Neural pathways in medial septal cholinergic modulation of chronic pain: distinct contribution of the anterior cingulate cortex and ventral hippocampus

Abstract

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.

Whole-Brain Mapping the Direct Inputs of Dorsal and Ventral CA1 Projection Neurons

“…In both the dCA1 and vCA1 tracing groups, the input neurons were found distributed widely in the medial septal complex subregion of PAL (Figure 6A). The inputs from the medial septal complex to the hippocampus play important roles in hippocampal spatial representation and cognition (Mamad et al, 2015;Jiang et al, 2018;Muller and Remy, 2018). As shown in Figure 6B, the inputs from MS to dCA1 and vCA1 PNs were similar (dCA1: 0.76 ± 0.06 versus vCA1: 0.74 ± 0.02, P = 0.748), while NDB contributed more direct afferents to vCA1 than dCA1 with CSIs of 0.93 ± 0.03 and 0.27 ± 0.03 (P < 0.01), respectively (Figure 6B).…”

Neuregulin1-ErbB4 Signaling in Spinal Cord Participates in Electroacupuncture Analgesia in Inflammatory Pain

“…To avoid the effect of spontaneous motor activity and sensorimotor coordination on nociceptive behavioral tests, open field test and rotarod test were performed as described previously (Duan et al, 2014;Jiang et al, 2018). For open field test, mice were placed into the center of the chamber (40 cm × 40 cm × 40 cm) which located in a sound proof box and allowed to explore for 30 min.…”

“…Inflammatory phenotypes in the injected paw induced by CFA lasted for 2 weeks as described previously and including edema, redness and hypersensitivities to noxious stimuli (Kumar et al, 2016;Jiang et al, 2018). We found that the basic mechanical withdrawal threshold and thermal latency in the three groups were similar; the injection of CFA significantly decreased the mechanical threshold and thermal latency of mice, which was ameliorated by EA treatment [F (2 , 27) = 147.2, p < 0.0001; F (2 , 27) = 173.3, p < 0.0001, respectively; Figures 1C,D].…”

Novel Projections to the Cerebrospinal Fluid-Contacting Nucleus From the Subcortex and Limbic System in Rat

“…The CSF-contacting nucleus participates in pain modulation (Wang et al, 2014;Liu et al, 2017;Zhou et al, 2017), and it receives several pain-related regions in the subcortex and limbic system. The MS and diagonal band complex is crucial for information processing and chronic pain behavior (Jiang et al, 2018). These brain regions are involved in nociception modulation, especially that of affective, motivational, and cognitive behaviors (Ang et al, 2017).…”