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Neural pathways in medial septal cholinergic modulation of chronic pain

distinct contribution of the anterior cingulate cortex and ventral hippocampus

Jiang, Ying-Yinga; Shao, Shana; Zhang, Yua; Zheng, Jiea; Chen, Xia; Cui, Shuanga; Liu, Feng-Yua; Wan, Youa,b; Yi, Minga,*

doi: 10.1097/j.pain.0000000000001240
Research Paper

One specific behavior can be synergistically modulated by different neural pathways. Medial septal (MS) cholinergic system innervates widespread cortical and subcortical regions and participates in pain modulation, but the underlying neural pathways are not fully understood. This study examined the contribution of MS cholinergic neurons and 2 neural pathways: MS–rostral anterior cingulate cortex (rACC) and MS–ventral hippocampal CA1 (vCA1), in modulating perceptual and affective pain behaviors in a mouse model of chronic inflammatory pain. We found that chronic pain activated MS cholinergic neurons and pyramidal neurons in the rACC, but suppressed pyramidal neuronal activities in the vCA1, all of which contributed to the maintenance of pathological pain. Chemogenetic inhibition of MS cholinergic neurons or the MS–rACC pathway inhibited rACC pyramidal neuronal activities and attenuated perceptual and affective dimensions of chronic pain. By contrast, chemogenetic activation of MS cholinergic neurons also produced analgesia, but by rescuing hypofunctional pyramidal neurons in vCA1. These results clearly demonstrate that the MS cholinergic system differentially modulates chronic inflammatory pain through MS–rACC or MS–vCA1 pathways. More significantly, our research provides evidence for a novel paradigm of neural circuit modulation: MS cholinergic inhibition and activation induce similar analgesia but through distinct neural pathways.

Overall, our work confirms the central cholinergic system as a therapeutic target of pathological pain, and demonstrates that the medial septal (MS) cholinergic system differentially modulates chronic inflammatory pain through MS–rostral anterior cingulate cortex or MS–ventral hippocampal CA1 pathways. More significantly, it represents a novel paradigm of neuromodulation: similar behavioral outcomes are achieved on opposite manipulation of the same brain region but through distinct neural pathways.

aDepartment of Neurobiology, School of Basic Medical Sciences, Neuroscience Research Institute, Beijing, Peoples Republic of China

bKey Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, Peoples Republic of China

Corresponding author. Address: Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing 100191, China. Tel.: +86-10-82805083. E-mail address: (M. Yi).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Y. Wan and M. Yi contributed equally to the manuscript.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received December 18, 2017

Received in revised form March 28, 2018

Accepted April 03, 2018

© 2018 International Association for the Study of Pain
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