Neural control of gut homeostasis

The gut-brain axis is a coordinated communication system that not only maintains homeostasis, but significantly influences higher cognitive functions and emotions, as well as neurological and behavioral disorders. Among the large populations of sensory and motor neurons that innervate the gut, insights into the function of primary afferent nociceptors, whose cell bodies reside in the dorsal root ganglia and nodose ganglia, have revealed their multiple crosstalk with several cell types within the gut wall, including epithelial, vascular, and immune cells. These bidirectional communications have immunoregulatory functions, control host response to pathogens, and modulate sensations associated with gastrointestinal disorders, through activation of immune cells and glia in the peripheral and central nervous system, respectively. Here, we will review the cellular and neurochemical basis of these interactions at the periphery, in dorsal root ganglia, and in the spinal cord. We will discuss the research gaps that should be addressed to get a better understanding of the multifunctional role of sensory neurons in maintaining gut homeostasis and regulating visceral sensitivity.

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OP0083 DORSAL ROOT GANGLIA INFILTRATING MACROPHAGES MAINTAIN OSTEOARTHRITIS PAIN

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4354 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 55.2-56

Author(s):

R. Raoof ◽

C. Martin ◽

H. De Visser ◽

J. Prado ◽

S. Versteeg ◽

...

Keyword(s):

Knee Joint ◽

Dorsal Root Ganglia ◽

Immune Cells ◽

Dorsal Root ◽

Weight Bearing ◽

Joint Damage ◽

Osteoarthritis Pain ◽

Knee Pathology ◽

Femoral Condyles ◽

Over Time

Background:Pain is a major debilitating symptom of knee osteoarthritis (OA). However, the extent of joint damage in OA does not correlate well with the severity of pain. The mechanisms that govern OA pain are poorly understood. Immune cells infiltrating nervous tissue may contribute to pain maintenance.Objectives:Here we investigated the role of macrophages in the initiation and maintenance of OA pain.Methods:Knee joint damage was induced by an unilateral injection of mono-iodoacetate (MIA) or after application of a groove at the femoral condyles of rats fed on high fat diet. Pain-like behaviors were followed over time using von Frey test and dynamic weight bearing. Joint damage was assessed by histology. Dorsal root ganglia (DRG) infiltrating immune cells were assessed over time using flow cytometry. To deplete monocytes and macrophages, Lysmcrex Csfr1-Stop-DTR were injected intrathecal or systemically with diptheria toxin (DT).Results:Intraarticular monoiodoacetate injection induced OA and signs of persistent pain, such as mechanical hyperalgesia and deficits in weight bearing. The persisting pain-like behaviors were associated with accumulation of F4/80+macrophages with an M1-like phenotype in the lumbar DRG appearing from 1 week after MIA injection, and that persisted till at least 4 weeks after MIA injection. Macrophages infiltrated DRG were also observed in the rat groove model of OA, 12 weeks after application of a groove at the femoral condyles. Systemic or local depletion of DRG macrophages during established MIA-induced OA completely ablated signs of pain, without affecting MIA-induced knee pathology. Intriguingly when monocytes/macrophages were depleted prior to induction of osteoarthritis, pain-like behaviors still developed, however these pain-like behaviors did not persist over time.In vitro,sensory neurons innervating the affected OA joint programmed macrophages into a M1 phenotype. Local repolarization of M1-like DRG macrophages towards M2 by intrathecal injection of M2 macrophages or anti-inflammatory cytokines resolved persistent OA-induced pain.Conclusion:Overall we show that macrophages infiltrate the DRG after knee damage and acquire a M1-like phenotype and maintain pain independent of the lesions in the knee joint. DRG-infiltrating macrophages are not required for induction of OA pain. Reprogramming M1-like DRG-infiltrating macrophages may represent a potential strategy to treat OA pain.Acknowledgments:This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreements No 814244 and No 642720. Dutch Arthritis SocietyDisclosure of Interests:Ramin Raoof: None declared, Christian Martin: None declared, Huub de Visser: None declared, Judith Prado: None declared, Sabine Versteeg: None declared, Anne Heinemans: None declared, Simon Mastbergen: None declared, Floris Lafeber Shareholder of: Co-founder and shareholder of ArthroSave BV, Niels Eijkelkamp: None declared

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Melatonin Reduces Excitability in Dorsal Root Ganglia Neurons with Inflection on the Repolarization Phase of the Action Potential

International Journal of Molecular Sciences ◽

10.3390/ijms20112611 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2611 ◽

Cited By ~ 2

Author(s):

Klausen Oliveira-Abreu ◽

Nathalia Silva-dos-Santos ◽

Andrelina Coelho-de-Souza ◽

Francisco Ferreira-da-Silva ◽

Kerly Silva-Alves ◽

...

Keyword(s):

Action Potential ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Neuronal Excitability ◽

Input Resistance ◽

Cell Types ◽

Neuronal Population ◽

Resting Membrane Potential ◽

Electrophysiological Properties ◽

Repolarization Phase

Melatonin is a neurohormone produced and secreted at night by pineal gland. Many effects of melatonin have already been described, for example: Activation of potassium channels in the suprachiasmatic nucleus and inhibition of excitability of a sub-population of neurons of the dorsal root ganglia (DRG). The DRG is described as a structure with several neuronal populations. One classification, based on the repolarizing phase of the action potential (AP), divides DRG neurons into two types: Without (N0) and with (Ninf) inflection on the repolarization phase of the action potential. We have previously demonstrated that melatonin inhibits excitability in N0 neurons, and in the present work, we aimed to investigate the melatonin effects on the other neurons (Ninf) of the DRG neuronal population. This investigation was done using sharp microelectrode technique in the current clamp mode. Melatonin (0.01–1000.0 nM) showed inhibitory activity on neuronal excitability, which can be observed by the blockade of the AP and by the increase in rheobase. However, we observed that, while some neurons were sensitive to melatonin effect on excitability (excitability melatonin sensitive—EMS), other neurons were not sensitive to melatonin effect on excitability (excitability melatonin not sensitive—EMNS). Concerning the passive electrophysiological properties of the neurons, melatonin caused a hyperpolarization of the resting membrane potential in both cell types. Regarding the input resistance (Rin), melatonin did not change this parameter in the EMS cells, but increased its values in the EMNS cells. Melatonin also altered several AP parameters in EMS cells, the most conspicuously changed was the (dV/dt)max of AP depolarization, which is in coherence with melatonin effects on excitability. Otherwise, in EMNS cells, melatonin (0.1–1000.0 nM) induced no alteration of (dV/dt)max of AP depolarization. Thus, taking these data together, and the data of previous publication on melatonin effect on N0 neurons shows that this substance has a greater pharmacological potency on Ninf neurons. We suggest that melatonin has important physiological function related to Ninf neurons and this is likely to bear a potential relevant therapeutic use, since Ninf neurons are related to nociception.

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Activation of a nerve injury transcriptional signature in airway-innervating sensory neurons after LPS induced lung inflammation

10.1101/669374 ◽

2019 ◽

Author(s):

Melanie Maya Kaelberer ◽

Ana Isabel Caceres ◽

Sven-Eric Jordt

Keyword(s):

Nerve Injury ◽

Sensory Neurons ◽

Dorsal Root Ganglia ◽

Lung Inflammation ◽

Dorsal Root ◽

The Other ◽

Sensory Ganglia ◽

Functional Changes ◽

Transcriptional Signature ◽

Nodose Ganglia

ABSTRACTThe lungs, the immune and nervous systems functionally interact to respond to respiratory environmental exposures and infections. The lungs are innervated by vagal sensory neurons of the jugular and nodose ganglia, fused together in smaller mammals as the jugular-nodose complex (JNC). While the JNC shares properties with the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG), these sensory structures express differential sets of genes that reflect their unique functionalities. Here, we used RNAseq in mice to identify the differential transcriptomes of the three sensory ganglia types. Using a fluorescent retrograde tracer and fluorescence-activated cell sorting we isolated a defined population of airway-innervating JNC neurons and determined their differential transcriptional map after pulmonary exposure to lipopolysaccharide (LPS), a major mediator of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after infection with Gram-negative bacteria or inhalation of organic dust. JNC neurons activated an injury response program leading to increased expression of gene products such as the G-protein coupled receptors, Cckbr, inducing functional changes in neuronal sensitivity to peptides, and Gpr151, also rapidly induced upon neuropathic nerve injury in pain models. Unique JNC-specific transcripts, present at only minimal levels in TG, DRG and other organs, were identified. These included TMC3, encoding for a putative mechanosensor, and Urotensin 2B, a hypertensive peptide. These findings highlight the unique properties of the JNC and reveal that ALI/ARDS rapidly induce a nerve-injury related state changing vagal excitability.SIGNIFICANCE STATEMENTThe lungs are innervated by sensory neurons of the jugular-nodose ganglia complex (JNC) that detect toxic exposures and interact with lung-resident cells and the immune system to respond to pathogens and inflammation. Here we report the expression of specific genes that differentiate these neurons from neurons in the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG). Through nerve tracing we identified and isolated airway innervating JNC neurons and determined their differential transcriptional map after lung inflammation induced by a bacterial product, lipopolysaccharide (LPS). We observed the rapid activation of a nerve injury transcriptional program that increased nerve sensitivity to inflammation. This mechanism may result in more permanent nerve injury associated with chronic cough and other respiratory complications.

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miR-129-5p and miR-130a-3p Regulate VEGFR-2 Expression in Sensory and Motor Neurons during Development

International Journal of Molecular Sciences ◽

10.3390/ijms21113839 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3839 ◽

Cited By ~ 1

Author(s):

Kevin Glaesel ◽

Caroline May ◽

Katrin Marcus ◽

Veronika Matschke ◽

Carsten Theiss ◽

...

Keyword(s):

Dorsal Root Ganglia ◽

Motor Neurons ◽

Dorsal Root ◽

Neurological Diseases ◽

Neuronal Cell ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Expression Control ◽

Endothelial Growth Factor

The wide-ranging influence of vascular endothelial growth factor (VEGF) within the central (CNS) and peripheral nervous system (PNS), for example through effects on axonal growth or neuronal cell survival, is mainly mediated by VEGF receptor 2 (VEGFR-2). However, the regulation of VEGFR-2 expression during development is not yet well understood. As microRNAs are considered to be key players during neuronal maturation and regenerative processes, we identified the two microRNAs (miRNAs)—miR-129-5p and miR-130a-3p—that may have an impact on VEGFR-2 expression in young and mature sensory and lower motor neurons. The expression level of VEGFR-2 was analyzed by using in situ hybridization, RT-qPCR, Western blot, and immunohistochemistry in developing rats. microRNAs were validated within the spinal cord and dorsal root ganglia. To unveil the molecular impact of our candidate microRNAs, dissociated cell cultures of sensory and lower motor neurons were transfected with mimics and inhibitors. We depicted age-dependent VEGFR-2 expression in sensory and lower motor neurons. In detail, in lower motor neurons, VEGFR-2 expression was significantly reduced during maturation, in conjunction with an increased level of miR-129-5p. In sensory dorsal root ganglia, VEGFR-2 expression increased during maturation and was accompanied by an overexpression of miR-130a-3p. In a second step, the functional significance of these microRNAs with respect to VEGFR-2 expression was proven. Whereas miR-129-5p seems to decrease VEGFR-2 expression in a direct manner in the CNS, miR-130a-3p might indirectly control VEGFR-2 expression in the PNS. A detailed understanding of genetic VEGFR-2 expression control might promote new strategies for the treatment of severe neurological diseases like ischemia or peripheral nerve injury.

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Targeted expression of an oncogenic adaptor protein v-Crk potentiates axonal growth in dorsal root ganglia and motor neurons in vivo

Developmental Brain Research ◽

10.1016/s0165-3806(99)00072-3 ◽

1999 ◽

Vol 116 (1) ◽

pp. 29-39 ◽

Cited By ~ 10

Author(s):

David E Weinstein ◽

Kostantin Dobrenis ◽

Raymond B Birge

Keyword(s):

Dorsal Root Ganglia ◽

Motor Neurons ◽

Dorsal Root ◽

Adaptor Protein ◽

Axonal Growth ◽

Targeted Expression

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Notochord grafts do not suppress formation of neural crest cells or commissural neurons

Development ◽

10.1242/dev.116.4.877 ◽

1992 ◽

Vol 116 (4) ◽

pp. 877-886 ◽

Cited By ~ 5

Author(s):

K.B. Artinger ◽

M. Bronner-Fraser

Keyword(s):

Neural Crest ◽

Dorsal Root Ganglia ◽

Motor Neurons ◽

Neural Tube ◽

Dorsal Root ◽

Neuronal Cell ◽

Neural Crest Cells ◽

Floor Plate ◽

Commissural Neurons ◽

Neuronal Cell Bodies

Grafting experiments previously have established that the notochord affects dorsoventral polarity of the neural tube by inducing the formation of ventral structures such as motor neurons and the floor plate. Here, we examine if the notochord inhibits formation of dorsal structures by grafting a notochord within or adjacent to the dorsal neural tube prior to or shortly after tube closure. In all cases, neural crest cells emigrated from the neural tube adjacent to the ectopic notochord. When analyzed at stages after ganglion formation, the dorsal root ganglia appeared reduced in size and shifted in position in embryos receiving grafts. Another dorsal cell type, commissural neurons, identified by CRABP and neurofilament immunoreactivity, differentiated in the vicinity of the ectopic notochord. Numerous neuronal cell bodies and axonal processes were observed within the induced, but not endogenous, floor plate 1 to 2 days after implantation but appeared to be cleared with time. These results suggest that dorsally implanted notochords cannot prevent the formation of neural crest cells or commissural neurons, but can alter the size and position of neural crest-derived dorsal root ganglia.

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Inhibition of c-Jun phosphorylation reduces axonal outgrowth of adult rat nodose ganglia and dorsal root ganglia sensory neurons

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2004.07.001 ◽

2004 ◽

Vol 27 (3) ◽

pp. 267-279 ◽

Cited By ~ 110

Author(s):

Charlotta Lindwall ◽

Lars Dahlin ◽

Göran Lundborg ◽

Martin Kanje

Keyword(s):

Sensory Neurons ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Axonal Outgrowth ◽

Adult Rat ◽

Nodose Ganglia

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Experimental Porcine Polioencephalomyelitis in Germfree Pigs

Pathologia veterinaria ◽

10.1177/030098586700400207 ◽

1967 ◽

Vol 4 (2) ◽

pp. 186-198

Author(s):

John F. Long ◽

Adalbert Koestner ◽

Leopold Liss

Keyword(s):

Spinal Cord ◽

Sensory Neurons ◽

Dorsal Root Ganglia ◽

Motor Neurons ◽

Dorsal Root ◽

Ganglion Cells ◽

Silver Impregnation ◽

Microglial Cells ◽

Regressive Phase

The neuronal changes and glial response in the spinal cord were studied by silver impregnation techniques in 23 germfree pigs orally infected with a porcine polioencephalomyelitis viras. By the sixth day swelling occurred in motor neurons. During the next 24 to 96 hours this progressed to diffuse chromatolysis, vesiculation, necrosis, and neuronophagia in massive areas of the ventral horns. Massive degeneration of axons in tracts originating in the ventral horns and from dorsal root ganglia correlated well with the extensive destruction of both motor and sensory neurons. The initial responses to necrosis of ganglion cells were infiltration and proliferation of microglial cells. As active neuronal destruction ceased (about two weeks following infection) the microglial reaction began to decline and proliferative astrocytosis became the predominant feature. The paucity of surviving neurons in the ventral horns, and the density of the mesh of astrocytic processes marked the chronic regressive phase of the disease.

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Microtubule-associated protein 2 within axons of spinal motor neurons: associations with microtubules and neurofilaments in normal and beta,beta'-iminodipropionitrile-treated axons.

The Journal of Cell Biology ◽

10.1083/jcb.100.1.74 ◽

1985 ◽

Vol 100 (1) ◽

pp. 74-85 ◽

Cited By ~ 66

Author(s):

S C Papasozomenos ◽

L I Binder ◽

P K Bender ◽

M R Payne

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Peripheral Nervous System ◽

Dorsal Root Ganglia ◽

Motor Neurons ◽

Dorsal Root ◽

Spinal Motor Neurons ◽

Spinal Motor ◽

The Central Nervous System

We have examined the distribution of microtubule-associated protein 2 (MAP2) in the lumbar segment of spinal cord, ventral and dorsal roots, and dorsal root ganglia of control and beta,beta'-iminodipropionitrile-treated rats. The peroxidase-antiperoxidase technique was used for light and electron microscopic immunohistochemical studies with two monoclonal antibodies directed against different epitopes of Chinese hamster brain MAP2, designated AP9 and AP13. MAP2 immunoreactivity was present in axons of spinal motor neurons, but was not detected in axons of white matter tracts of spinal cord and in the majority of axons of the dorsal root. A gradient of staining intensity among dendrites, cell bodies, and axons of spinal motor neurons was present, with dendrites staining most intensely and axons the least. While dendrites and cell bodies of all neurons in the spinal cord were intensely positive, neurons of the dorsal root ganglia were variably stained. The axons of labeled dorsal root ganglion cells were intensely labeled up to their bifurcation; beyond this point, while only occasional central processes in dorsal roots were weakly stained, the majority of peripheral processes in spinal nerves were positive. beta,beta'-Iminodipropionitrile produced segregation of microtubules and membranous organelles from neurofilaments in the peripheral nervous system portion and accumulation of neurofilaments in the central nervous system portion of spinal motor axons. While both anti-MAP2 hybridoma antibodies co-localized with microtubules in the central nervous system portion, only one co-localized with microtubules in the peripheral nervous system portion of spinal motor axons, while the other antibody co-localized with neurofilaments and did not stain the central region of the axon which contained microtubules. These findings suggest that (a) MAP2 is present in axons of spinal motor neurons, albeit in a lower concentration or in a different form than is present in dendrites, and (b) the MAP2 in axons interacts with both microtubules and neurofilaments.

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