Inhibition of Microglial Activation in the Amygdala Reverses Stress-Induced Abdominal Pain in the Male Rat
| Autor: | Beverley Greenwood-Van Meerveld, Tian Yuan, Krishna Manohar, Albert Orock, Rocco Latorre |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Minocycline p38 Mitogen-Activated Protein Kinases Irritable Bowel Syndrome Stereotaxic Techniques PCR polymerase chain reaction 0302 clinical medicine Glucocorticoid receptor Chronic stress ANOVA analysis of variance Original Research PSD95 postsynaptic density protein 95 TNF tumor necrosis factor Neuronal Plasticity Microglia Central nucleus of the amygdala CeA central nucleus of the amygdala Gastroenterology Visceral Pain phospho-p38 MAPK phosphorylated p38 mitogen-activated protein kinase mRNA messenger RNA medicine.anatomical_structure Brain–Gut Axis 030211 gastroenterology & hepatology Visceral Hypersensitivity VMR visceromotor behavioral response WAS water avoidance stress medicine.medical_specialty IBS irritable bowel syndrome MAP Kinase Signaling System p38 mitogen-activated protein kinases Central nervous system PBS phosphate-buffered saline CNS central nervous system FPO fecal pellet output 03 medical and health sciences Receptors Glucocorticoid CORT corticosterone CRF corticotropin-release factor IBS Internal medicine medicine Animals Humans lcsh:RC799-869 GR glucocorticoid receptor Hepatology Chemokine CX3CL1 business.industry Chronic Psychological Stress Central Amygdaloid Nucleus CRD colorectal distension IL interleukin Rats Disease Models Animal 030104 developmental biology Endocrinology lcsh:Diseases of the digestive system. Gastroenterology business Postsynaptic density Stress Psychological |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 3, Pp 527-543 (2020) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2020.04.020 |
| Popis: | Background & Aims Psychological stress is a trigger for the development of irritable bowel syndrome and associated symptoms including abdominal pain. Although irritable bowel syndrome patients show increased activation in the limbic brain, including the amygdala, the underlying molecular and cellular mechanisms regulating visceral nociception in the central nervous system are incompletely understood. In a rodent model of chronic stress, we explored the role of microglia in the central nucleus of the amygdala (CeA) in controlling visceral sensitivity. Microglia are activated by environmental challenges such as stress, and are able to modify neuronal activity via synaptic remodeling and inflammatory cytokine release. Inflammatory gene expression and microglial activity are regulated negatively by nuclear glucocorticoid receptors (GR), which are suppressed by the stress-activated pain mediator p38 mitogen-activated protein kinases (MAPK). Methods Fisher-344 male rats were exposed to water avoidance stress (WAS) for 1 hour per day for 7 days. Microglia morphology and the expression of phospho-p38 MAPK and GR were analyzed via immunofluorescence. Microglia-mediated synaptic remodeling was investigated by quantifying the number of postsynaptic density protein 95–positive puncta. Cytokine expression levels in the CeA were assessed via quantitative polymerase chain reaction and a Luminex assay (Bio-Rad, Hercules, CA). Stereotaxic infusion into the CeA of minocycline to inhibit, or fractalkine to activate, microglia was followed by colonic sensitivity measurement via a visceromotor behavioral response to isobaric graded pressures of tonic colorectal distension. Results WAS induced microglial deramification in the CeA. Moreover, WAS induced a 3-fold increase in the expression of phospho-p38 and decreased the ratio of nuclear GR in the microglia. The number of microglia-engulfed postsynaptic density protein 95–positive puncta in the CeA was increased 3-fold by WAS, while cytokine levels were unchanged. WAS-induced changes in microglial morphology, microglia-mediated synaptic engulfment in the CeA, and visceral hypersensitivity were reversed by minocycline whereas in stress-naïve rats, fractalkine induced microglial deramification and visceral hypersensitivity. Conclusions Our data show that chronic stress induces visceral hypersensitivity in male rats and is associated with microglial p38 MAPK activation, GR dysfunction, and neuronal remodeling in the CeA. Graphical abstract |
| Databáze: | OpenAIRE |
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