Abstract
The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation.
Highlights
The nervous system regulates and coordinates physiological functions and defense mechanisms
This is important as cholinergic neurons can secrete GABA with ACh and targeting vesicular acetylcholine transporter (VAChT) allows for selective manipulation of ACh release [28,29,30,31]
We show a role for forebrain cholinergic signaling and the M1 muscarinic acetylcholine receptors (mAChRs) in the brain neuronal regulation of inflammation through vagus nerve-mediated signaling
Summary
The nervous system regulates and coordinates physiological functions and defense mechanisms. Galantamine, an acetylcholinesterase inhibitor, which increases acetylcholine levels suppresses peripheral pro-inflammatory cytokine levels acting through a brain mAChR-mediated mechanism [13,14,15] These cholinergic effects in the brain are linked with activation of the vagus nerve-based inflammatory reflex [11, 13, 14, 16, 17], a physiological immunoregulatory circuit [18, 19] with recently demonstrated utility in treating human inflammatory diseases [20, 21]. The cholinergic system in the brain has a diverse topographic neuronal organization and projection patterns [22, 23], and specific insight into the role of cholinergic pathways and receptors in the brain in peripheral immunoregulation is presently lacking
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