Innocuous touch of the skin is detected by distinct populations of neurons, the low-threshold mechanoreceptors (LTMRs), which are classified as Aβ-, Aδ-, and C-LTMRs. Here, we report genetic labeling ...of LTMR subtypes and visualization of their relative patterns of axonal endings in hairy skin and the spinal cord. We found that each of the three major hair follicle types of trunk hairy skin (guard, awl/auchene, and zigzag hairs) is innervated by a unique and invariant combination of LTMRs; thus, each hair follicle type is a functionally distinct mechanosensory end organ. Moreover, the central projections of Aβ-, Aδ-, and C-LTMRs that innervate the same or adjacent hair follicles form narrow LTMR columns in the dorsal horn. These findings support a model of mechanosensation in which the activities of Aβ-, Aδ-, and C-LTMRs are integrated within dorsal horn LTMR columns and processed into outputs that underlie the perception of myriad touch sensations.
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► Genetic labeling reveals low-threshold mechanoreceptor circuitry in the mouse ► Low-threshold mechanoreceptors innervate hair follicles and form lanceolate endings ► Each hair follicle type displays a unique combination of mechanoreceptor endings ► Central endings of mechanoreceptors form columns in the spinal cord dorsal horn
Genetic labeling of neurons in the mouse skin enables visualization of touch circuits and shows that different types of hair follicles are innervated by a unique combination of mechanosensory neurons, suggesting that each hair follicle is a functionally distinct mechanosensory organ.
Partisan conflicts have been frequently analysed in comparative political science research. Yet little is known about the dimensions of political conflict at the local level in multi-level ...democracies. This article contributes to the literature on the estimation and analysis of party positions by first presenting a new dataset of more than 800 local party manifestos in Germany that allows for a systematic analysis of the dimensions of political conflict at the German local level. Secondly, it is demonstrated that (semi-)automatic content analysis of these texts offers a promising approach for gaining new insights into local party positions. Thirdly, the empirical analysis of German local party manifestos shows that partisan conflicts are not only structured along the left-right dimension but also along a dimension which distinguishes between parties addressing 'local' and 'national' issues to a varying degree in their manifestos, due to the different behaviour of established and populist parties.
•Developmental injury uniquely impacts neuroimmune communication.•Immature immune cells may retain cellular memories of aversive stimuli.•Data discussed highlights important advances and ongoing ...questions in the field.
A peripheral injury drives neuroimmune interactions at the level of the injury and throughout the neuraxis. Understanding these systems will be beneficial in the pursuit to target persistent pain that involves both neural and immune components. In this review, we discuss the impact of injury on the development of neuroimmune signaling, along with data that suggest a possible cellular immune memory. We also discuss the parallel effects of injury in the nervous system and immune related areas including bone marrow, lymph node and central nervous system-related cells. Finally, we relate these findings to patient populations and current research that evaluates human tissue.
The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box-binding ...homeobox 2 (Zeb2, also called Sip1) transcription factor is a critical intrinsic timer that controls the onset of SC differentiation by recruiting histone deacetylases HDAC 1 and 2 (HDAC1/2) and nucleosome remodeling and deacetylase complex (NuRD) co-repressor complexes in mice. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene encoding the Notch effector Hey2 as a potent inhibitor for Schwann cell differentiation. Strikingly, a genetic Zeb2 variant associated with Mowat-Wilson syndrome disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.
Hyaluronan (HA) is a glycosaminoglycan that consists of single‐chain polymers of disaccharide units of glucuronic acid and N‐acetylglucosamine. It is a chief constituent of the extracellular matrix. ...About 27% of the total HA in the body is expressed in the skeleton and connective tissue, while 8% is expressed in muscles. In physiological conditions, HA functions as a lubricant and viscoelastic shock absorber. Additionally, HA is part of complex cellular signaling which modulates nociception and inflammation. This study aims to understand the role that HA plays in the musculoskeletal system, specifically in muscles and the surrounding fascia. This review is also intended to further understand HA homeostasis and the process of its synthesis, degradation, and clearance from the local tissue. The authors examined muscle pain and stiffness as pathological conditions associated with HA accumulation.
•Overexpression of Sox11 in sensory neurons promotes neurite growth.•Sox11 enhances the responsiveness of DRG neurons to GDNF and artemin but not NGF.•Results suggest that sox11 may promote nerve ...regeneration by altering their responsiveness to GDNF family ligands.
The peripherally projecting axons of dorsal root ganglion (DRG) neurons readily regenerate after damage while their centrally projecting branches do not regenerate to the same degree after injury. One important reason for this inconsistency is the lack of pro-regeneration gene expression that occurs in DRG neurons after central injury relative to peripheral damage. The transcription factor SRY-box-containing gene 11 (Sox11) may be a crucial player in the regenerative capacity of axons as previous evidence has shown that it is highly upregulated after peripheral axon damage but not after central injury. Studies have also shown that overexpression or inhibition of Sox11 after peripheral nerve damage can promote or block axon regeneration, respectively. To further understand the mechanisms of how Sox11 regulates axon growth, we artificially overexpressed Sox11 in DRG neurons in vitro to determine if increased levels of this transcription factor could enhance neurite growth. We found that Sox11 overexpression significantly enhanced neurite branching in vitro, and specifically induced the expression of glial cell line-derived neurotrophic factor (GDNF) family receptors, GFRα1 and GFRα3. The upregulation of these receptors by Sox11 overproduction altered the neurite growth patterns of DRG neurons alone and in response to growth factors GDNF and artemin; ligands for GFRα1 and GFRα3, respectively. These data support the role of Sox11 to promote neurite growth by altering responsiveness of neurotrophic factors and may provide mechanistic insight as to why peripheral axons of sensory neurons readily regenerate after injury, but the central projections do not have an extensive regenerative capacity.
To facilitate analyses of purinergic signaling in peripheral nerve glia, we review recent literature and catalog purinergic receptor mRNA expression in cultured mouse Schwann cells (SCs). Purinergic ...signaling can decrease developmental SC proliferation, and promote SC differentiation. The purinergic receptors P2RY2 and P2RX7 are implicated in nerve development and in the ratio of Remak SCs to myelinating SCs in differentiated peripheral nerve. P2RY2, P2RX7, and other receptors are also implicated in peripheral neuropathies and SC tumors. In SC tumors lacking the tumor suppressor NF1, the SC pathway that suppresses SC growth through P2RY2‐driven β‐arrestin‐mediated AKT signaling is aberrant. SC‐released purinergic agonists acting through SC and/or neuronal purinergic receptors activate pain responses. In all these settings, purinergic receptor activation can result in calcium‐independent and calcium‐dependent release of SC ATP and UDP, growth factors, and cytokines that may contribute to disease and nerve repair. Thus, current research suggests that purinergic agonists and/or antagonists might have the potential to modulate peripheral glia function in development and in disease.
MAIN POINTS
SC purinergic receptors are implicated in suppressing SC proliferation, increasing SC differentiation, and elevating intracellular Ca2+ during nerve development in response to injury and/or in disease.
P1R, P2XR, and P2YR receptors expressed in SCs and adjacent neurons need further study.
While much is known about the functional properties of cutaneous nociceptors, relatively little is known about the comprehensive functional properties of group III and IV muscle afferents. We have ...developed a mouse ex vivo forepaw muscle, median and ulnar nerve, dorsal root ganglion (DRG), spinal cord recording preparation to examine the functional response properties, neurochemical phenotypes, and spinal projections of individual muscle afferents. We found that the majority of group III and IV muscle afferents were chemosensitive (52%) while only 34% responded to mechanical stimulation and fewer (32%) responded to thermal stimuli. The chemosensitive afferents could be grouped into those that responded to a "low"-metabolite mixture containing amounts of lactate and ATP at pH 7.0 simulating levels observed in muscle during exercise (metaboreceptors) and a "high"-metabolite mixture containing lactic acid concentrations and ATP at pH 6.6 mimicking levels observed during ischemic contractions (metabo-nociceptors). While the majority of the metabo-nociceptive fibers responding to the higher concentration levels were found to contain acid-sensing ion channel 3 (ASIC3) and/or transient receptor potential vanilloid type 1 (TRPV1), metaboreceptors responding to the lower concentration levels lacked these receptors. Anatomically, group III muscle afferents were found to have projections into laminae I and IIo, and deeper laminae in the spinal cord, while all functional types of group IV muscle afferents projected primarily into both laminae I and II. These results provide novel information about the variety of sensory afferents innervating the muscle and provide insight into the types of fibers that may exhibit plasticity after injuries.
Abstract
Mitochondrial disorders are the result of nuclear and mitochondrial DNA mutations that affect multiple organs, with the central and peripheral nervous system often affected. Currently, there ...is no cure for mitochondrial disorders. Currently, gene therapy offers a novel approach for treating monogenetic disorders, including nuclear genes associated with mitochondrial disorders. We utilized a mouse model carrying a knockout of the mitochondrial fusion–fission-related gene solute carrier family 25 member 46 (Slc25a46) and treated them with neurotrophic AAV–PHP.B vector carrying the mouse Slc25a46 coding sequence. Thereafter, we used immunofluorescence staining and western blot to test the transduction efficiency of this vector. Toluidine blue staining and electronic microscopy were utilized to assess the morphology of optic and sciatic nerves following treatment, and the morphology and respiratory chain activity of mitochondria within these tissues were determined as well. The adeno-associated virus (AAV) vector effectively transduced in the cerebrum, cerebellum, heart, liver and sciatic nerves. AAV–Slc25a46 treatment was able to rescue the premature death in the mutant mice (Slc25a46−/−). The treatment-improved electronic conductivity of the peripheral nerves increased mobility and restored mitochondrial complex activities. Most notably, mitochondrial morphology inside the tissues of both the central and peripheral nervous systems was normalized, and the neurodegeneration, chronic neuroinflammation and loss of Purkinje cell dendrites observed within the mutant mice were alleviated. Overall, our study shows that AAV–PHP.B’s neurotrophic properties are plausible for treating conditions where the central nervous system is affected, such as many mitochondrial diseases, and that AAV–Slc25a46 could be a novel approach for treating SLC25A46-related mitochondrial disorders.
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