Afferent Innervation Research Articles

A5662 Effects of Neurogenic CGRP on Renal Afferent Peptidergic Neurons

Objectives: Although release of the proinflammatory vasodilator CGRP from peptidergic afferent nerves is unquestioned it is not known if released neurogenic CGRP will affect renal afferent innervation in return thus influencing sympathetic activity e.g. in hypertension. Hence we wanted to test the hypothesis that CGRP elicits action potential production related to TRPV1 receptor stimulation in cultured renal neurons. Methods: Cultured dorsal root ganglion neurons (Th11-L2) of rats with renal afferents were investigated in current clamp mode to asses action potential generation or in voltage clamp mode to investigate inward currents during stimulation of TRPV1 receptors with acid of pH 6 (−80 mV holding voltage) and/or administration of CGRP (0,5 μmol). Furthermore, renal slices were incubated to study CGRP release due to TRPV1 receptor stimulation. (CGRP concentrations assessed in organ bath). Results: More than 90 DRG neurons with renal afferents were tested. Addition of CGRP did not change action potential generation nor inward currents. Proton stimulation (ph 6) of TRPV1 markedly increased long-term inward currents (baseline −361,7 +/− 89,6 pA vs. −1393,3+/−337,3* pA, p < 0,05, mean +/- SEM). The co-stimulation of renal neurons with protons (pH 6) and CGRP impaired sustained inward current as compared to proton stimulation alone (baseline −478,2 +/−54,4 pA vs. −767,6+/−89,6* pA, p < 0,05). CGRP release of renal slices increased significantly after TRPV1 receptor stimulation (on average: 21+/−4 pg/ml CGRP). Conclusion: In contrast to our hypothesis CGRP could not elicit action potentials in afferent neurons related to the kidney but even impaired electric currents in general after TRPV1 receptor stimulation. Hence, renal CGRP secretion from peptidergic afferent nerves might decrease further neuronal CGRP release.

The metabolic role of vagal afferent innervation.

The regulation of energy and glucose balance contributes to whole-body metabolic homeostasis, and such metabolic regulation is disrupted in obesity and diabetes. Metabolic homeostasis is orchestrated partly in response to nutrient and vagal-dependent gut-initiated functions. Specifically, the sensory and motor fibres of the vagus nerve transmit intestinal signals to the central nervous system and exert biological and physiological responses. In the past decade, the understanding of the regulation of vagal afferent signals and of the associated metabolic effect on whole-body energy and glucose balance has progressed. This Review highlights the contributions made to the understanding of the vagal afferent system and examines the integrative role of the vagal afferent in gastrointestinal regulation of appetite and glucose homeostasis. Investigating the integrative and metabolic role of vagal afferent signalling represents a potential strategy to discover novel therapeutic targets to restore energy and glucose balance in diabetes and obesity.

Cutaneous afferent innervation of the human foot sole: what can we learn from single-unit recordings?

Cutaneous afferents convey exteroceptive information about the interaction of the body with the environment and proprioceptive information about body position and orientation. Four classes of low-threshold mechanoreceptor afferents innervate the foot sole and transmit feedback that facilitates the conscious and reflexive control of standing balance. Experimental manipulation of cutaneous feedback has been shown to alter the control of gait and standing balance. This has led to a growing interest in the design of intervention strategies that enhance cutaneous feedback and improve postural control. The advent of single-unit microneurography has allowed the firing and receptive field characteristics of foot sole cutaneous afferents to be investigated. In this review, we consolidate the available cutaneous afferent microneurographic recordings from the foot sole and provide an analysis of the firing threshold, and receptive field distribution and density of these cutaneous afferents. This work enhances the understanding of the foot sole as a sensory structure and provides a foundation for the continued development of sensory augmentation insoles and other tactile enhancement interventions.

Sympatho-excitatory response to pulmonary chemosensitive spinal afferent activation in anesthetized, vagotomized rats.

The sensory innervation of the lung is well known to be innervated by nerve fibers of both vagal and sympathetic origin. Although the vagal afferent innervation of the lung has been well characterized, less is known about physiological effects mediated by spinal sympathetic afferent fibers. We hypothesized that activation of sympathetic spinal afferent nerve fibers of the lung would result in an excitatory pressor reflex, similar to that previously characterized in the heart. In this study, we evaluated changes in renal sympathetic nerve activity (RSNA) and hemodynamics in response to activation of TRPV1‐sensitive pulmonary spinal sensory fibers by agonist application to the visceral pleura of the lung and by administration into the primary bronchus in anesthetized, bilaterally vagotomized, adult Sprague‐Dawley rats. Application of bradykinin (BK) to the visceral pleura of the lung produced an increase in mean arterial pressure (MAP), heart rate (HR), and RSNA. This response was significantly greater when BK was applied to the ventral surface of the left lung compared to the dorsal surface. Conversely, topical application of capsaicin (Cap) onto the visceral pleura of the lung, produced a biphasic reflex change in MAP, coupled with increases in HR and RSNA which was very similar to the hemodynamic response to epicardial application of Cap. This reflex was also evoked in animals with intact pulmonary vagal innervation and when BK was applied to the distal airways of the lung via the left primary bronchus. In order to further confirm the origin of this reflex, epidural application of a selective afferent neurotoxin (resiniferatoxin, RTX) was used to chronically ablate thoracic TRPV1‐expressing afferent soma at the level of T1–T4 dorsal root ganglia pleura. This treatment abolished all sympatho‐excitatory responses to both cardiac and pulmonary application of BK and Cap in vagotomized rats 9–10 weeks post‐RTX. These data suggest the presence of an excitatory pulmonary chemosensitive sympathetic afferent reflex. This finding may have important clinical implications in pulmonary conditions inducing sensory nerve activation such as pulmonary inflammation and inhalation of chemical stimuli.

Sensory evoked cortical potentials of the lower urinary tract in healthy men.

To assess the afferent innervation of various locations in the male lower urinary tract (LUT) using sensory evoked cortical potentials (SEPs). Twelve healthy men (mean age: 29.6 ± 7.2 years, mean height: 1.8 ± 0.1 m) underwent repetitive slow (0.5 Hz/1 ms) and fast (3 Hz/0.2 ms) electrical stimulations of bladder (dome/trigone) and urethral (proximal/membranous/distal) locations with simultaneous cortical SEP recording (Cz-Fz). Latencies (ms) and peak-to-peak amplitudes (μV) for SEP components P1, N1, and P2 were analyzed. Tibial SEPs were assessed as methodological control. The reproducibility was investigated from between visits and inter-rater assessments using Bland-Altman plots. Statistical tests comprised analysis of variance (ANOVA), linear regressions, and paired t-tests. Values are given as mean ± standard deviation. Typical LUTSEPs with P1, N1, and P2 components were successfully detected (100% responder rate) for slow but less successfully for fast stimulation. The slow stimulation provided reproducible LUTSEPs with position specific N1 latencies: dome 125.6 ± 21.3 ms, trigone 122.9 ± 20.5 ms, proximal- 116.1 ± 21.4 ms, membraneous- 118.8 ± 29.3 ms, and distal urethra 108.8 ± 17.8 ms. Despite good inter-rater agreement, latency variability between and within subjects was higher for LUTSEPs than for tibial SEPs. N1 latencies became shorter (P < 0.01) with increasing subject age for bladder dome and distal urethra stimulation. LUTSEPs can be successfully obtained for different LUT locations in men using slow electrical stimulation. Location specific differences in N1 latencies may indicate different local afferent innervation. Larger variability of LUTSEPs versus tibial SEPs may be related to the more challenging approach and afferent fibre access within the LUT. Further studies optimizing measurement and analysis approach are required.

Directional selectivity of afferent neurons in zebrafish neuromasts is regulated by Emx2 in presynaptic hair cells.

The orientation of hair bundles on top of sensory hair cells (HCs) in neuromasts of the lateral line system allows fish to detect direction of water flow. Each neuromast shows hair bundles arranged in two opposing directions and each afferent neuron innervates only HCs of the same orientation. Previously, we showed that this opposition is established by expression of Emx2 in half of the HCs, where it mediates hair bundle reversal (<xref ref-type="bibr" rid="bib15">Jiang et al., 2017</xref>). Here, we show that Emx2 also regulates neuronal selection: afferent neurons innervate either Emx2-positive or negative HCs. In emx2 knockout and gain-of-function neuromasts, all HCs are unidirectional and the innervation patterns and physiological responses of the afferent neurons are dependent on the presence or absence of Emx2. Our results indicate that Emx2 mediates the directional selectivity of neuromasts by two distinct processes: regulating hair bundle orientation in HCs and selecting afferent neuronal targets.

The chemorepellent draxin is involved in hippocampal mossy fiber projection

Lamina-specific afferent innervation of the mammalian hippocampus is critical for its function. We investigated the relevance of the chemorepellent draxin to the laminar projections of three principal hippocampal afferents: mossy fibers, entorhinal, and associational/commissural fibers. We observed that draxin deficiency led to abnormal projection of mossy fibers but not other afferents. Immunohistochemical analysis indicated that draxin is expressed in the dentate gyrus and cornu ammonis (CA) 3 at postnatal day 0, when dentate granule cells begin to extend mossy fibers towards CA3. Furthermore, a neurite growth assay using dissociated cells of the neonatal dentate gyrus revealed that draxin inhibited the growth of calbindin-D28k-expressing mossy fibers in vitro. Taken together, we conclude that draxin is a key molecule in the regulation of mossy fiber projections.

Single Cell Gene Expression Analysis and 3‐D Mapping of Cardiac Ganglia

The intrinsic nervous system within the heart influences cardiac function at both physiological and molecular levels. The human cardiac ganglionic innervation organized into functionally distinct ganglia is composed of 14,000 neurons. Recent studies suggest that ganglia work together in an interaction network to control cardiac function. It has been shown that cardiac neurons are functionally heterogeneous and that the specific neuronal network that influences each neuron can also be broadly heterogeneous. Functional understanding of the complexity within cardiac intrinsic nervous system and its communication to and from the autonomic centers of the central nervous system is incomplete. Additionally, there is sparse knowledge of the spatial organization of these neuronal phenotypes within and among cardiac ganglia.In this study we aim to identify distinct spatially organized neuronal transcriptional phenotypes with high resolution using a novel combination of immunohistochemistry ‐ labeling and 3‐D reconstruction of the whole rat heart along with transcriptomic data of single neuron samples collected from rat hearts. Block face imaging of several rat hearts along with cresyl‐violet stained sections is being used to construct a 3‐D atlas of the rat heart with ontological information and spatial neuronal locational information (in collaboration with MBF Biosciences). We are collecting single neurons as well as neuron pools (comprising of 5 or 10 cells) using Laser Capture Microdissection from rat hearts. These samples are being processed for transcriptome analysis (multiplexed RNA‐seq). We are using BioMark multiplex RT‐qPCR system to validate our transcriptional data obtained from RNA Seq. Transcriptional data along with spatial location of hundreds neurons per heart thus obtained will enable us to map molecular profiles of cardiac ganglia heterogeneity.We have demonstrated the ability to identify molecular phenotypes of neurons through preliminary examination of ~250 laser captured neurons using multiplex RT‐qPCR. We have also generated a more targeted list of cardiac ganglia specific genes through microarray experiments comparing neuron‐enriched sections of the heart with unenriched myocardium. Multiplexed RT‐qPCR data shows distinct molecular phenotypes emerge even with consideration of only ~40 genes. We were able to identify dopaminergic, catecholaminergic, and two types of cholinergic neurons from these data. Within each larger phenotype there exists heterogeneity of transcriptional states that support the need for further investigation.Along with circuit relevance of ganglia projections we will be able to generate a cardiac neuro‐reference framework atlas with neuronal distribution, density of innervation, receptive (sensory) or motor fields and terminal structures of axons from different peripheral ganglia and vagal nuclei. Our study will provide a new holistic view of vagal and spinal afferent, autonomic efferent (sympathetic and parasympathetic), and cardiac ganglionic innervation of the heart in 3‐D whole heart qualitatively and quantitatively.Support or Funding InformationSPARC‐OT2‐OD023848This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Neurogenic CGRP on Renal Afferent Peptidergic Neurons

Although release of the proinflammatory vasodilator CGRP from peptidergic afferent nerves is generally unquestioned the matter is far less investigated with respect to afferent renal innvervation that is said to be involved in sympathetic control and blood pressure regulation. Furthermore, it is not known in how far released neurogenic CGRP will affect renal afferent innervation in return. Hence we wanted to test the hypothesis that CGRP elicits action potential production related to TRPV1 receptor stimulation in cultured neurons with afferent projections from the kidney in vivo.Cultured dorsal root ganglion neurons (Th11‐L2) of rats with renal afferents in vivo were investigated in current clamp mode to asses action potential generation or in voltage clamp mode to investigate inward currents during stimulation of TRPV1 receptors with acid of pH 6 (−80 mV holding voltage) and/or administration of CGRP (0,5 μmol). Furthermore, renal slices were incubated during baseline, experimental stimulation period and recovery to study CGRP release due to TRPV1 receptor stimulation (capsaicin 10−6 M, increased proton concentrations). CGRP concentrations in the organ bath were assessed with a commercial kit. Capsazepine was used for TRPV1 receptor blockadeMore than 90 DRG neurons with renal afferents were tested. Addition of CGRP did not change action potential generation nor inward currents. Proton stimulation (ph 6) of TRPV1 markedly increased long‐term inward currents (baseline −361,7 +/− 89,6 pA vs. −1393,3+/−337,3 pA, p&lt;0,05, mean +/− SEM). The co‐stimulation of renal neurons with protons (pH 6) and CGRP led to an impairment of sustained inward current as compared to proton stimulation alone (baseline − 478,2 +/−54,4 pA vs. −767,6+/−89,6 pA, p&lt;0,05, mean +/− SEM). Baseline CGRP release of renal slices (2.5 to 6 pg/ml) increased significantly after TRPV1 receptor stimulation (on average: 21+4 pg/ml CGRP).In contrast to our hypothesis CGRP could not elicit action potentials in afferent neurons related to the kidney but even impaired electric currents in general after TRPV1 receptor stimulation. Hence, renal CGRP secretion from peptidergic afferent nerves might decrease further neuronal CGRP release.Support or Funding InformationDFG Deutsche Forschungsgemeinschaft VE 104/4‐1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Organization of afferents to the orbitofrontal cortex in the rat.

The prefrontal cortex (PFC) is usually defined as the frontal cortical area receiving a mediodorsal thalamic (MD) innervation. Certain areas in the medial wall of the rat frontal area receive a MD innervation. A second frontal area that is the target of MD projections is located dorsal to the rhinal sulcus and often referred to as the orbitofrontal cortex (OFC). Both the medial PFC and OFC are comprised of a large number of cytoarchitectonic regions. We assessed the afferent innervation of the different areas of the OFC, with a focus on projections arising from the mediodorsal thalamic nucleus, the basolateral nucleus of the amygdala, and the midbrain dopamine neurons. Although there are specific inputs to various OFC areas, a simplified organizational scheme could be defined, with the medial areas of the OFC receiving thalamic inputs, the lateral areas of the OFC being the recipient of amygdala afferents, and a central zone that was the target of midbrain dopamine neurons. Anterograde tracer data were consistent with this organization of afferents, and revealed that the OFC inputs from these three subcortical sites were largely spatially segregated. This spatial segregation suggests that the central portion of the OFC (pregenual agranular insular cortex) is the only OFC region that is a prefrontal cortical area, analogous to the prelimbic cortex in the medial prefrontal cortex. These findings highlight the heterogeneity of the OFC, and suggest possible functional attributes of the three different OFC areas.

Charcot spinal arthropathy.

Charcot spinal arthropathy (CSA) is a rare progressive disorder of vertebral joint degeneration that occurs in the setting of any condition characterized by decreased afferent innervation with loss of deep pain and proprioceptive sensation in the vertebral column. While surgical circumferential arthrodesis remains the most effective treatment modality, it is associated with multiple complications, including hardware construct failure. This manuscript represents an up-to-date narrative review of the treatment of CSA, its associated complications, and complication prevention.

Tyrosine hydroxylase and/or rBAT positive neuron in primary afferent innervates in the nucleus tractus solitarii

Tyrosine hydroxylase and/or rBAT positive neuron in primary afferent innervates in the nucleus tractus solitarii

Distinct Expression of Phenotypic Markers in Placodes- and Neural Crest-Derived Afferent Neurons Innervating the Rat Stomach.

Visceral pain is initiated by activation of primary afferent neurons among which the capsaicin-sensitive (TRPV1-positive) neurons play an important role. The stomach is a common source of visceral pain. Similar to other organs, the stomach receives dual spinal and vagal afferent innervation. Developmentally, spinal dorsal root ganglia (DRG) and vagal jugular neurons originate from embryonic neural crest and vagal nodose neurons originate from placodes. In thoracic organs the neural crest- and placodes-derived TRPV1-positive neurons have distinct phenotypes differing in activation profile, neurotrophic regulation and reflex responses. It is unknown to whether such distinction exists in the stomach. We hypothesized that gastric neural crest- and placodes-derived TRPV1-positive neurons express phenotypic markers indicative of placodes and neural crest phenotypes. Gastric DRG and vagal neurons were retrogradely traced by DiI injected into the rat stomach wall. Single-cell RT-PCR was performed on traced gastric neurons. Retrograde tracing demonstrated that vagal gastric neurons locate exclusively into the nodose portion of the rat jugular/petrosal/nodose complex. Gastric DRG TRPV1-positive neurons preferentially expressed markers PPT-A, TrkA and GFRα3 typical for neural crest-derived TRPV1-positive visceral neurons. In contrast, gastric nodose TRPV1-positive neurons preferentially expressed markers P2X2 and TrkB typical for placodes-derived TRPV1-positive visceral neurons. Differential expression of neural crest and placodes markers was less pronounced in TRPV1-negative DRG and nodose populations. There are phenotypic distinctions between the neural crest-derived DRG and placodes-derived vagal nodose TRPV1-positive neurons innervating the rat stomach that are similar to those described in thoracic organs.

Hydrodissection of Wiltse's Plane to Facilitate Exposure During Minimally Invasive Transforaminal Lumbar Interbody Fusion.

Traditional posterior lumbar approaches in a transforaminal lumbar interbody fusion (TLIF) require subperiosteal dissection of bilateral paraspinal muscles to provide adequate exposure. This may traumatize the multifidus muscle and its afferent innervations leading to postoperative paraspinal muscle atrophy. Minimizing such intraoperative trauma has been identified as an important factor in the reduction of postoperative lumbar pain. An approach via a blunt dissection through Wiltse’s plane, which lies between the longissimus and multifidus muscles, may minimize postoperative pain. Definition of this plane may be facilitated by local injection of 1% lidocaine within the plane itself, as well as in the musculature defining its borders.In this paper, we demonstrate this technique with a 55-year-old female patient who presented with left-sided radicular leg pain in an L5 distribution. Wiltse plane hydrodissection was utilized in performing an L4-5 TLIF. Ultrasound images of the patient’s sub-fascial musculature were obtained pre- and posthydrodissection to assess the elucidation of this plane through this technique. Intraoperative images were obtained following dissection of Wiltse’s plane to further illustrate the facilitation of exposure of Wiltse’s plane through hydrodissection. Postoperatively the patient did well citing a complete resolution of her radicular pain. She did not require intravenous (IV) pain medication, as her postoperative pain was well controlled with oral pain medication. She was mobilized on post-op day one, and discharged home on post-op day two with minimal back pain.Our initial experience supports the feasibility, safety, and effectiveness of hydrodissection of Wiltse’s plane to facilitate exposure during a minimally invasive TLIF and thereby reducing postoperative pain.

Acupuncture points can be identified as cutaneous neurogenic inflammatory spots

Acupuncture, a traditional medical procedure practised for over 2000 years in Asia, stimulates specific but poorly defined sites called acupoints. To date, no unique anatomical acupoint structures have been found. However, noxious sensory signals from visceral organs produce hypersensitive spots on the skin (neurogenic spots), caused by cutaneous neurogenic inflammation, in the dermatome that overlaps with visceral afferent innervations. Here, we show that an acupoint is one form of neurogenic inflammation on the skin. Various studies have demonstrated that acupoints show mechanical hypersensitivity and have high electrical conductance. Stimulation of acupoints produces needling sensations caused by the activation of small diameter afferent nerve fibres and therapeutic effects on the associated visceral organs, which is likely due to the release of endogenous opioids. The present study provides experimental evidence that neurogenic spots exhibit all the characteristics of the acupoints listed above. In addition, the stimulation of neurogenic spots by electrical, mechanical, or chemical means alleviated pathological conditions in rat colitis and hypertension models via the endogenous opioid system. Our results suggest that acupoints associated with internal organs may be identical to neurogenic inflammatory spots on the skin, which are produced by activation of somatic afferents in abnormal conditions of visceral organs.

Genetic loss of the muscarinic M3 receptor markedly alters bile formation and cholestatic liver injury in mice.

Hepatic innervation represents a potentially underestimated regulator of liver function and regeneration. The muscarinic 3 receptor (M3 -R) is the primary cholangiocyte receptor for the afferent parasympathetic innervation of bile ducts. We aimed to determine the specific role of the M3 -R in bile formation and models for cholestatic liver disease in mice. We compared bile flow and composition in M3 -R knock-out mice (M3 -R-/- ) and wild type littermates (WT). Furthermore, we compared liver inury of M3 -R-/- and WT mice after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding, a well-characterized preclinical model of cholestatic liver disease. To analyze the possible role of the M3 -R as a therapeutic target, we treated 4-week-old Mdr2-/- mice, a preclinical model for sclerosing cholangitis, with the M3 -R agonist bethanechol for 4 weeks. M3 -R-/- mice showed significantly reduced bile flow compared to WT mice, most likely due to decreased biliary HCO3- secretion. However, even aged M3 -R-/- mice did not spontaneously develop liver injury or cholestasis. Challenging M3 -R-/- and WT littermates with DDC feeding showed substantially aggravated liver injury in M3 -R-/- mice. After 4 weeks bethanechol treatment, Mdr2-/- mice showed less liver injury compared to controls. Our experimental findings suggest that M3 -R-signalling significantly influences bile formation. Loss of the M3 -R increases susceptibility to cholestatic injury in DDC-fed mice. Since treatment of Mdr2-/- mice with a M3 -R agonist decreases liver injury, M3-R signaling may represent a therapeutic target in specific cholangiopathies.

Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source.

See Basbaum (doi:10.1093/brain/awx227) for a scientific commentary on this article. Peripheral neuropathic pain arises as a consequence of injury to sensory neurons; the development of ectopic activity in these neurons is thought to be critical for the induction and maintenance of such pain. Local anaesthetics and anti-epileptic drugs can suppress hyperexcitability; however, these drugs are complicated by unwanted effects on motor, central nervous system and cardiac function, and alternative more selective treatments to suppress hyperexcitability are therefore required. Here we show that a glutamate-gated chloride channel modified to be activated by low doses of ivermectin (but not glutamate) is highly effective in silencing sensory neurons and reversing neuropathic pain-related hypersensitivity. Activation of the glutamate-gated chloride channel expressed in either rodent or human induced pluripotent stem cell-derived sensory neurons in vitro potently inhibited their response to both electrical and algogenic stimuli. We have shown that silencing is achieved both at nerve terminals and the soma and is independent of membrane hyperpolarization and instead likely mediated by lowering of the membrane resistance. Using intrathecal adeno-associated virus serotype 9-based delivery, the glutamate-gated chloride channel was successfully targeted to mouse sensory neurons in vivo, resulting in high level and long-lasting expression of the channel selectively in sensory neurons. This enabled reproducible and reversible modulation of thermal and mechanical pain thresholds in vivo; analgesia was observed for 3 days after a single systemic dose of ivermectin. We did not observe any motor or proprioceptive deficits and noted no reduction in cutaneous afferent innervation or upregulation of the injury marker ATF3 following prolonged glutamate-gated chloride channel expression. Established mechanical and cold pain-related hypersensitivity generated by the spared nerve injury model of neuropathic pain was reversed by ivermectin treatment. The efficacy of ivermectin in ameliorating behavioural hypersensitivity was mirrored at the cellular level by a cessation of ectopic activity in sensory neurons. These findings demonstrate the importance of aberrant afferent input in the maintenance of neuropathic pain and the potential for targeted chemogenetic silencing as a new treatment modality in neuropathic pain.

Multiscale mechanics of the cervical facet capsular ligament, with particular emphasis on anomalous fiber realignment prior to tissue failure.

The facet capsular ligaments encapsulate the bilateral spinal facet joints and are common sources of painful injury due to afferent innervation. These ligaments exhibit architectural complexity, which is suspected to contribute to the experimentally observed lack of co-localization between macroscopic strain and microstructural tissue damage. The heterogeneous and multiscale nature of this ligament, combined with challenges in experimentally measuring its microscale mechanics, hinders the ability to understand sensory mechanisms under normal or injurious loading. Therefore, image-based, subject-specific, multiscale finite-element models were constructed to predict the mechanical responses of the human cervical facet capsular ligament under uniaxial tensile stretch. The models precisely simulated the force-displacement responses for all samples ([Formula: see text]) and showed promise in predicting the magnitude and location of peak regional strains at two different displacements. Yet, there was a loss of agreement between the model and experiment in terms of fiber organization at large tissue stretch, possibly due to a lack of accounting for tissue failure. The mean fiber stretch ratio predicted by the models was found to be significantly higher in regions that exhibited anomalous fiber realignment experimentally than in regions with normal realignment ([Formula: see text]). The development of microstructural abnormalities was associated with the predicted fiber-level stretch ([Formula: see text]), but not with the elemental maximum principal stress or maximum principal strain by logistic regression. The multiscale models elucidate a potential mechanical basis for predicting injury-prone tissue domains and for defining the relationships between macroscopic ligament stretch and microscale pathophysiology in the subfailure regime.

Wnt9a Can Influence Cell Fates and Neural Connectivity across the Radial Axis of the Developing Cochlea.

Vertebrate hearing organs manifest cellular asymmetries across the radial axis that underlie afferent versus efferent circuits between the inner ear and the brain. Therefore, understanding the molecular control of patterning across this axis has important functional implications. Radial axis patterning begins before the cells become postmitotic and is likely linked to the onset of asymmetric expression of secreted factors adjacent to the sensory primordium. This study explores one such asymmetrically expressed gene, Wnt9a, which becomes restricted to the neural edge of the avian auditory organ, the basilar papilla, by embryonic day 5 (E5). Radial patterning is disrupted when Wnt9a is overexpressed throughout the prosensory domain beginning on E3. Sexes were pooled for analysis and sex differences were not studied. Analysis of gene expression and afferent innervation on E6 suggests that ectopic Wnt9a expands the neural-side fate, possibly by re-specifying the abneural fate. RNA sequencing reveals quantitative changes, not only in Wnt-pathway genes, but also in genes involved in axon guidance and cytoskeletal remodeling. By E18, these early patterning effects are manifest as profound changes in cell fates [short hair cells (HCs) are missing], ribbon synapse numbers, outward ionic currents, and efferent innervation. These observations suggest that Wnt9a may be one of the molecules responsible for breaking symmetry across the radial axis of the avian auditory organ. Indirectly, Wnt9a can regulate the mature phenotype whereby afferent axons predominantly innervate neural-side tall HCs, resulting in more ribbon synapses per HC compared with abneural-side short HCs with few ribbons and large efferent synapses.SIGNIFICANCE STATEMENT Wnts are a class of secreted factors that are best known for stimulating cell division in development and cancer. However, in certain contexts during development, Wnt-expressing cells can direct neighboring cells to take on specific fates. This study suggests that the Wnt9a ligand may play such a role in the developing hearing organ of the bird cochlea. This was shown through patterning defects that occur in response to the overexpression of Wnt9a. This manipulation increased one type of sensory hair cell (tall HCs) at the expense of another (short HCs) that is usually located furthest from the Wnt9a source. The extraneous tall HCs that replaced short HCs showed some physiological properties and neuronal connections consistent with a fate switch.

Physiopathologie de l’hypoactivité détrusorienne de la personne âgée

The aim of this study was to review the evidence regarding the pathophysiology of detrusor underactivity in the elderly. A literature review was conducted in July 2016 using the Medline/Pubmed database limiting the search to works in English or French. The prevalence of detrusor underactivity has been reported to range from 8% to 48% depending on the definition used and the age of the population studied. Current data suggest that aging may itself be a causative factor of detrusor underactivity through myogenic dysfunctions (ultrastructural degeneration of the detrusor muscle) and neurogenic dysfunctions (by degeneration of efferent but mostly afferent innervation mechanisms). Beyond these inherently age-related mechanisms, many comorbidities whose prevalence increase with age (diabetes, bladder outlet obstruction, estrogen deficiency, atherosclerosis, etc.) may be implicated in the development of detrusor underactivity in the elderly. The role played by detrusor overactivity in the appearance of detrusor underactivity must be considered separately as both seem to be the expression of the same condition of the lower urinary tract responding to different stages and secondary to numerous etiopathogenic factors which modulate its progression and clinical expressions. Pathophysiology of detrusor underactivity remains poorly understood but seems to imply myogenic and neurogenic factors which are favored, besides the aging per se, by various and numerous comorbidities which prevalence increase with age (diabetes, bladder outlet obstruction…).