The anti-inflammation response of ST36 (Zusanli) and autonomic circuits of somatosensory neurons

In the issue (2020;108(3):436-450) of Neuron, Liu et al. at Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, elegantly show how electrical stimulation of primary somatosensory neurons at different body regions can tap into discreet autonomic circuits and, depending on the parameters, initiate either pro- or anti-inflammatory effects. Key to this study was the development of advanced genetic and intersectional mouse models, which allowed them to specifically kill/silence the NPY+ sympathetic neurons and/or adrenal chromaffin cells. This opens for the first time direct functional experimentation of the contribution of each of these for the anti-inflammatory reflex. In these mice, they induced systemic inflammation and characterized the anti-inflammatory role of the neural circuitry engaged by electrical acupuncture stimulation at different body regions and with different stimuli intensities.

They identify that two different somatosensory-autonomic pathways can be activated. The first is a spinal sympathetic pathway. The authors use activity markers and retrograde tracing to establish that the pathway involves afferent DRG sensory neurons, efferent spinal cord preganglionic neurons, and suprarenal ganglionic sympathetic neurons, while preganglionic neurons of the vagus nerve in the DMV remained silent. This first pathway has a general anti-inflammatory role because ablation of the sympathetic neurons prior to systemic inflammation increases production of inflammatory cytokines and decreases survival in the sepsis animal model.

Once this is established, the authors tap into this circuit using electrical acupuncture. They find that its stimulation by electrical acupuncture has anti-inflammatory effects when the stimulation precedes inflammation. Consistent with this, ablating sympathetic neurons abrogated the beneficial effects of electrical stimulation, while ablation of only chromaffin cells had no effect on the stimuli-induced anti-inflammation, and hence the effects rely on sympathetic neurons, although a redundant role of chromaffin cells could not be ruled out. This pathway can be activated by electrical stimulation in both the abdomen (ST25 acupoint) and hindlimb (ST36 acupoint) and is recruited only at high intensities of stimulation. Similar results as obtained by electrical activation were seen using chemogenetic activation of NPY+ sympathetic neurons, and furthermore, chemogenetic inactivation of the NPY+ sympathetic neurons eliminated the anti-inflammatory effects of electrical stimulation. Furthermore, electrical acupuncture was shown by the authors to not only reduce systemic inflammation, but also significantly improve survival, an effect that also relied on sympathetic neurons.

The second pathway is a DRG somatosensory afferent system, which ascends into the brainstem engaging the DMV and thus acts through the vagus efferent system. This circuit could only be activated by electrical stimulation of the hindlimb, but not abdomen, and was activated at low-intensity stimulation. Thus, while hindlimb stimulation at high intensity activates a spinal circuitry (see above), low intensity activates the vagus efferent system. The anti-inflammatory effect of this circuit was found to rely on chromaffin cells of the adrenal gland and the release of catecholamines, and consistently, it was abolished when chromaffin cells were selectively ablated. Furthermore, in contrast to the spinal circuit accessed by high-intensity stimulation, the vagus pathway mainly involved anti-inflammatory effects in non-splenic tissues. Combined, the authors convincingly demonstrate that two independent pathways with different mechanisms and target organs can selectively be activated.

The study by Liu et al. breaks new ground. They highlight the importance of discreet somatosensory-autonomic reflex circuits and show that different pathways can be accessed by electrical stimulation with different functional outcomes, which could help in developing new nerve stimulation paradigms to treat systemic inflammation.


1. Shenbin Liu , Zhi-Fu Wang , Yang-Shuai Su , Russell S Ray , Xiang-Hong Jing , Yan-Qing Wang , Qiufu Ma.Somatotopic Organization and Intensity Dependence in Driving Distinct NPY-Expressing Sympathetic Pathways by Electroacupuncture. Neuron. 2020;108(3):436-450.e7. doi: 10.1016/j.neuron.2020.07.015.

2. Jussi Kupari,Patrik Ernfors. Pricking into Autonomic Reflex Pathways by Electrical Acupuncture. Neuron. 2020 Nov 11;108(3):395-397. doi: 10.1016/j.neuron.2020.09.026.

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