J Neurosci︱ Junli Cao’s research group reveals the loop mechanism of the anterior cingulate gyrus to regulate mirror pain

Author ︱ Junli Cao, edited by Suwan Hu ︱ Sizhen Wang Mirror-image pain (MIP) is a phenomenon of increased pain sensitivity of the whole body relative to the actual injury site
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In clinical studies, MIP symptoms are common in patients with chronic pain such as complex regional pain syndrome, rheumatoid arthritis, toothache, and chronic migraine, which are mainly manifested as hyperalgesia or tactile pain in the contralateral part
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MIP is often masked by pain at the primary site
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After occlusion therapy was used to relieve the pain at the primary site, the patient still complained of pain in the contralateral body, suggesting that MIP may be independent of the primary site [1]
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MIP may increase the difficulty of treating chronic pain, so prevention of MIP has important clinical significance
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 In view of the mechanism of MIP, researchers proposed that glial cell activation and other inflammatory factors and central sensitization-related neurological factors may jointly participate in the occurrence and development of MIP [2]
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However, most of the current research is still focused on inflammatory factors, and the research on neurological factors is obviously insufficient
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In the process of chronic pain, how pain information is transmitted to the contralateral side through the central mechanism to cause MIP is still unclear
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 On October 12, 2021, Professor Junli Cao’s research group from Xuzhou Medical University published a research paper entitled "Contralateral Projection of Anterior Cingulate Cortex Contributes to Mirror-Image Pain" in the Journal of Neuroscience, revealing that the anterior cingulate cortex (anterior cingulate cortex (ACC) loop on MIP regulation
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Hu Suwan and Zhang Qi are the co-first authors of the paper, and Professor Cao Junli is the corresponding author of the paper
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In this study, the authors found that unilateral chronic constrictive injury of the sciatic nerve (CCI) damages the contralateral ACC mid-span corpus callosum projection pyramidal neurons, which mediate the contralateral MIP of CCI, while CCI-induced primary pain has no effect; the non-transcorpus callosal projection pyramidal neurons in the contralateral ACC participate in the regulation of CCI-induced primary pain, but have no effect on the MIP of the CCI contralateral side
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This study reveals that a new ACC transcorpus callosum projection loop is involved in the regulation of MIP behavior in chronic pain, which enriches our understanding of the central mechanism that provides MIP in chronic pain
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The researchers first performed unilateral hind paw CCI modeling of mice and observed pain behavior
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After 7-14 days of modeling, the pain threshold of the contralateral hind paw was significantly reduced, and MIP appeared
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A previous study reported that the MIP phenomenon was accompanied by increased bilateral cerebral blood flow in the sensory cortex of four individuals, including ACC [3]
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ACC is a brain area closely related to pain control [4]
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The researchers performed immunofluorescence staining on mouse ACC brain slices and found that the number of c-Fos-positive neurons in the ACC on both sides of CCI mice expressing MIP increased significantly, and most of them were co-labeled with the pyramidal neuron marker CaMKIIα
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This result suggests that under the chronic pain state caused by CCI, the excitability of bilateral ACC neurons is increased, and pyramidal neurons are dominant
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 Next, the method of chemical genetics was used to specifically inhibit the pyramidal neurons in the ACC on both sides, and it was found that inhibiting the ACC pyramidal neurons on the ipsilateral side of CCI can alleviate the MIP behavior of CCI mice; inhibiting the ACC pyramidal neurons on the opposite side of CCI to MIP The behavior has no effect (Figure 1)
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When the ACC pyramidal neurons on the contralateral side of CCI were specifically damaged, the MIP of CCI mice was significantly relieved
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The researchers speculate that the above difference may be due to the slow process of CCI's contralateral ACC pyramidal neurons in regulating MIP
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In order to further judge, the researchers repeatedly inhibited these neurons and found that the MIP of CCI mice was relieved (Figure 2)
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These results indicate that CCI contralateral ACC pyramidal neurons can regulate contralateral MIP behavior caused by CCI
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Figure 1 The effect of inhibiting the ACC pyramidal neurons on both sides on pain behavior respectively (picture quoted from: Hu et al.
, J Neurosci 2021) Figure 2 Specific damage and repeated inhibition of CCI contralateral ACC pyramidal neurons on pain Behavioral influence (picture quoted from: Hu et al.
, J Neurosci 2021) In order to explore the downstream loop mechanism of CCI contralateral ACC pyramidal neurons to regulate MIP, the researchers used the defective herpes simplex virus (HSV) The anterograde transsingle synaptic tracing strategy mediated [5] traces the downstream brain areas of the ACC pyramidal neurons on the contralateral side of the CCI
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The results suggest that some neurons in the ipsilateral ACC of CCI receive single-synaptic projections from the contralateral ACC pyramidal neurons, and this projection is a transcallosal projection (Figure 3)
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Subsequently, the researchers performed immunofluorescence staining on ACC brain slices under the premise of labeling the pyramidal neurons projecting across the corpus callosum in the contralateral ACC of CCI, and found that in the labeled pyramidal neurons of CCI mice expressing MIP, c- The positive rate of Fos increased significantly
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This result suggests that the excitability of pyramidal neurons projecting across the corpus callosum in the contralateral ACC of CCI is increased
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Figure 3 HSV-mediated tracing of the downstream brain area of ​​ACC pyramidal neurons on the contralateral side of CCI (picture quoted from: Hu et al.
, J Neurosci 2021) further specifically inhibits these pyramidal neurons and affects mice Pain behavior is tested
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The results showed that the hyperalgesia of both hind paws of CCI mice was not affected
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After repeatedly inhibiting this part of neurons, the MIP of CCI mice was significantly relieved, but the CCI side pain sensitivity was not affected
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The specific apoptotic CCI contralateral pyramidal neurons projecting across the corpus callosum also obtained similar results (Figure 4)
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These results indicate that the pyramidal neurons projecting across the corpus callosum in the CCI contralateral ACC can mediate MIP caused by CCI, but have no effect on primary pain
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Figure 4 The effect of repeated inhibition and specific destruction of the pyramidal neurons projecting across the corpus callosum in the CCI contralateral ACC on pain behavior (picture quoted from: Hu et al.
, J.
Neurosci.
2021) To further explore the contralateral CCI Another part of the non-trans-corpus callosal projection of pyramidal neurons in ACC regulates the role of MIP.
The researchers introduced the "cre-off" system [6], combined with chemical genetics, to specifically inhibit this part of the non-trans-callosal projection.
Pyramidal neurons
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Subsequently, it was found that single or repeated inhibition of non-transcorporeal pyramidal neurons in the contralateral ACC of CCI did not change the MIP caused by CCI, but it could alleviate the pain-sensitive behavior on the CCI side (Figure 5)
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This result suggests that the non-transcallosal pyramidal neurons in the CCI contralateral ACC mediate the primary pain caused by CCI, but have no effect on MIP
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Figure 5 The effect of single and repeated inhibition of the non-transcorpus callosum projection of pyramidal neurons in the CCI contralateral ACC on pain behavior (picture quoted from: Hu et al.
, J Neurosci 2021) Figure 6 CCI contralateral ACC cones Schematic diagram of the mechanism of neuron-mediated primary pain and MIP (picture quoted from: Hu et al.
, J Neurosci 2021).
Conclusion and discussion of the article, inspiration and prospects.
Previous studies believe that both primary pain and secondary MIP are caused by the glial in the spinal cord.
Caused by cell activation [7]
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Glial cells may communicate with other glial cells through mechanisms such as gap junctions, calcium waves, and the release of inflammatory factors, so as to transmit pain information to the contralateral side [7]
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However, the production of MIP is unlikely to be entirely attributable to inflammatory factors in the spinal cord
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If there is no fine control from the nervous system, MIP may appear in uncertain body parts rather than precise mirror positions [2]
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Therefore, the neural control from the high-level center may play a very important role in the occurrence and development of MIP
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In this work, the researchers demonstrated the regulatory role of ACC projection across the corpus callosum in the production of MIP
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 At present, there are still some unresolved problems in the study.
For example, repeated inhibition of the pyramidal neurons in the contralateral ACC of CCI can achieve the mitigation effect of MIP.
Is this situation related to the delayed appearance of MIP compared with the primary pain, that is, CCI Whether the contralateral ACC mediates the effect of MIP is a slow process
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In addition, the downstream mechanism of CCI's contralateral ACC across the corpus callosum to regulate MIP is still unclear
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In addition, whether other nuclei/regions of the nervous system with contralateral projections (such as other cortex, spinal cord, etc.
) have similar regulatory effects on MIP, this question still needs to be further explored
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 In summary, this study revealed that under chronic pain, the two groups of pyramidal neurons with transcorporal projection and nontranscorporal projection in the contralateral ACC mediate CCI-induced MIP and primary pain, respectively (Figure 6)
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This study may provide a new direction for further exploration of the central mechanism of pain metastasis under chronic pain
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Original link: https:// Hu Suwan (left), first author, doctoral student at Xuzhou Medical University; Zhang Qi (middle) , The first author, a doctoral student at Xuzhou Medical University; Cao Junli (right), the corresponding author, a professor at Xuzhou Medical University
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(Photo provided from: Cao Junli Laboratory) Introduction to the research group: Cao Junli, Professor, Director of Jiangsu Clinical Anesthesiology Center, Director of Jiangsu Key Laboratory of Anesthesiology, Director of Key Laboratory of Anesthesia and Psychotropic Drug Research and Evaluation of the State Food and Drug Administration
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Changjiang Scholar Distinguished Professor of the Ministry of Education, selected by the National "Hundreds, Thousands of Talents Project", selected by the state for young and middle-aged experts with outstanding contributions, experts with special allowances from the State Council, the first level of the "333" talent project in Jiangsu Province
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He has long been engaged in the study of the neurobiological mechanism of chronic pain and pain-depression comorbidities.
Research papers have been published in international academic journals such as Biological Psychiatry, PNAS, Current Biology, Neuropsychopharmacology, Journal of Neuroscience, Anesthesiology, Pain, etc.

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We sincerely invite students, postdoctoral fellows and researchers who are interested in the study of the neurobiological mechanism of chronic pain to join us
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Contact: caojl0310@aliyun.
com
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Selected articles from previous issues [1] Nat Commun︱Non-human primate (monkey marmoset) autism model reveals the biological abnormalities in the early development of human diseases [2] Cell Discovery︱Ma Yuanwu/Shen Bin team achieved rat mitochondrial DNA for the first time [3] Dev Cell︱ Lactic acid promotes the B-side of peripheral nerve injury repair: Long-term lactic acid metabolism of axons can lead to oxidative stress and axon degeneration [4] Nat Commun︱ selectively inhibits microglia activation It is expected to alleviate the pathological transmission of α-syn [5] Science︱ Serotonin helps overcome cocaine addiction? [6] Mol Psychiatry︱ Gao Tianming’s research group reveals the different roles of astrocytes and neurons in synaptic plasticity and memory [7] Sci Transl Med︱ Xiang Xianyuan and others reveal the brain’s immune cells crazy sugar phagocytosis, helping nerves Early diagnosis of degenerative diseases [8] A new mechanism of Mol Cell︱ Alzheimer's disease: Tau protein oligomerization induces the RNA binding protein HNRNPA2B1 nuclear cell transport and mediates the enhancement of m6A-RNA modification [9] Cereb Cortex | Li Tao project The group reported the abnormality of the cortical myelin covariation network with deep features of the cerebral cortex in schizophrenia [10] Cell︱ hold hands, advance and retreat together! The formation of a cellular network between microglia to work together to degrade pathological α-syn [11] lipids and Alzheimer's disease! The lack of sulfatide in the myelin sheath of the central nervous system in adulthood can lead to Alzheimer’s disease-like neuroinflammation and cognitive impairment [12] Science Frontier Review ︱Regulatory mechanism of nicotinic acetylcholine receptor accessory molecules and disease treatment transformation Application prospects [13] Brain | For the first time! PAX6 may be a key factor in the pathogenesis of Alzheimer’s disease and a new therapeutic target [14] Nat Biomed Eng︱Ye Yuru’s team developed a new strategy for whole-brain gene editing-mediated treatment of Alzheimer’s disease [15] Luo Liqun Science Center Interpretation of the system ︱Nerve loop structure-a high-quality scientific research training course recommendation for the system that makes the brain "computer" run at high speed [1] A guide to data graphs! How good is it to learn these software? 【2】JAMA Neurol︱Attention! Young people are more likely to suffer from "Alzheimer's disease"? [3] Patch clamp and optogenetics and calcium imaging technology seminar (October 30-31) References (slide up and down to view) [1] CJ Sinnott, JM Garfield, G.