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Cholinergic signaling in the forebrain regulates peripheral inflammation
Author(s) -
Pavlov Valentin A.,
Lehner Kurt R.,
Chavan Sangeeta S.,
Prado Vania F.,
Prado Marco A.M.,
Tracey Kevin J.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb798
Subject(s) - cholinergic , muscarinic acetylcholine receptor , basal forebrain , acetylcholine , cholinergic neuron , vesicular acetylcholine transporter , muscarinic acetylcholine receptor m4 , neuroscience , forebrain , inflammation , medicine , biology , endocrinology , receptor , central nervous system , choline acetyltransferase
The brain regulates physiological functions integral to survival. Relatively little is known about the brain neuronal regulation of peripheral immune function. Brain cholinergic signals have been implicated in controlling peripheral inflammation, but specific insight is lacking. Here, utilizing neuron‐and receptor‐specific approaches, we studied the role of forebrain cholinergic signaling and the M1 muscarinic acetylcholine receptor (M1 mAChR) in the regulation of peripheral inflammation. Forebrain‐specific Cre‐ lox P‐based ablation of the vesicular acetylcholine transporter (required for synaptic acetylcholine release) and vagotomy abolished the suppression of serum TNF by the centrally‐acting cholinergic drug galantamine in murine endotoxemia. Basal forebrain cholinergic neurons innervate areas with abundant M1 mAChR localization. Enhancement of acetylcholine action on the brain M1 mAChR with the selective positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF levels in endotoxemia. Peripheral administration of the centrally‐acting BQCA also suppressed TNF levels and improved survival in endotoxemia, effects abolished in M1 mAChR KO mice. Optogenetic stimulation of basal forebrain cholinergic neurons in the medial septum reduced serum TNF in endotoxemic mice as compared to sham stimulation. These findings provide novel insights into brain regulation of peripheral inflammation and are of interest for developing new brain‐based treatments for inflammatory conditions. Support or Funding Information This work was supported by the following grants from the National Institute of General Medical Sciences, NIH: RO1GM089807 (to VAP and KJT) and RO1GM057226 (to KJT).