Somatotopic Organization and Intensity Dependence in Driving Distinct NPY-Expressing Sympathetic Pathways by Electroacupuncture

Shenbin Liu, Zhi-Fu Wang, Yang-Shuai Su, Russell S Ray, Xiang-Hong Jing, Yan-Qing Wang, Qiufu Ma, Shenbin Liu, Zhi-Fu Wang, Yang-Shuai Su, Russell S Ray, Xiang-Hong Jing, Yan-Qing Wang, Qiufu Ma

Abstract

The neuroanatomical basis behind acupuncture practice is still poorly understood. Here, we used intersectional genetic strategy to ablate NPY+ noradrenergic neurons and/or adrenal chromaffin cells. Using endotoxin-induced systemic inflammation as a model, we found that electroacupuncture stimulation (ES) drives sympathetic pathways in somatotopy- and intensity-dependent manners. Low-intensity ES at hindlimb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on NPY+ adrenal chromaffin cells. High-intensity ES at the abdomen activates NPY+ splenic noradrenergic neurons via the spinal-sympathetic axis; these neurons engage incoherent feedforward regulatory loops via activation of distinct adrenergic receptors (ARs), and their ES-evoked activation produces either anti- or pro-inflammatory effects due to disease-state-dependent changes in AR profiles. The revelation of somatotopic organization and intensity dependency in driving distinct autonomic pathways could form a road map for optimizing stimulation parameters to improve both efficacy and safety in using acupuncture as a therapeutic modality.

Keywords: ST25 and ST36 acupoints; adrenal chromaffin cells; adrenergic receptors; electroacupuncture; neuropeptide Y; somatosensory autonomic pathways; spleen; sympathetic neurons; systemic inflammation; vagal-adrenal axis.

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.. Intersectional marking of NPY Cre…
Figure 1.. Intersectional marking of NPYCre-expressing sympathetic cells.
(A-C) Colocalization of tdTomato with NPY, DBH orVAChT mRNA or the TH protein in sections through sympathetic ganglia (“g.”) and adrenal glands of adultNPYDBH-tdTomato mice. (D) Schematic illustration of splenic subcapsular regions. RP: red pulp, MZ: marginal zone, WP: white pulp. (E) Splenic innervations by NPYDBH-tdTomato+ fibers. Arrows and arrowheads in WPs: fibers along the arterioles and the periarteriolar lymphatic sheath, respectively. “*”: fibers innervating the trabeculae. (F) A representative image showing tdTomato overlapping with TH in a WP. n = 5–6 mice for all groups. Scale bars, 100 μm.
Figure 2.. Intersectional ablation of peripheral and…
Figure 2.. Intersectional ablation of peripheral and adrenal NPYDBH cells.
(A) Intraperitoneal injection (i.p.) of PEGyDT to create NPYDBH (peri.)-Abl [“(peri.)-Abl”] mice. “WT”: wild type littermates. All NPYCre cells were labeled by tdTomato from an unshown reporter allele. (B) Ablation of NPYCre-tdTomato+ cells in suprarenal ganglia (t8 = 13.1, ***P < 0.001) and adrenal glands (t8 = 14.96, ***P < 0.001). (C) Intra-adrenal medulla injection of PEGyDT to create NPYDBH (adrenal)-Abl mice [“(adrenal)-Abl”]. (D) Ablation of NPYCre-tdTomato+ cells in adrenal glands, but not in suprarenal ganglia compared with WT mice (adrenal,t8 = 11.68, ***P < 0.001; suprarenal, t8 = 0.659, NS, no significant,P = 0.528). n = 5 mice for all groups. Two-side student’s unpairedt-test in B and D. Data are shown as mean ± SEM. Scale bars, 100 μm.
Figure 3.. Ablation of NPY DBH sympathetic…
Figure 3.. Ablation of NPYDBH sympathetic cells caused an increase in LPS-induced TNF-α production.
(A-B) LPS induced a larger increase of TNF-α levels in NPYDBH (peri.)-Abl mice compared with WT mice in serum and in spleen. Two-way ANOVA plus post-hoc Tukey test. Serum:F1, 20 = 13.457, P = 0.002; spleen: F1, 16 = 13.174, P < 0.001. ***P < 0.001; NS, not significant,P = 0.913 in A and 0.892 in B. (C) TNF-α immunostaining images through splenic red pulps (“RP”) and white pulps (“WP”). (D) TNF-α expression (by immunostaining) in splenic macrophages with indicated markers in LPS-treated wild type (WT) versus NPYDBH (peri.)-Abl mice (two-side student’s unpaired t test;t8 = 1.528 for F4/80, NS, not significant,P = 0.165; t8 = 13.36 for CD169 and 12.22 for CD68, ***P < 0.001). Arrowheads indicate co-localized cells. N = 5 mice for all groups. Data are shown as mean ± SEM. Scale bars, 100 μm.
Figure 4.. Requirement of NPY DBH cells…
Figure 4.. Requirement of NPYDBH cells for preST25 ES-evoked anti-inflammatory effects.
(A) Schematics showing the abdominal ST25 acupoint. (B) Modulation of LPS-induced TNF-α by ST25 ES (F3, 20 = 43.772, P < 0.001; ***P < 0.001; ###P< 0.001; NS, P = 0.406). (C) c-Fos induction by ST25 ES in ChAT+ neurons in the spinal intermediolateral nuclei (“IML”). F2, 14 = 86.02, P < 0.001; ***P< 0.001; NS, P = 0.519. (D) c-Fos induction in suprarenal ganglia (“g.”) by 3.0 mA compared with sham 0 mA ES (two-side student’s unpairedt-test, t8 = 4.97, **P = 0.001). (E-F) Loss of 3.0 mA preST25 ES-evoked reduction of TNF-α in NPYDBH(peri.)-Abl mice compared with wild type (WT) mice, both in serum (F1, 20 = 19.113, P < 0.001;***P < 0.001; NS, P = 0.715) and in spleen (F1, 16 = 13.147, P = 0.012;***P < 0.001; NS, P = 0.783). (G, H) 3.0 mA preST25 ES (compared with 0 mA ES) reduced LPS-induced fatality in WT mice but not in (peri.)-Abl mice (n = 24–25 mice per group; log-rank test, **P = 0.007; NS, P = 0.418). (I) Loss of 3.0 mA preST25 ES-induced splenic noradrenaline release in (peri.)-Abl mice compared with WT mice (F1, 16 = 79.677, P < 0.001; *P < 0.05, ***P < 0.001; NS, P = 0.915). (J) Splenic TNF-α immunostaining in LPS-treated mice receiving 3.0 mA preST25 ES. Increased signals in NPYDBH (peri.)-Abl mice compared with WT mice (two-side student’s unpairedt-test, t8 = 6.856, ***P < 0.001). (K) A blockage of 3.0 mA preST25 ES-evoked reduction in serum TNF-α in LPS-treated C57BL/6 mice by ICI 118,551 (a β2-AR antagonist) (F1, 16 = 61.757, P< 0.001; ***P < 0.001; **P = 0.006; NS, P = 0.254). (L) preST25 ES evokes NPYDBH cell- and β2 AR-dependent anti-inflammatory pathways, via segmental and/or spinal-supra-spinal pathways (“dashed”, to be determined). “Sym. g.”: sympathetic ganglia. n = 5–6 mice for all mouse groups (except G and H). One-way (B, C) or two-way (E, F, I, K) ANOVA plus post hoc Tukey test. NS, not significant. Data are shown as mean ± SEM. Scale bars, 100 μm.
Figure 5.. Activation of NPY DBH sympathetic…
Figure 5.. Activation of NPYDBH sympathetic cells switched to promote inflammation following LPS pre-exposure.
(A) 3.0 mA postST25 ES, performed 1.5 hours after LPS exposure, increased lethality in LPS-treated C57BL/6J mice (log-rank test; 0 mA, n = 23; 3.0 mA, n = 22; **P = 0.006). (B) Loss of 3.0 mA postST25 ES-evoked increase in serum TNF-α in NPYDBH (peri.)-Abl mice compared with wild type (WT) mice (F1, 20 = 5.602, P < 0.05; ***P < 0.001; NS, P = 0.271). (C) Splenectomy, compared with sham surgery, blocked postST25 ES-evoked increase in serum TNF-α (F1, 16 = 39.871,P < 0.001; ***P < 0.001; NS,P = 0.125). (D) Heat map of quantitative RT-PCR results, showing changes in various adrenergic receptor (AR) expression 1 hour after LPS injection (two-side student’s unpaired t-test; β1:t8 = −0.049, P = 0.962; β2: t8 = −3.840, **P= 0.015; β3: t8 = −0.671,P = 0.521; α1a: t8 = −3.764, **P = 0.016; α1b:t8 = −0.876, P = 0.406; a1d: t8 = −0.270, P = 0.794; α2a: t8 = −2.957, *P= 0.018; α2c: t8 = −6.328, ***P < 0.001; α2b: Mann-Whitney Rank Sum test, *P = 0.016). (E) α2-AR antagonist Yohimbine blocked postST25 ES-evoked increase of TNF-α (F1, 20 = 59.709,P < 0.001;***P < 0.001, *P = 0.016). (F) Co-treatment with Yohimbine allowed 3.0 mA postST25 ES to promote survival for LPS-treated C57BL/6J mice (log-rank test, *P = 0.045). (G) postST25 ES drive NPYDBH cell-dependent pro-inflammatory pathways, via activation of α2 ARs. (H) Schematic description of incoherent feed-forward loops. ES-evoked noradrenaline release from NPYDBH cells modulates LPS-induced TNF-α production (via activation of TLR4) in splenic cells, via activation of β2 and a2 ARs that produce the negative and positive modulatory legs, respectively. n = 22–24 mice (A, F) and 5–6 mice for all other groups. NS: not significant. Data are shown as mean ± SEM.
Figure 6.. 0.5 mA ES at ST36…
Figure 6.. 0.5 mA ES at ST36 attenuated ongoing systemic inflammation.
(A) Schematic showing the hindlimb ST36 acupoint. (B) ES induced c-Fos in ChAT+ neurons in the dorsal motor nuclei of the vagus (“DMV”). Arrowheads: co-expression. Two-side student’s unpaired t-tests,t9 = 7.09, ***P < 0.001. (C) 0.5 mA ST36 ES increased catecholamine release (“NA” for noradrenaline, “A” for adrenaline, “DA” for dopamine) in WT, but not in NPYDBH (adrenal)-Abl mice [F1, 20 = 40.560 (“NA”), 69.780 (“A”), 60.912 (“DA”), P < 0.001; ***P < 0.001; NS, P = 0.483 (“NA”), 0.734 (“A”), and 0.757 (“DA”)]. (D) 0.5 mA preST36 ES reduced LPS-induced TNF-α in WT, but not in (adrenal)-Abl mice (F1,20 = 20.457, P < 0.001; ***P < 0.001; NS, left, P = 0.064, right, P =0.893). (E) 0.5 mA preST36 ES reduced LPS-induced TNF-α in mice with sham surgery, but not with subdiaphragmatic vagotomy (“sVX”) (F1, 20 = 72.188, P < 0.001;**P < 0.01; NS, P = 0.628). (F) 0.5 mA preST36 ES promoted survival compared with 0 mA ES (0 mA, n = 28; 0.5 mA, n = 33, log-rank test, *P = 0.019). (G) 0.5 mA postST36 ES reduced LPS-induced TNF-α in WT, but not in (adrenal)-Abl mice (F1, 20 = 23.155, P < 0.001; ***P < 0.001; NS, left, P = 0.147, right, P =0.550). (H) Loss of 0.5 mA postST36 ES-evoked TNF-α reduction by subdiaphragmatic vagotomy (“sVX”) compared with sham surgery (F1, 20 = 81.237, P < 0.001; ***P < 0.001; *P = 0.025; NS,P = 0.315). (I) 0.5 mA postST36 ES improved survival compared with 0 mA ES (0 mA, n = 23; 0.5 mA, n = 28, log-rank test, **P = 0.001). (J) ES drives two autonomic pathways and modulates LPS-induced inflammation in somatotopy-, intensity-, and disease state-dependent manners. Sym. g.: sympathetic ganglia. IML: spinal intermediolateral nuclei. Adrenal g.: adrenal gland. Noradren.: Noradrenergic. Chroma.: Chromaffin. n = 5–6 mice for all groups (except F and I). Two-way ANOVA pluspost hoc Tukey’s test (C, D, E, G, and H). NS, not significant. Data are shown as mean ± SEM. Scale bars, 100 μm.

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