• Qian Zhai, Dengming Lai, Ping Cui, Rui Zhou, Qixing Chen, Jinchao Hou, Yunting Su, Libiao Pan, Hui Ye, Jing-Wei Zhao, and Xiangming Fang.
• 1Department of Anesthesiology and Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 2Clinical Research Center, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China. 3Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, China. 4Department of Anatomy, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, China.
• Crit. Care Med. 2017 Oct 1; 45 (10): e1075-e1082.

ObjectivesBasal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored.DesignAnimal research.SettingUniversity research laboratory.SubjectsMale wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice.InterventionsThe cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used.Measurements And Main ResultsPhotostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation.ConclusionsThese results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis.

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