisker map, had the strongest combination tuning. Thus, each S1 column contains a rate code for local motion sequences involving the CW, thus providing a basis for higher-order feature extraction.


Asunto(s)
Mecanorreceptores/citología , Corteza Somatosensorial/citología , Percepción del Tacto/fisiología , Vibrisas/inervación , Animales , Ratones , Tacto/fisiología
3.
PLoS Biol ; 17(7): e3000326, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31260439

RESUMEN

Sensory hair cells are mechanoreceptors required for hearing and balance functions. From embryonic development, hair cells acquire apical stereociliary bundles for mechanosensation, basolateral ion channels that shape receptor potential, and synaptic contacts for conveying information centrally. These key maturation steps are sequential and presumed coupled; however, whether hair cells emerging postnatally mature similarly is unknown. Here, we show that in vivo postnatally generated and regenerated hair cells in the utricle, a vestibular organ detecting linear acceleration, acquired some mature somatic features but hair bundles appeared nonfunctional and short. The utricle consists of two hair cell subtypes with distinct morphological, electrophysiological and synaptic features. In both the undamaged and damaged utricle, fate-mapping and electrophysiology experiments showed that Plp1+ supporting cells took on type II hair cell properties based on molecular markers, basolateral conductances and synaptic properties yet stereociliary bundles were absent, or small and nonfunctional. By contrast, Lgr5+ supporting cells regenerated hair cells with type I and II properties, representing a distinct hair cell precursor subtype. Lastly, direct physiological measurements showed that utricular function abolished by damage was partially regained during regeneration. Together, our data reveal a previously unrecognized aberrant maturation program for hair cells generated and regenerated postnatally and may have broad implications for inner ear regenerative therapies.


Asunto(s)
Diferenciación Celular/fisiología , Células Ciliadas Auditivas/fisiología , Células Ciliadas Vestibulares/fisiología , Mecanorreceptores/fisiología , Regeneración/fisiología , Sáculo y Utrículo/fisiología , Animales , Fenómenos Electrofisiológicos/fisiología , Células Ciliadas Auditivas/citología , Células Ciliadas Vestibulares/citología , Mecanorreceptores/citología , Ratones Transgénicos , Sáculo y Utrículo/citología , Transmisión Sináptica/fisiología
4.
Ann Anat ; 225: 28-32, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31195095

RESUMEN

Anterior cruciate ligament (ACL) tears is a devastating injury and one of the most common knee injuries experienced by athletes in the United States. Although patients reach maximal subjective improvement by one-year following ACL reconstruction, many patients often experience moderate to severe post-operative pain. Opioids, intra-articular injections, and regional anesthesia have been previously implemented to mediate post-operative pain. However, chronic opioid usage has become an epidemic in the United States. Alternative analgesic modalities, such as nerve blocks, have been implemented in clinical practice to provide adequate pain relief and minimize opioid usage. Periarticular injections targeted towards local neurological structures performed concomitantly with nerve blocks provides superior pain relief and satisfaction than isolated nerve blocks. Therefore, it is imperative for physicians to understand local neurological anatomy around the knee joint in order to provide adequate analgesia while minimizing opioid consumption. This purpose of this investigation is to summarize (1) neurogenic origins of pain generators and mediators in sites affected by ACL reconstruction and autograft harvest sites and (2) analgesia utilized in ACL reconstruction.


Asunto(s)
Reconstrucción del Ligamento Cruzado Anterior , Ligamento Cruzado Anterior/anatomía & histología , Articulación de la Rodilla/irrigación sanguínea , Articulación de la Rodilla/inervación , Dolor Postoperatorio/etiología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Anestesia Local , Anestésicos Locales/administración & dosificación , Ligamento Cruzado Anterior/inervación , Ligamento Cruzado Anterior/cirugía , Autoinjertos , Canales Iónicos/metabolismo , Mecanorreceptores/fisiología , Bloqueo Nervioso , Neuropéptidos/metabolismo , Neuropéptidos/fisiología , Nocicepción/fisiología , Nociceptores/fisiología
5.
Brain Struct Funct ; 224(6): 2247-2267, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31190162

RESUMEN

We describe a set of perivascular interneurons (PINs) with series of fibro-vesicular complexes (FVCs) throughout the gray matter of the adult rabbit and rat brains. PIN-FVCs are ubiquitous throughout the brain vasculature as detected in Golgi-impregnated specimens. Most PINs are small, aspiny cells with short or long (> 1 mm) axons that split and travel along arterial blood vessels. Upon ramification, axons form FVCs around the arising vascular branches; then, paired axons run parallel to the vessel wall until another ramification ensues, and a new FVC is formed. Cytologically, FVCs consist of clusters of perivascular bulbs (PVBs) encircling the precapillary and capillary wall surrounded by end-feet and the extracellular matrix of endothelial cells and pericytes. A PVB contains mitochondria, multivesicular bodies, and granules with a membranous core, similar to Meissner corpuscles and other mechanoreceptors. Some PVBs form asymmetrical, axo-spinous synapses with presumptive adjacent neurons. PINs appear to correspond to the type 1 nNOS-positive neurons whose FVCs co-label with markers of sensory fiber-terminals surrounded by astrocytic end-feet. The PIN is conserved in adult cats and rhesus monkey specimens. The location, ubiquity throughout the vasculature of the mammalian brain, and cytological organization of the PIN-FVCs suggests that it is a sensory receptor intrinsic to the mammalian neurovascular unit that corresponds to an afferent limb of the sensorimotor feed-back mechanism controlling local blood flow.


Asunto(s)
Axones/metabolismo , Encéfalo/metabolismo , Células Endoteliales/metabolismo , Mecanorreceptores/metabolismo , Sinapsis/metabolismo , Animales , Gatos , Aparato de Golgi/metabolismo , Interneuronas/metabolismo , Mamíferos , Conejos , Ratas , Células Receptoras Sensoriales/metabolismo
6.
Neuron ; 103(4): 598-616.e7, 2019 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-31248728

RESUMEN

Dorsal root ganglion (DRG) sensory neuron subtypes defined by their in vivo properties display distinct intrinsic electrical properties. We used bulk RNA sequencing of genetically labeled neurons and electrophysiological analyses to define ion channel contributions to the intrinsic electrical properties of DRG neuron subtypes. The transcriptome profiles of eight DRG neuron subtypes revealed differentially expressed and functionally relevant genes, including voltage-gated ion channels. Guided by these data, electrophysiological analyses using pharmacological and genetic manipulations as well as computational modeling of DRG neuron subtypes were undertaken to assess the functions of select voltage-gated potassium channels (Kv1, Kv2, Kv3, and Kv4) in shaping action potential (AP) waveforms and firing patterns. Our findings show that the transcriptome profiles have predictive value for defining ion channel contributions to sensory neuron subtype-specific intrinsic physiological properties. The distinct ensembles of voltage-gated ion channels predicted to underlie the unique intrinsic physiological properties of eight DRG neuron subtypes are presented.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Canales Iónicos/fisiología , Células Receptoras Sensoriales/fisiología , Potenciales de Acción , Vías Aferentes/fisiología , Animales , Simulación por Computador , Ganglios Espinales/citología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Canales Iónicos/biosíntesis , Canales Iónicos/genética , Mecanorreceptores/fisiología , Ratones , Ratones Transgénicos , Modelos Neurológicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/fisiología , ARN/genética , Células Receptoras Sensoriales/química , Células Receptoras Sensoriales/clasificación , Transcriptoma
7.
Med Sci Monit ; 25: 4784-4792, 2019 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-31249285

RESUMEN

BACKGROUND The present study was performed to assess the effect of mechanical stretch on the proliferation and contractile function of hBSMCs. MATERIAL AND METHODS hBSMCs and ICCs were seeded at 8×104 cells/well in 6-well silicone elastomer-bottomed culture plates coated with type I collagen, and grown to 80% confluence in DMEM/10% FBS and a 5% CO2 humidified atmosphere at 37°C. Cells of hBSMCs and hBSMCs/ICCs of co-culture were then subjected to continuous cycles of stretch-relaxation using a computer-driven, stretch-inducing device. The treated concentration of imatinib was 10 µM. Mechanisms underlying observed hBSMCs contraction were examined using Western blotting and RT-PCR. The 0.1 µM carbachol was separately added to the experimental groups, and 300 s was recorded by laser scanning confocal microscope. RESULTS We found that mechanical stretch increased contraction and proliferation of hBSMCs. Calcium ion activity increased significantly after mechanical stretch. The number of hBSMCs was significantly increased after the combination mechanical stretch with ICCs treatment. After combination mechanical stretch with hBSMCs/ICCs treatment, the mRNA and protein level of M2, M3, and c-kit were significantly increased. After combination of mechanical stretch with no imatinib treatment, the proliferation of hBSMCs was higher than others, and the mRNA and protein level of M2 and M3 were significantly increased. CONCLUSIONS We revealed that ICCs could promote hBSMC proliferation and contraction, and cyclic stretch could promote acetylcholine receptor M2 and M3 caused by c-kit in the ICCs, which promoted the contraction of hBSMCs.


Asunto(s)
Células Intersticiales de Cajal/fisiología , Mecanorreceptores/fisiología , Miocitos del Músculo Liso/fisiología , Vejiga Urinaria/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Humanos , Fenómenos Mecánicos , Contracción Muscular/fisiología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores Muscarínicos/metabolismo , Estrés Mecánico
8.
Science ; 364(6439)2019 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-31048465

RESUMEN

Central nervous system (CNS) circuit development requires subcellular control of synapse formation and patterning of synapse abundance. We identified the Drosophila membrane-anchored phosphatase of regenerating liver (Prl-1) as an axon-intrinsic factor that promotes synapse formation in a spatially restricted fashion. The loss of Prl-1 in mechanosensory neurons reduced the number of CNS presynapses localized on a single axon collateral and organized as a terminal arbor. Flies lacking all Prl-1 protein had locomotor defects. The overexpression of Prl-1 induced ectopic synapses. In mechanosensory neurons, Prl-1 modulates the insulin receptor (InR) signaling pathway within a single contralateral axon compartment, thereby affecting the number of synapses. The axon branch-specific localization and function of Prl-1 depend on untranslated regions of the prl-1 messenger RNA (mRNA). Therefore, compartmentalized restriction of Prl-1 serves as a specificity factor for the subcellular control of axonal synaptogenesis.


Asunto(s)
Axones/fisiología , Sistema Nervioso Central/crecimiento & desarrollo , Proteínas de Drosophila/fisiología , Drosophila melanogaster/crecimiento & desarrollo , Proteínas Tirosina Fosfatasas/fisiología , Sinapsis/fisiología , Animales , Axones/enzimología , Sistema Nervioso Central/enzimología , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Locomoción/genética , Locomoción/fisiología , Mecanorreceptores/enzimología , Fosfatidilinositoles/metabolismo , Dominios Proteicos , Proteínas Tirosina Fosfatasas/química , Proteínas Tirosina Fosfatasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Sinapsis/enzimología
9.
Mol Brain ; 12(1): 31, 2019 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-30943999

RESUMEN

Merkel discs, located in skin touch domes and whisker hair follicles, are tactile end organs essential for environmental exploration, social interaction, and tactile discrimination. Recent studies from our group and two others have shown that mechanical stimulation excites Merkel cells via Piezo2 channel activation to subsequently activate sensory neural pathways. We have further shown that mechanical stimulation leads to the release of 5-HT from Merkel cells to synaptically transmit tactile signals to whisker afferent nerves. However, a more recent study using skin touch domes has raised the possibility that Merkel discs are adrenergic synapses. It was proposed that norepinephrine is released from Merkel cells upon mechanical stimulation to subsequently activate ß2 adrenergic receptors on Merkel disc nerve endings leading to nerve impulses. In the present study, we examined effects of norepinephrine and ß2 adrenergic receptor antagonist ICI 118,551 on Merkel disc mechanoreceptors in mouse whisker hair follicles. We show that norepinephrine did not directly induce impulses from Merkel disc mechanoreceptors. Furthermore, we found that ICI 118,551 at 50 µM inhibited voltage-gated Na+ channels and suppressed impulses of Merkel disc mechanoreceptors, but ICI 118,551 at 1 µM had no effects on the impulse. These findings challenge the hypothesis of Merkel discs being adrenergic synapses.


Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Folículo Piloso/metabolismo , Mecanorreceptores/metabolismo , Células de Merkel/metabolismo , Norepinefrina/farmacología , Propanolaminas/farmacología , Sinapsis/metabolismo , Vibrisas/efectos de los fármacos , Vías Aferentes/efectos de los fármacos , Vías Aferentes/metabolismo , Animales , Folículo Piloso/efectos de los fármacos , Células de Merkel/efectos de los fármacos , Sinapsis/efectos de los fármacos
10.
PLoS One ; 14(4): e0213847, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30990818

RESUMEN

Bioengineering, which studies the principles and design of biological systems, is a field that has inspired the development of several technologies that are currently in use. In this work, we use concepts from the fish lateral line sensing mechanism and apply them to seismic imaging processing. The lateral line is a sensory system composed of an integrated array of mechanical sensors spanning along the fish body. We compare the array of sensors along body fish with the seismic acquisition, which employs an array of equally spaced identical mechanical sensors to image the Earth's subsurface. In both situations, the mechanical sensors capture and process mechanical vibrations from the environment to produce useful information. We explore the strategy of using the low-pass and high-pass sensors schema of fish lateral line to improve the seismic technique. We use the full-wave inversion method to compare the conventional acquisition procedure of identical sensors with alternative sets of different sensors, which mimics the fish lateral line. Our results show that the alternate sensors arrangement surpasses the performance of the conventional acquisition method, using just half of the input information. The results point at an image processing technique that is computationally more efficient and economical than the usual seismic processing method.


Asunto(s)
Bioingeniería/métodos , Desastres/prevención & control , Terremotos , Monitoreo del Ambiente/instrumentación , Mecanorreceptores/fisiología , Animales , Monitoreo del Ambiente/métodos , Diseño de Equipo , Peces/fisiología , Geografía , Procesamiento de Imagen Asistida por Computador , Sistema de la Línea Lateral/citología , Sistema de la Línea Lateral/fisiología , Sistemas Microelectromecánicos
11.
Proc Natl Acad Sci U S A ; 116(15): 7343-7352, 2019 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-30918125

RESUMEN

Mechanoreceptive organelles (MOs) are specialized subcellular entities in mechanoreceptors that transform extracellular mechanical stimuli into intracellular signals. Their ultrastructures are key to understanding the molecular nature and mechanics of mechanotransduction. Campaniform sensilla detect cuticular strain caused by muscular activities or external stimuli in Drosophila Each campaniform sensillum has an MO located at the distal tip of its dendrite. Here we analyzed the molecular architecture of the MOs in fly campaniform mechanoreceptors using electron microscopic tomography. We focused on the ultrastructural organization of NompC (a force-sensitive channel) that is linked to the array of microtubules in these MOs via membrane-microtubule connectors (MMCs). We found that NompC channels are arranged in a regular pattern, with their number increasing from the distal to the proximal end of the MO. Double-length MMCs in nompC 29+29ARs confirm the ankyrin-repeat domain of NompC (NompC-AR) as a structural component of MMCs. The unexpected finding of regularly spaced NompC-independent linkers in nompC 3 suggests that MMCs may contain non-NompC components. Localized laser ablation experiments on mechanoreceptor arrays in halteres suggest that MMCs bear tension, providing a possible mechanism for why the MMCs are longer when NompC-AR is duplicated or absent in mutants. Finally, mechanical modeling shows that upon cuticular deformation, sensillar architecture imposes a rotational activating force, with the proximal end of the MO, where more NOMPC channels are located, being subject to larger forces than the distal end. Our analysis reveals an ultrastructural pattern of NompC that is structurally and mechanically optimized for the sensory functions of campaniform mechanoreceptors.


Asunto(s)
Proteínas de Drosophila , Mecanorreceptores , Mecanotransducción Celular , Orgánulos , Canales Receptores Transitorios de Potencial , Animales , Membrana Celular/química , Membrana Celular/genética , Membrana Celular/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Mecanorreceptores/química , Mecanorreceptores/metabolismo , Microtúbulos/química , Microtúbulos/metabolismo , Orgánulos/química , Orgánulos/genética , Orgánulos/metabolismo , Canales Receptores Transitorios de Potencial/química , Canales Receptores Transitorios de Potencial/genética , Canales Receptores Transitorios de Potencial/metabolismo
12.
Neuron ; 102(2): 407-419.e8, 2019 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-30824353

RESUMEN

Foraging strategies emerge from genetically encoded programs that are similar across animal species. Here, we examine circuits that control a conserved foraging state, local search behavior after food removal, in Caenorhabditis elegans. We show that local search is triggered by two parallel groups of chemosensory and mechanosensory glutamatergic neurons that detect food-related cues. Each group of sensory neurons suppresses distinct integrating neurons through a G protein-coupled metabotropic glutamate receptor, MGL-1, to release local search. The chemosensory and mechanosensory modules are separate and redundant; glutamate release from either module can drive the full behavior. A transition from local search to global search over several minutes after food removal is associated with two changes in circuit function. First, the spontaneous activity of sensory neurons falls. Second, the motor pattern generator for local search becomes less responsive to sensory input. This multimodal, distributed short-term food memory provides robust control of an innate behavior.


Asunto(s)
Conducta Apetitiva/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Células Quimiorreceptoras/metabolismo , Mecanorreceptores/metabolismo , Neuronas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Caenorhabditis elegans , Conducta Alimentaria , Neuronas/fisiología
13.
Microscopy (Oxf) ; 68(3): 207-215, 2019 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-30860586

RESUMEN

The touch domes of mammalian hairy skin are mechanoreceptors characterized by the accumulation of Merkel cell-neurite complexes at the epidermal base. In this study, we examined the shape, size, and density of the touch dome of human skin of the forearm and the abdomen through scanning electron microscopy (SEM). Human skin samples were obtained from donated bodies, as well as a patient who underwent biopsy. Skin pieces were treated with a KOH-collagenase method for the separation of the epidermis from the dermis. The basal surface of the separated epidermis was then observed using SEM. The touch dome was clearly determined as a concave area bordered by a thick epidermal ridge, where neural components accumulated. The touch dome was rather independent from hair follicles, although they were sometimes located beside the touch dome. The average size and density of the touch dome were 0.06 mm2 and 3.82 cm2 in the forearm, and 0.10 mm2 and 1.30 cm2 in the abdomen, respectively. Our results suggested that the regional difference in size and density of the touch dome might be related to the sensation's sensitivity as touch spots in human hairy skin.


Asunto(s)
Mecanorreceptores/ultraestructura , Células de Merkel/ultraestructura , Microscopía Electrónica de Rastreo/métodos , Piel/ultraestructura , Tacto/fisiología , Abdomen , Anciano , Femenino , Antebrazo , Humanos , Masculino , Persona de Mediana Edad , Piel/anatomía & histología
14.
J Mol Histol ; 50(3): 229-237, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30927131

RESUMEN

At present, a few studies have been done on the changes in the distribution, morphology and quantity of mechanoreceptors in anterior cruciate ligament (ACL) with age. In this study, we observed the changes in mechanoreceptors of healthy rabbits' ACL with age. We found that rabbits' ACLs contained 5 kinds of mechanoreceptors including Ruffini corpuscles, Pacinian corpuscles, Golgitendon bodies, free nerve endings and atypical mechanoreceptors. In each ACL, free nerve endings were the most followed by Ruffini corpuscles, Pacinian corpuscles, Golgitendon bodies and atypical mechanoreceptors in the younger than one-old rabbits. Most of the mechanoreceptors were distributed in the synovium near the attachment points of ACL with the femur and tibia. The total quantity of mechanoreceptors were the most in the 3- and 6-month groups, but did not show a significant difference between the two group (P > 0.05). However, there were significant differences in the total quantity of mechanoreceptors between other groups (all P < 0.05). RT-PCR indicated that NEFM and S100B levels increased with age, and reached a peak in the 1-year group with significant differences as compared to other groups. NEFM and S100B levels were the second in 6-month and 2-year groups and the lowest in the 1-week group. We can conclude that in rabbits' ACLs, free nerve endings are the most common, followed by Ruffini corpuscles, Pacinian corpuscles and Golgitendon bodies. The total quantity of mechanoreceptors reaches a peak in 3 months, while NEFM and S100B reach a peak in 1 year.


Asunto(s)
Envejecimiento/genética , Proteínas de Neurofilamentos/genética , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Tibia/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Ligamento Cruzado Anterior/metabolismo , Ligamento Cruzado Anterior/patología , Modelos Animales de Enfermedad , Humanos , Mecanorreceptores/metabolismo , Conejos , Tibia/patología
15.
Mol Biol Cell ; 30(10): 1182-1197, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30865562

RESUMEN

Previously, we had shown that high magnitude stretch (HMS), rather than low magnitude stretch (LMS), induced significant apoptosis of skeletal muscle C2C12 myoblasts. However, the molecular mechanism remains obscure. In this study, we found that p53 protein accumulated in the nucleus of LMS-loaded cells, whereas it translocated into mitochondria of HMS-loaded cells. Knocking down endogenous p53 by shRNA abrogated HMS-induced apoptosis. Furthermore, we demonstrated that overaccumulation of reactive oxygen species (ROS) during HMS-inactivated AKT that was activated in LMS-treated cells, which accounted for the distinct p53 subcellular localizations under HMS and LMS. Blocking ROS generation by N-acetylcysteine (NAC) or overexpressing constitutively active AKT vector (CA-AKT) inhibited HMS-incurred p53 mitochondrial translocation and promoted its nuclear targeting. Moreover, both NAC and CA-AKT significantly attenuated HMS-induced C2C12 apoptosis. Finally, we found that Ser389 phosphorylation of p53 was a downstream event of ROS-inactivated AKT pathway, which was critical to p53 mitochondrial trafficking during HMS stimuli. Transfecting p53-shRNA C2C12s with the mutant p53 (S389A) that was unable to target p53 to mitochondria underwent significantly lower apoptosis than transfection with wild-type p53. Altogether, our study uncovered that mitochondrial localization of p53, resulting from p53 Ser389 phosphorylation through ROS-inactivated AKT pathway, prompted C2C12 myoblast apoptosis during HMS stimulation.


Asunto(s)
Mioblastos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/fisiología , Línea Celular , Humanos , Mecanorreceptores/metabolismo , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Fosforilación , Transducción de Señal
16.
Am J Physiol Renal Physiol ; 316(6): F1103-F1113, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-30908933

RESUMEN

Neural mechanisms of lower urinary tract symptoms in obstruction-induced bladder overactivity remain unclear. We made the first single unit recordings from different types of spinal afferents to determine the effects of bladder outlet obstruction in guinea pigs. A model of gradual bladder outlet obstruction in male guinea pigs was used to produce overactive bladder. Conscious voiding was assessed in metabolic cages, and micturition was recorded in anesthetized guinea pigs in vivo. Single unit extracellular recordings were made ex vivo from spinal afferent nerves in flat sheet preparations of the bladder. Guinea pigs with partially obstructed bladders showed a significant increase in conscious voiding frequency compared with sham-operated guinea pigs. Also, nonvoiding contractions increased significantly in both frequency and amplitude. Although spontaneous firing of low-threshold bladder afferents was increased, their stretch-induced firing was reduced. The proportion of capsaicin-sensitive low-threshold afferents increased in obstructed bladders. Interestingly, spontaneous and stretch-induced firing were both significantly increased in high-threshold afferents after obstruction. In summary, sensory signaling increased in the obstructed bladder during the filling phase. This is largely mediated by low-threshold stretch-sensitive afferents that are activated by increased local nonvoiding contractions. Increased spontaneous firing by high-threshold afferents also contributes. Our findings revealed a complex effect of bladder outlet obstruction on different types of bladder afferents that needs consideration for potential therapeutic targeting of lower urinary tract symptoms in obstruction-induced bladder overactivity.


Asunto(s)
Nervios Espinales/fisiopatología , Obstrucción del Cuello de la Vejiga Urinaria/complicaciones , Vejiga Urinaria Hiperactiva/etiología , Vejiga Urinaria/inervación , Urodinámica , Potenciales de Acción , Vías Aferentes/metabolismo , Vías Aferentes/fisiopatología , Animales , Modelos Animales de Enfermedad , Cobayas , Masculino , Mecanorreceptores/metabolismo , Umbral Sensorial , Nervios Espinales/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/fisiopatología , Micción
17.
Pain ; 160(5): 1146-1155, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30920428

RESUMEN

Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. In nerve-injured rats, oxytocin depolarized LTMRs towards normal (Em = -69 ± 1.9 mV) and, in 6 of 21 neurons, resulted in spontaneous action potentials. By contrast, oxytocin hyperpolarized HTMRs (Em = -68 ± 2.7 mV before vs -80 ± 3.2 mV during oxytocin exposure; P < 0.01). These effects were reversed after removal of oxytocin, and oxytocin had minimal effects in neurons from sham surgery animals. Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 µm, range 16-57 µm) than immunonegative neurons (26 ± 3.4 µm, range 15-43 µm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.


Asunto(s)
Ganglios Espinales/patología , Nociceptores/efectos de los fármacos , Oxitocina/uso terapéutico , Traumatismos de los Nervios Periféricos/patología , Células Receptoras Sensoriales/efectos de los fármacos , Tacto , Potenciales de Acción/efectos de los fármacos , Vías Aferentes/fisiopatología , Animales , Modelos Animales de Enfermedad , Estimulación Eléctrica , Femenino , Mecanorreceptores/efectos de los fármacos , Nociceptores/fisiología , Oxitocina/farmacología , Umbral del Dolor/efectos de los fármacos , Traumatismos de los Nervios Periféricos/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de Vasopresinas/metabolismo , Células Receptoras Sensoriales/fisiología
18.
Bioinspir Biomim ; 14(3): 035003, 2019 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-30856616

RESUMEN

Aquatic animals commonly sense flow using superficial neuromasts (SNs), which are receptors that extend from the body's surface. The lateral line of fishes is unique among these systems because it additionally possesses receptors, the canal neuromasts (CNs), that are recessed within a channel. The lateral line has inspired the development of engineered sensors and concepts in the analysis of flow fields for submersible navigation. The biophysics of CNs are known to be different from the SNs and thereby offer a distinct submodality. However, it is generally unclear whether CNs play a distinct role in behavior. We therefore tested whether CNs enhance foraging in the dark by zebrafish (Danio rerio), a behavior that we elicited with a vibrating rod. We found that juvenile fish, which have only SNs, bite at this rod at about one-third the rate and from as little as one-third the distance of adults for a high-frequency stimulus (50 < f  < 100 Hz). We used novel techniques for manipulating the lateral line in adults to find that CNs offered only a modest benefit at a lower frequency (20 Hz) and that foraging was mediated entirely by cranial neuromasts. Consistent with our behavioral results, biophysical models predicted CNs to be more than an order of magnitude more sensitive than SNs at high frequencies. This enhancement helps to overcome the rapid spatial decay in high-frequency components in the flow around the stimulus. These findings contrast what has been previously established for fishes that are at least ten-times the length of zebrafish, which use trunk CNs to localize prey. Therefore, CNs generally enhance foraging, but in a manner that varies with the size of the fish and its prey. These results have the potential to improve our understanding of flow sensing in aquatic animals and engineered systems.


Asunto(s)
Conducta Alimentaria/fisiología , Sistema de la Línea Lateral/fisiología , Mecanorreceptores/fisiología , Percepción/fisiología , Pez Cebra/fisiología , Animales , Sistema de la Línea Lateral/anatomía & histología , Pez Cebra/anatomía & histología
19.
Am J Physiol Gastrointest Liver Physiol ; 316(4): G473-G481, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30702901

RESUMEN

Visceral pain is one of the principal complaints of patients with irritable bowel syndrome, and this pain is reliably evoked by mechanical distension and stretch of distal colon and rectum (colorectum). This study focuses on the biomechanics of the colorectum that could play critical roles in mechanical neural encoding. We harvested the distal 30 mm of the colorectum from mice, divided evenly into three 10-mm-long segments (colonic, intermediate and rectal), and conducted biaxial mechanical stretch tests and opening-angle measurements for each tissue segment. In addition, we determined the collagen fiber orientations and contents across the thickness of the colorectal wall by nonlinear imaging via second harmonic generation (SHG). Our results reveal a progressive increase in tissue compliance and prestress from colonic to rectal segments, which supports prior electrophysiological findings of distinct mechanical neural encodings by afferents in the lumbar splanchnic nerves (LSN) and pelvic nerves (PN) that dominate colonic and rectal innervations, respectively. The colorectum is significantly more viscoelastic in the circumferential direction than in the axial direction. In addition, our SHG results reveal a rich collagen network in the submucosa and orients approximately ±30° to the axial direction, consistent with the biaxial test results presenting almost twice the stiffness in axial direction versus the circumferential direction. Results from current biomechanical study strongly indicate the prominent roles of local tissue biomechanics in determining the differential mechanical neural encoding functions in different regions of the colorectum. NEW & NOTEWORTHY Mechanical distension and stretch-not heat, cutting, or pinching-reliably evoke pain from distal colon and rectum. We report different local mechanics along the longitudinal length of the colorectum, which is consistent with the existing literature on distinct mechanotransduction of afferents innervating proximal and distal regions of the colorectum. This study draws attention to local mechanics as a potential determinant factor for mechanical neural encoding of the colorectum, which is crucial in visceral nociception.


Asunto(s)
Colon , Síndrome del Colon Irritable/fisiopatología , Recto , Nervios Esplácnicos/fisiopatología , Dolor Visceral , Animales , Fenómenos Biomecánicos , Colon/inervación , Colon/patología , Colon/fisiopatología , Modelos Animales de Enfermedad , Región Lumbosacra/inervación , Mecanorreceptores , Ratones , Pelvis/inervación , Recto/inervación , Recto/patología , Recto/fisiopatología , Microscopía de Generación del Segundo Armónico/métodos , Dolor Visceral/etiología , Dolor Visceral/fisiopatología
20.
eNeuro ; 6(1)2019.
Artículo en Inglés | MEDLINE | ID: mdl-30783617

RESUMEN

Low-threshold mechanosensitive C fibers (C-LTMRs) that express the vesicular glutamate transporter VGLUT3 are thought to signal affective touch, and may also play a role in mechanical allodynia. However, the nature of the central termination of C-LTMRs in the dorsal horn remains largely unexplored. Here, we used light and electron microscopy in combination with VGLUT3 immunolabeling as a marker of C-LTMR terminations to investigate this issue. VGLUT3+ C-LTMRs formed central terminals of Type II glomeruli in the inner part of lamina II of the dorsal horn, often establishing multiple asymmetric synapses with postsynaptic dendrites but also participating in synaptic configurations with presynaptic axons and dendrites. Unexpectedly, essentially all VGLUT3+ C-LTMR terminals showed substantial VGLUT1 expression in the rat, whereas such terminals in mice lacked VGLUT1. Most VGLUT3+ C-LTMR terminals exhibited weak-to-moderate VGLUT2 expression. Further, C-LTMR terminals formed numerous synapses with excitatory protein kinase Cγ (PKCγ) interneurons and inhibitory parvalbumin neurons, whereas synapses with calretinin neurons were scarce. C-LTMR terminals rarely if ever established synapses with neurokinin 1 receptor (NK1R)-possessing dendrites traversing lamina II. Thus, VGLUT3+ C-LTMR terminals appear to largely correspond to neurofilament-lacking central terminals of Type II glomeruli in inner lamina II and can thus be identified at the ultrastructural level by morphological criteria. The participation of C-LTMR terminals in Type II glomeruli involving diverse populations of interneuron indicates highly complex modes of integration of C-LTMR mediated signaling in the dorsal horn. Furthermore, differences in VGLUT1 expression indicate distinct species differences in synaptic physiology of C-LTMR terminals.


Asunto(s)
Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Mecanorreceptores/citología , Fibras Nerviosas Amielínicas/metabolismo , Médula Espinal/citología , Sinapsis/metabolismo , Proteínas de Transporte Vesicular de Glutamato/metabolismo , Animales , Femenino , Expresión Génica , Proteínas de Andamiaje Homer/metabolismo , Masculino , Mecanorreceptores/metabolismo , Ratones Endogámicos C57BL , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo
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