scholarly journals Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury

2022 ◽  
Author(s):  
Qiao-Yun Li ◽  
Pei-Wen Yao ◽  
Jin-Yu Liu ◽  
Yi-Wen Duan ◽  
Shao-Xia Chen ◽  
...  
Keyword(s):  
Anterior Cingulate Cortex ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Pyramidal Neurons ◽  
Cingulate Cortex ◽  
Mirror Image ◽  
Anterior Cingulate ◽  
Designer Drugs ◽  
Cortical Region ◽  
Tnf Α

Abstract Background: Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus results in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain. Methods: The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Viral injections for the designer receptors exclusively activated by designer drugs (DREADD) were used to modulate ACC pyramidal neurons. Immunohistochemistry, immunofluorescence, western blotting, protein microarray were used to detect the regulation of inflammatory signaling.Results: Increased expressions of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokine CX3CL1 in ACC induced by unilateral nerve injury were observed on the contralateral side in the SNI group but on the bilateral side in the L5-VRT group, representing a stronger immune response to L5-VRT surgery. In remote ACC, both SNI and L5-VRT induced robust bilateral increase in the protein level of Nav1.6 (SCN8A), a major voltage-gated sodium channel (VGSC) that regulates neuronal activity in the mammalian nervous system. However, the L5-VRT-induced Nav1.6 response occurred at PO 3d, earlier than the SNI-induced one, 7 days after surgery. Modulating ACC pyramidal neurons via DREADD-Gq or DREADD-Gi greatly changed the ACC CX3CL1 levels and the mechanical paw withdrawal threshold. Neutralization of endogenous ACC CX3CL1 by contralateral anti-CX3CL1 antibody attenuated the induction and the maintenance of mechanical allodynia and eliminated the upregulation of CX3CL1, TNF-α and Nav1.6 protein levels in ACC induced by SNI. Furthermore, contralateral ACC anti-CX3CL1 also inhibited the expression of ipsilateral spinal c-Fos, Iba1, CD11b, TNF-α and IL-6. Conclusions: The descending facilitation function mediated by CX3CL1 and its downstream cascade may play a pivotal role, leading to enhanced pain sensitization and even mirror-image pain. Strategies that target chemokine-mediated ACC hyperexcitability may lead to novel therapies for the treatment of neuropathic pain.

scholarly journals Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bastiaan van der Veen ◽  
Sampath K. T. Kapanaiah ◽  
Kasyoka Kilonzo ◽  
Peter Steele-Perkins ◽  
Martin M. Jendryka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Anterior Cingulate Cortex ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Pyramidal Neurons ◽  
Treatment Options ◽  
Pyramidal Cells ◽  
Cingulate Cortex ◽  
Cell Types ◽  
Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

scholarly journals A transcriptomic analysis of neuropathic pain in the anterior cingulate cortex after nerve injury

Bioengineered ◽  
2022 ◽  
Vol 13 (2) ◽  
pp. 2058-2075
Author(s):  
Yu Zhang ◽  
Shiwei Jiang ◽  
Fei Liao ◽  
Zhifeng Huang ◽  
Xin Yang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Anterior Cingulate Cortex ◽  
Nerve Injury ◽  
Cingulate Cortex ◽  
Transcriptomic Analysis ◽  
Anterior Cingulate

scholarly journals The PKCγ neurons in anterior cingulate cortex contribute to the development of neuropathic allodynia and pain-related emotion

2021 ◽  
Vol 17 ◽  
pp. 174480692110619
Author(s):  
Xiao Zhang ◽  
Peng Liu ◽  
Xiaolan He ◽  
Zhenhua Jiang ◽  
Qun Wang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Patch Clamp ◽  
Anterior Cingulate Cortex ◽  
Mechanical Allodynia ◽  
Pain Perception ◽  
Cingulate Cortex ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Fos Expression ◽  
Aversive Behavior

Background While the PKCγ neurons in spinal dorsal horn play an indispensable part in neuropathic allodynia, the exact effect of PKCγ neurons of brain regions in neuropathic pain remains elusive. Mounting research studies have depicted that the anterior cingulate cortex (ACC) is closely linked with pain perception and behavior, the present study was designed to investigate the contribution of PKCγ neurons in ACC to neuropathic allodynia and pain-related emotion in newly developed Prkcg-P2A-Tdtomato mice. Methods The c-fos expression in response to innocuous stimulation was used to monitor the activity of PKCγ in CCI (chronic constriction injury of the sciatic nerve) induced neuropathic pain condition. Activating or silencing ACC PKCγ neurons by chemogenetics was applied to observe the changes of pain behavior. The excitability of ACC PKCγ neurons in normal and CCI mice was compared by patch-clamp whole-cell recordings. Results The PKCγ-Tdtomato neurons were mainly distributed in layer III-Vof ACC. The Tdtomato was mainly expressed in ACC pyramidal neurons demonstrated by intracellular staining. The c-fos expression in ACC PKCγ neurons in response to innocuous stimulation was obviously elevated in CCI mice. The patch clamp recordings showed that ACC PKCγ-Tdtomato neurons were largely activated in CCI mice. Chemogenetic activation of ACC PKCγ neurons in Prkcg-icre mice induced mechanical allodynia and pain-related aversive behavior, conversely, silencing them in CCI condition significantly reversed the mechanical allodynia and pain-related place aversive behavior. Conclusion We conclude that the PKCγ neurons in ACC are closely linked with neuropathic allodynia and pain-related emotional behaviors.

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