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1.
Nature ; 585(7824): 245-250, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32884146

RESUMO

Adaptive behaviour crucially depends on flexible decision-making, which in mammals relies on the frontal cortex, specifically the orbitofrontal cortex (OFC)1-9. How OFC encodes decision variables and instructs sensory areas to guide adaptive behaviour are key open questions. Here we developed a reversal learning task for head-fixed mice, monitored the activity of neurons of the lateral OFC using two-photon calcium imaging and investigated how OFC dynamically interacts with primary somatosensory cortex (S1). Mice learned to discriminate 'go' from 'no-go' tactile stimuli10,11 and adapt their behaviour upon reversal of stimulus-reward contingency ('rule switch'). Imaging individual neurons longitudinally across all behavioural phases revealed a distinct engagement of S1 and lateral OFC, with S1 neural activity reflecting initial task learning, whereas lateral OFC neurons responded saliently and transiently to the rule switch. We identified direct long-range projections from lateral OFC to S1 that can feed this activity back to S1 as value prediction error. This top-down signal updated sensory representations in S1 by functionally remapping responses in a subpopulation of neurons that was sensitive to reward history. Functional remapping crucially depended on top-down feedback as chemogenetic silencing of lateral OFC neurons disrupted reversal learning, as well as plasticity in S1. The dynamic interaction of lateral OFC with sensory cortex thus implements computations critical for value prediction that are history dependent and error based, providing plasticity essential for flexible decision-making.


Assuntos
Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Reversão de Aprendizagem/fisiologia , Córtex Somatossensorial/citologia , Córtex Somatossensorial/fisiologia , Percepção do Tato/fisiologia , Adaptação Psicológica , Animais , Mapeamento Encefálico , Sinalização do Cálcio , Tomada de Decisões/fisiologia , Discriminação Psicológica/fisiologia , Masculino , Camundongos , Estimulação Física , Células Receptoras Sensoriais/metabolismo
2.
Nat Commun ; 11(1): 4514, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908139

RESUMO

The velocity of nerve conduction is moderately enhanced by larger axonal diameters and potently sped up by myelination of axons. Myelination thus allows rapid impulse propagation with reduced axonal diameters; however, no myelin-dependent mechanism has been reported that restricts radial growth of axons. By label-free proteomics, STED-microscopy and cryo-immuno electron-microscopy we here identify CMTM6 (chemokine-like factor-like MARVEL-transmembrane domain-containing family member-6) as a myelin protein specifically localized to the Schwann cell membrane exposed to the axon. We find that disruption of Cmtm6-expression in Schwann cells causes a substantial increase of axonal diameters but does not impair myelin biogenesis, radial sorting or integrity of axons. Increased axonal diameters correlate with accelerated sensory nerve conduction and sensory responses and perturbed motor performance. These data show that Schwann cells utilize CMTM6 to restrict the radial growth of axons, which optimizes nerve function.


Assuntos
Axônios/metabolismo , Proteínas da Mielina/metabolismo , Nervos Periféricos/citologia , Células de Schwann/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Axônios/ultraestrutura , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Microscopia Crioeletrônica , Masculino , Camundongos , Camundongos Knockout , Bainha de Mielina/metabolismo , Condução Nervosa , Nervos Periféricos/metabolismo , Nervos Periféricos/ultraestrutura , Proteômica , Células de Schwann/citologia , Células de Schwann/ultraestrutura , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/ultraestrutura
3.
Nat Commun ; 11(1): 4178, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826895

RESUMO

Friedreich's ataxia (FRDA) is an autosomal-recessive neurodegenerative and cardiac disorder which occurs when transcription of the FXN gene is silenced due to an excessive expansion of GAA repeats into its first intron. Herein, we generate dorsal root ganglia organoids (DRG organoids) by in vitro differentiation of human iPSCs. Bulk and single-cell RNA sequencing show that DRG organoids present a transcriptional signature similar to native DRGs and display the main peripheral sensory neuronal and glial cell subtypes. Furthermore, when co-cultured with human intrafusal muscle fibers, DRG organoid sensory neurons contact their peripheral targets and reconstitute the muscle spindle proprioceptive receptors. FRDA DRG organoids model some molecular and cellular deficits of the disease that are rescued when the entire FXN intron 1 is removed, and not with the excision of the expanded GAA tract. These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.


Assuntos
Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Gânglios Espinais/metabolismo , Edição de Genes/métodos , Proteínas de Ligação ao Ferro/genética , Organoides/metabolismo , Células Receptoras Sensoriais/metabolismo , Antioxidantes/farmacologia , Sistemas CRISPR-Cas , Diferenciação Celular , Cromatina/metabolismo , Ataxia de Friedreich/tratamento farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Íntrons , Mitocôndrias/metabolismo , Organoides/efeitos dos fármacos , Organoides/patologia , Células Receptoras Sensoriais/patologia , Análise de Sequência de RNA , Transcriptoma
4.
PLoS Genet ; 16(8): e1008942, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764744

RESUMO

To remodel functional neuronal connectivity, neurons often alter dendrite arbors through elimination and subsequent regeneration of dendritic branches. However, the intrinsic mechanisms underlying this developmentally programmed dendrite regeneration and whether it shares common machinery with injury-induced regeneration remain largely unknown. Drosophila class IV dendrite arborization (C4da) sensory neurons regenerate adult-specific dendrites after eliminating larval dendrites during metamorphosis. Here we show that the microRNA miR-87 is a critical regulator of dendrite regeneration in Drosophila. miR-87 knockout impairs dendrite regeneration after developmentally-programmed pruning, whereas miR-87 overexpression in C4da neurons leads to precocious initiation of dendrite regeneration. Genetic analyses indicate that the transcriptional repressor Tramtrack69 (Ttk69) is a functional target for miR-87-mediated repression as ttk69 expression is increased in miR-87 knockout neurons and reducing ttk69 expression restores dendrite regeneration to mutants lacking miR-87 function. We further show that miR-87 is required for dendrite regeneration after acute injury in the larval stage, providing a mechanistic link between developmentally programmed and injury-induced dendrite regeneration. These findings thus indicate that miR-87 promotes dendrite regrowth during regeneration at least in part through suppressing Ttk69 in Drosophila sensory neurons and suggest that developmental and injury-induced dendrite regeneration share a common intrinsic mechanism to reactivate dendrite growth.


Assuntos
Proteínas de Drosophila/genética , Metamorfose Biológica/genética , MicroRNAs/genética , Regeneração Nervosa/genética , Proteínas Repressoras/genética , Animais , Dendritos/genética , Dendritos/fisiologia , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Células Receptoras Sensoriais/metabolismo
5.
PLoS One ; 15(6): e0233991, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497060

RESUMO

Neuropeptides are secreted molecules that have conserved roles modulating many processes, including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated in neurological disorders such as epilepsy. However, much is unknown about the mechanisms regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motoneurons, as well as sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, which were previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic activity states to feedback on the motor circuit.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Neuropeptídeos/genética , Receptores Nicotínicos/genética , Transcriptoma , Animais , Caenorhabditis elegans/fisiologia , Perfilação da Expressão Gênica , Neurônios Motores/metabolismo , Mutação , Células Receptoras Sensoriais/metabolismo
6.
Expert Opin Pharmacother ; 21(13): 1629-1636, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32515664

RESUMO

INTRODUCTION: Pruritus is a debilitating symptom that significantly affects the quality of life of patients who suffer from it. Many current and emerging systemic treatments targeting the neural system have been successful in treating itch of various underlying etiologies. AREAS COVERED: A complete search of the PUBMED and Google Scholar databases was completed and literature pertinent to current and emerging systemic anti-pruritic drugs which target the neural system was compiled. The purpose of this review is to give the reader with an overview of the current and emerging systemic therapeutic options which target the neural system for chronic pruritus. The authors then provide the reader with their expert perspectives on the future of these therapies. EXPERT OPINION: Exciting new anti-pruritic therapies targeting the neural system which show promise include NK-1 inhibitors, opioid receptor modulators, and drugs targeting specific itch receptors such as Mrgpr, Nav1.7, and PAR2, as well as selective GABA modulators. Future studies should be conducted in order to fully understand these exciting therapeutic options.


Assuntos
Antipruriginosos/uso terapêutico , Vias Neurais/efeitos dos fármacos , Prurido/tratamento farmacológico , Prurido/etiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Doença Crônica , Humanos , Prurido/metabolismo , Qualidade de Vida , Células Receptoras Sensoriais/metabolismo
7.
Nature ; 583(7816): 415-420, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555456

RESUMO

Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms, including microorganisms1. Some bacteria produce bioactive neurotransmitters that have previously been proposed to modulate nervous system activity and behaviours of their hosts2,3. However, the mechanistic basis of this microbiota-brain signalling and its physiological relevance are largely unknown. Here we show that in Caenorhabditis elegans, the neuromodulator tyramine produced by commensal Providencia bacteria, which colonize the gut, bypasses the requirement for host tyramine biosynthesis and manipulates a host sensory decision. Bacterially produced tyramine is probably converted to octopamine by the host tyramine ß-hydroxylase enzyme. Octopamine, in turn, targets the OCTR-1 octopamine receptor on ASH nociceptive neurons to modulate an aversive olfactory response. We identify the genes that are required for tyramine biosynthesis in Providencia, and show that these genes are necessary for the modulation of host behaviour. We further find that C. elegans colonized by Providencia preferentially select these bacteria in food choice assays, and that this selection bias requires bacterially produced tyramine and host octopamine signalling. Our results demonstrate that a neurotransmitter produced by gut bacteria mimics the functions of the cognate host molecule to override host control of a sensory decision, and thereby promotes fitness of both the host and the microorganism.


Assuntos
Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/fisiologia , Comportamento Alimentar/fisiologia , Intestinos/microbiologia , Neurotransmissores/metabolismo , Providencia/metabolismo , Olfato/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Microbioma Gastrointestinal/fisiologia , Metabolômica , Mutação , Octanóis/farmacologia , Octopamina/biossíntese , Octopamina/metabolismo , Providencia/enzimologia , Providencia/fisiologia , Receptores de Amina Biogênica/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células Receptoras Sensoriais/metabolismo , Olfato/efeitos dos fármacos , Tiramina/biossíntese , Tiramina/metabolismo
8.
Cell Prolif ; 53(5): e12803, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32246537

RESUMO

OBJECTIVES: The aim of this study is to investigate the role of sensory nerve in tooth homeostasis and its effect on mesenchymal stromal/stem cells (MSCs) in dental pulp. MATERIALS AND METHODS: We established the rat denervated incisor models to identify the morphological and histological changes of tooth. The groups were as follows: IANx (inferior alveolar nerve section), SCGx (superior cervical ganglion removal), IANx + SCGx and Sham group. The biological behaviour of dental pulp stromal/stem cells (DPSCs) was evaluated. Finally, we applied activin B to DPSCs from sensory nerve-deficient microenvironment to analyse the changes of proliferation and apoptosis. RESULTS: Incisor of IANx and IANx + SCGx groups exhibited obvious disorganized tooth structure, while SCGx group only showed slight decrease of dentin thickness, implying sensory nerve, not sympathetic nerve, contributes to the tooth homeostasis. Moreover, we found sensory nerve injury led to disfunction of DPSCs via activin B/SMAD2/3 signalling in vitro. Supplementing activin B promoted proliferation and reduced apoptosis of DPSCs in sensory nerve-deficient microenvironment. CONCLUSIONS: This research first demonstrates that sensory nerve-deficient microenvironment impairs tooth haemostasis by inducing apoptosis of DPSCs via activin B/SMAD2/3 signalling. Our study provides the evidence for the crucial role of sensory nerve in tooth homeostasis.


Assuntos
Apoptose/fisiologia , Polpa Dentária/fisiologia , Homeostase/fisiologia , Células Receptoras Sensoriais/fisiologia , Células-Tronco/fisiologia , Dente/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Microambiente Celular/fisiologia , Técnicas de Cocultura/métodos , Polpa Dentária/metabolismo , Dentina/metabolismo , Dentina/fisiologia , Feminino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Dente/metabolismo
9.
Mol Cell ; 78(4): 577-583, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32275853

RESUMO

Host-associated microbiomes are emerging as important modifiers of brain activity and behavior. Metabolic, immune, and neuronal pathways are proposed to mediate communication across the so-called microbiota-gut-brain axis. However, strong mechanistic evidence, especially for direct signaling between microbes and sensory neurons, is lacking. Here, we discuss microbial regulation of short-chain fatty acids, neurotransmitters, as-yet-uncharacterized biochemicals, and derivatives of neuromodulatory drugs as important areas for assessing microbial interactions with the nervous system.


Assuntos
Encéfalo/microbiologia , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Neurotransmissores/metabolismo , Células Receptoras Sensoriais/microbiologia , Encéfalo/metabolismo , Trato Gastrointestinal/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais
10.
PLoS Biol ; 18(4): e3000220, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32315298

RESUMO

Many lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unknown. During Caenorhabditis elegans sleep, energetic stores are allocated to nonneural tasks with a resultant drop in the overall fat stores and energy charge. Mutants lacking KIN-29, the C. elegans homolog of a mammalian Salt-Inducible Kinase (SIK) that signals sleep pressure, have low ATP levels despite high-fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores corrects adiposity and sleep defects of kin-29 mutants. kin-29 sleep and energy homeostasis roles map to a set of sensory neurons that act upstream of fat regulation as well as of central sleep-controlling neurons, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Sono/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Núcleo Celular/metabolismo , Metabolismo Energético/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Mutação , Células Neuroendócrinas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Células Receptoras Sensoriais/metabolismo
11.
Nat Commun ; 11(1): 1585, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221292

RESUMO

Differential expression (DE) analysis and gene set enrichment (GSE) analysis are commonly applied in single cell RNA sequencing (scRNA-seq) studies. Here, we develop an integrative and scalable computational method, iDEA, to perform joint DE and GSE analysis through a hierarchical Bayesian framework. By integrating DE and GSE analyses, iDEA can improve the power and consistency of DE analysis and the accuracy of GSE analysis. Importantly, iDEA uses only DE summary statistics as input, enabling effective data modeling through complementing and pairing with various existing DE methods. We illustrate the benefits of iDEA with extensive simulations. We also apply iDEA to analyze three scRNA-seq data sets, where iDEA achieves up to five-fold power gain over existing GSE methods and up to 64% power gain over existing DE methods. The power gain brought by iDEA allows us to identify many pathways that would not be identified by existing approaches in these data.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , RNA-Seq , Análise de Célula Única , Estatística como Assunto , Animais , Simulação por Computador , Endoderma/citologia , Células Endoteliais/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Camundongos , Modelos Genéticos , Células Receptoras Sensoriais/metabolismo
12.
Nat Rev Gastroenterol Hepatol ; 17(6): 338-351, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152479

RESUMO

The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.


Assuntos
Sistema Nervoso Entérico/fisiologia , Motilidade Gastrointestinal/fisiologia , Sensação/fisiologia , Células Receptoras Sensoriais/fisiologia , Vias Aferentes/fisiologia , Fibras Autônomas Pré-Ganglionares/fisiologia , Vias Eferentes/fisiologia , Sistema Nervoso Entérico/metabolismo , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/fisiologia , Humanos , Mecanotransdução Celular/fisiologia , Complexo Mioelétrico Migratório/fisiologia , Vias Neurais/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Neurotransmissores/metabolismo , Células Receptoras Sensoriais/metabolismo , Serotonina/metabolismo
13.
Nat Commun ; 11(1): 1397, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170060

RESUMO

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.


Assuntos
Peptídeo Liberador de Gastrina/genética , Peptídeo Liberador de Gastrina/metabolismo , Dor/metabolismo , Prurido/metabolismo , Células Receptoras Sensoriais/metabolismo , Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Histamina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurotransmissores , Dor/patologia , Prurido/patologia , Células Receptoras Sensoriais/patologia , Pele/metabolismo , Pele/patologia , Transcriptoma
14.
PLoS One ; 15(3): e0229399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218560

RESUMO

The ability to avoid harmful or potentially harmful stimuli can help an organism escape predators and injury, and certain avoidance mechanisms are conserved across the animal kingdom. However, how the need to avoid an imminent threat is balanced with current behavior and modified by past experience is not well understood. In this work we focused on rapidly increasing temperature, a signal that triggers an escape response in a variety of animals, including the nematode Caenorhabditis elegans. We have developed a noxious thermal response assay using an infrared laser that can be automatically controlled and targeted in order to investigate how C. elegans responds to noxious heat over long timescales and to repeated stimuli in various behavioral and sensory contexts. High-content phenotyping of behavior in individual animals revealed that the C. elegans escape response is multidimensional, with some features that extend for several minutes, and can be modulated by (i) stimulus amplitude; (ii) other sensory inputs, such as food context; (iii) long and short-term thermal experience; and (iv) the animal's current behavioral state.


Assuntos
Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Caenorhabditis elegans/fisiologia , Reação de Fuga/fisiologia , Temperatura Alta , Células Receptoras Sensoriais/metabolismo , Sensação Térmica/fisiologia , Animais , Fenótipo , Células Receptoras Sensoriais/citologia
15.
J Neurosci ; 40(11): 2189-2199, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32019828

RESUMO

The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk.SIGNIFICANCE STATEMENT The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.


Assuntos
Dor Crônica/fisiopatologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Nociceptores/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Comunicação Celular , Células Cultivadas , Dor Crônica/induzido quimicamente , Meios de Cultivo Condicionados/farmacologia , Feminino , Gânglios Espinais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/farmacologia , Nociceptores/fisiologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/efeitos dos fármacos , Fator de Transcrição STAT5/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Transcrição Genética/efeitos dos fármacos
16.
Nature ; 579(7797): 101-105, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103180

RESUMO

Mating and egg laying are tightly cooordinated events in the reproductive life of all oviparous females. Oviposition is typically rare in virgin females but is initiated after copulation. Here we identify the neural circuitry that links egg laying to mating status in Drosophila melanogaster. Activation of female-specific oviposition descending neurons (oviDNs) is necessary and sufficient for egg laying, and is equally potent in virgin and mated females. After mating, sex peptide-a protein from the male seminal fluid-triggers many behavioural and physiological changes in the female, including the onset of egg laying1. Sex peptide is detected by sensory neurons in the uterus2-4, and silences these neurons and their postsynaptic ascending neurons in the abdominal ganglion5. We show that these abdominal ganglion neurons directly activate the female-specific pC1 neurons. GABAergic (γ-aminobutyric-acid-releasing) oviposition inhibitory neurons (oviINs) mediate feed-forward inhibition from pC1 neurons to both oviDNs and their major excitatory input, the oviposition excitatory neurons (oviENs). By attenuating the abdominal ganglion inputs to pC1 neurons and oviINs, sex peptide disinhibits oviDNs to enable egg laying after mating. This circuitry thus coordinates the two key events in female reproduction: mating and egg laying.


Assuntos
Copulação/fisiologia , Drosophila melanogaster/fisiologia , Vias Neurais/fisiologia , Oviposição/fisiologia , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Feminino , Gânglios Simpáticos/citologia , Masculino , Peptídeos/metabolismo , Células Receptoras Sensoriais/metabolismo , Abstinência Sexual/fisiologia
17.
Anesthesiology ; 132(4): 867-880, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32011337

RESUMO

BACKGROUND: Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. METHODS: In male Wistar rats (n = 5 to 8 per group) with Freund's complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. RESULTS: In rats with Freund's complete adjuvant-induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). CONCLUSIONS: Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors.


Assuntos
Citocromo P-450 CYP11B2/biossíntese , Hiperalgesia/metabolismo , Medição da Dor/métodos , Células Receptoras Sensoriais/metabolismo , Adjuvantes Imunológicos/toxicidade , Aldosterona/biossíntese , Animais , Adjuvante de Freund/toxicidade , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Medição da Dor/efeitos dos fármacos , Estimulação Física/efeitos adversos , Ratos , Ratos Wistar , Células Receptoras Sensoriais/efeitos dos fármacos
18.
Anesth Analg ; 131(1): 298-306, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31990732

RESUMO

BACKGROUND: Anti-inflammatory corticosteroids are a common treatment for different conditions involving chronic pain and inflammation. Clinically used steroids target the glucocorticoid receptor (GR) for its anti-inflammatory effects. We previously reported that GR in sensory neurons may play central roles in some pain models and that GR immunoreactivity signal in dorsal root ganglia (DRG) decreased after local inflammation of the DRG (a model of low back pain). In the current study, we aimed to determine if similar changes in GR signal also exist in a skin inflammation model, the complete Freund's adjuvant (CFA) model (a model of peripheral inflammatory pain), in which the terminals of the sensory neurons rather than the somata are inflamed. METHODS: A low dose of CFA was injected into the hind paw to establish the peripheral inflammation model in Sprague-Dawley rats of both sexes, as confirmed by measurements of behavior and paw swelling. Immunohistochemical and western blotting techniques were used to determine the expression pattern of the GR in the inflamed hind paw and the DRGs. Plasma corticosterone levels were measured with radioimmunoassay. RESULTS: The immunohistochemical staining revealed that GR is widely expressed in the normal DRG and skin tissues. Paw injection with CFA caused upregulation of the GR in the skin tissue on postinjection day 1, mostly detected in the dermis area. However, paw inflammation significantly reduced the GR signal in the L5 DRG 1 day after the injection. The GR downregulation was still evident 14 days after CFA inflammation. On day 1, western blotting confirmed this downregulation and showed that it could also be observed in the contralateral L5 DRG, as well as in the L2 DRG (a level which does not innervate the paw). Plasma corticosterone levels were elevated in both sexes on day 14 after CFA compared to day 1, suggesting autologous downregulation of the GR by corticosterone may have contributed to the downregulation observed on day 14 but not day 1. CONCLUSIONS: There are distinctive patterns of GR activation under different pain conditions, depending on the anatomical location. The observed downregulation of the GR in sensory neurons may have a significant impact on the use of steroids as treatment in these conditions and on the regulatory effects of endogenous glucocorticoids.


Assuntos
Modelos Animais de Doenças , Hiperalgesia/metabolismo , Receptores de Glucocorticoides/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Feminino , Adjuvante de Freund/toxicidade , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos
19.
Sci Rep ; 10(1): 1300, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992767

RESUMO

The dorsal root ganglia (DRG) house the primary afferent neurons responsible for somatosensation, including pain. We previously identified Jedi-1 (PEAR1/MEGF12) as a phagocytic receptor expressed by satellite glia in the DRG involved in clearing apoptotic neurons during development. Here, we further investigated the function of this receptor in vivo using Jedi-1 null mice. In addition to satellite glia, we found Jedi-1 expression in perineurial glia and endothelial cells, but not in sensory neurons. We did not detect any morphological or functional changes in the glial cells or vasculature of Jedi-1 knockout mice. Surprisingly, we did observe changes in DRG neuron activity. In neurons from Jedi-1 knockout (KO) mice, there was an increase in the fraction of capsaicin-sensitive cells relative to wild type (WT) controls. Patch-clamp electrophysiology revealed an increase in excitability, with a shift from phasic to tonic action potential firing patterns in KO neurons. We also found alterations in the properties of voltage-gated sodium channel currents in Jedi-1 null neurons. These results provide new insight into the expression pattern of Jedi-1 in the peripheral nervous system and indicate that loss of Jedi-1 alters DRG neuron activity indirectly through an intercellular interaction between non-neuronal cells and sensory neurons.


Assuntos
Potenciais de Ação , Receptores de Superfície Celular/deficiência , Células Receptoras Sensoriais/metabolismo , Animais , Biomarcadores , Linhagem Celular , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neuroglia/metabolismo , Neuroglia/ultraestrutura , Técnicas de Patch-Clamp , Células Receptoras Sensoriais/ultraestrutura
20.
Insect Biochem Mol Biol ; 118: 103313, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31911087

RESUMO

Sensory neuron membrane proteins (SNMPs) play a critical role in the insect olfactory system but there is a deficit of functional studies beyond Drosophila. Here, we use a combination of available genome sequences, manual curation, genome and transcriptome data, phylogenetics, expression profiling and gene knockdown to investigate SNMP superfamily in various insect species with a focus on Lepidoptera. We curated 81 genes from 36 insect species and identified a novel lepidopteran SNMP gene family, SNMP3. Phylogenetic analysis shows that lepidopteran SNMP3, but not the previously annotated lepidopteran SNMP2, is the true homologue of the dipteran SNMP2. Digital expression, microarray and qPCR analyses show that the lepidopteran SNMP1 is specifically expressed in adult antennae. SNMP2 is widely expressed in multiple tissues while SNMP3 is specifically expressed in the larval midgut. Microarray analysis suggest SNMP3 may be involved in the silkworm immunity response to virus and bacterial infections. We functionally characterized SNMP1 in the silkworm using RNA interference (RNAi) and behavioral assays. Our results suggested that Bombyx mori SNMP1 is a functional orthologue of the Drosophila melanogaster SNMP1 and plays a critical role in pheromone detection. Split-ubiquitin yeast hybridization study shows that BmorSNMP1 has a protein-protein interaction with the pheromone receptor (BmorOR1), and the co-receptor (BmorOrco). Concluding, we propose a novel molecular model in which BmorOrco, BmorSNMP1 and BmorOR1 form a heteromer in the detection of the silkworm sex pheromone bombykol.


Assuntos
Borboletas/genética , Proteínas de Insetos/genética , Proteínas de Membrana/genética , Mariposas/genética , Proteínas do Tecido Nervoso/genética , Animais , Borboletas/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Membrana/metabolismo , Mariposas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Filogenia , Células Receptoras Sensoriais/metabolismo , Análise de Sequência de DNA , Especificidade da Espécie
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