Neurosci Bull︱ Li Yunqing’s research team reveals that changes in nerve plasticity in the anterior cingulate gyrus are related to hyperalgesia and anxiety in chronic pancreatitis

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Wang Sizhen's article︱Ren Dan, edited by Bai Yang︱Wang Sizhen's recurrent or persistent abdominal pain is one of the most significant symptoms of chronic pancreatitis (CP) 1.
Seriously affect the quality of life of CP patients
.

In recent years, the focus of research on chronic pancreatitis pain has shifted from the anatomical mechanism of the pancreas to the neurobiological mechanism, which can be summarized as the following three processes: peripheral sensitization, pancreatic neuropathy and The neuroplasticity of the central pain loop [1] is changed
.

Visceral information can be transmitted to the nucleus tractus solitarius (NTS) through the bilateral vagus nerves [2,3], and then transmitted to higher-level centers, such as locus and arm The paranucleus, rostral ventromedial nucleus, amygdala and thalamus[4,5], and finally reach the limbic system and the cognitive center of the brain, participate in the regulation of pain-related emotions[2]
.

Anterior cingulate cortex (ACC) is a key hub for intestinal-related visceral sensory transmission and visceral movement regulation, and it is also involved in pain perception and the regulation of pain negative emotions
.

Long-term potentiation of excitatory synaptic transmission in ACC is believed to maintain pathological pain and pain-related anxiety
.

However, in the state of CP pain, whether there are changes in neuroplasticity in ACC is still unclear
.

In addition, ACC-related neural pathways involved in visceral pain information transmission or regulation have received little attention
.

 On December 15, 2021, the team of Professor Yunqing Li from the Air Force Military Medical University of the People’s Liberation Army and the Department of Human Anatomy of Guangxi Medical University published a study titled "Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats" on Neuroscience Bulletin.
Thesis
.

Ren Dan, Li Jiani, Qiu Xintong and Wan Faping are the co-first authors of the paper, and Professor Li Yunqing and Bai Yang’s attending physician are corresponding authors
.

This study illustrates that changes in neuroplasticity in the anterior cingulate gyrus are involved in the maintenance of hyperalgesia and anxiety caused by chronic pancreatitis in the treatment of CP pain.
ACC is a potential neuromodulation intervention target
.

 The previous research of the research group showed that NTS is an important afferent center for visceral pain caused by CP and angina [6]
.

Therefore, it is suggested that ACC may directly receive the input of visceral pain information from NTS, and the changes in neuroplasticity in ACC are related to hyperalgesia and anxiety of CP
.

 The research group used trinitrobenzene sulfonic acid (TNBS) to be injected into the pancreatic duct of rats to establish a CP model.
Through behavioral and morphological observations, CP caused behavioral changes in rat visceral pain, NTS and ACC were positive for FOS There is a significant increase in neurons and time-dependent
.

Through the intra-NTS injection of cis-standard virus, combined with the intra-ACC injection of fluorogold (FG) reverse labeling technique (Figure 1A), it was observed that the ACC received the direct projection from the NTS (Figure 1 DF), and finally contacted CaMKII in the ACC.
Positive neurons have more contact connections and FOS expression is positive
.

These morphological data suggest that the postsynaptic pyramidal neurons in ACC may play a major role in the transmission or regulation of CP-related pain information
.

Figure 1 High expression of VGluT1 in ACC of CP rats induced by TNBS (Source: Ren, D.
, et al.
, Neurosci.
Bull.
2021) Vesicular glutamate transporter 1 (VGluT1) is Essential for excitatory synaptic transmission, glutamate needs to be transported into synaptic vesicles and released by exocytosis in the cerebral cortex.
Therefore, the expression of VGluT1 can not only represent the content of glutamate, but also affect neurotransmission.
Efficacy [7]
.

The research team used immunohistochemical double staining and molecular biology methods to detect the expression of VGluT1 in ACC
.

Among them, the double immunostaining of VGluT1 and NeuN showed that compared with the control group (sham group), the number of VGluT1 positive axon terminals in the TNBS group was larger and the contact with neurons was closer (figure).
2 A1-4)
.

At the same time, western blot was used to detect the up-regulation of VGluT1 in ACC in the TNBS-induced CP pain model (Figure 2 B, C)
.

These data indicate that visceral pain in chronic pancreatitis induced by TNBS stimulates the release of glutamate, which provides presynaptic evidence for the enhancement of synaptic transmission in ACC
.

Figure 2 TNBS-induced high expression of VGluT1 in ACC of CP rats (Source: Ren, D.
, et al.
, Neurosci.
Bull.
2021) N-methyl-D-aspartate receptor (N-methyl- D-aspartate receptor, NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, AMPAR) mediates excitatory synaptic transmission of glutamate
.

The researchers separated the membrane protein and cytoplasmic protein of ACC, and detected that the expression of NR2B membrane protein was significantly up-regulated in the ACC of CP rats by western blot (Figure 3 B, H), while the cytoplasmic protein content was significantly down-regulated (Figure 3 B, H) 3 C, I)
.

In addition, the membrane protein expression of pNR2B increased significantly with the prolongation of TNBS-induced CP (Figure 3B, J).
Although the expression of cytoplasmic protein pNR2B in the TNBS group had a downward trend, no significant difference was observed (Figure 3C).
, K)
.

As a key subunit of AMPAR, GluR1 produces AMPAR transport and integration in the synaptic membrane, and the overexpression of GluR1 is related to the maintenance of somatic and visceral chronic pain [8]
.

The research team observed that the expression of GluR1 in the membrane protein of the TNBS group was significantly higher than that of the sham group (Figure 3 B, D), and there was no significant change in the cytoplasmic protein GluR1 (Figure 3 C, E)
.

In addition, the content of phosphorylated GluR1 also increased during CP (Figure 3 C, F), while the content of cytoplasmic protein pGluR1 remained unchanged (Figure 3 C, G)
.

These results indicate that the enhanced ACC postsynaptic transmission induced by CP induced by TNBS may be related to the membrane transport and phosphorylation modification of the GluR1 and NR2B subunits
.

Figure 3 TNBS-induced transport of glutamate receptor subunits and their phosphorylated receptors to the membrane in ACC of CP rats (Source: Ren, D.
, et al.
, Neurosci.
Bull.
2021) Finally, the research team Microinjection of NMDAR and AMPAR antagonists CNQX and AP-5 into ACC to block excitatory synaptic transmission and significantly reduce abdominal mechanical hyperalgesia in CP rats, which is similar to the analgesic effect of endomorphin administered in ACC (Picture 4)
.

Inhibiting the excitability of ACC pyramidal neurons by chemical genetics can reduce hyperalgesia and anxiety (Figure 5); activating these neurons by optogenetic methods failed to aggravate the above behavioral changes
.

These results suggest that in the CP state, the activation of ACC excitatory neurons has reached a peak in the CP state, so further enhancing its activity cannot cause more pain
.

However, inhibiting the activity of pyramidal neurons in ACC can alleviate the pain and related anxiety of chronic pancreatitis
.

 Figure 4 ACC bilateral microinjection of CNQX and AP-5 can relieve visceral pain and anxiety in CP rats (Source: Ren, D.
, et al.
, Neurosci.
Bull.
2021) Figure 5 Chemical genetics inhibition Lateral ACC pyramidal neurons can alleviate visceral pain response and anxiety-like behaviors in CP rats (Source: Ren, D.
, et al.
, Neurosci.
Bull.
2021) The results of this study indicate that the anterior cingulate gyrus (ACC) receives direct ascending projections from the nucleus tractus solitarius (NTS), which is a key relay station for visceral sensory afferents, and this neural circuit is in the pain state of chronic pancreatitis (CP) Is activated, ACC may be an important part of the uptransmission system of abdominal hyperalgesia in CP rats
.

 The up-regulation of pyramidal neurons and their synaptic transmission and glutamate receptor expression in ACC play a key role in hyperalgesia and anxiety in CP rats
.

 In CP model rats, the presynaptic glutamate release of pyramidal neurons in ACC increased, and the postsynaptic glutamate receptor and phosphorylation expression increased, suggesting that there is central sensitization in the state of CP pain.
The excitability of pyramidal neurons in ACC has a significant analgesic effect, which is equivalent to the effect of local administration of opioids
.

It can be seen that ACC is a potential target of neuromodulation intervention in the treatment of CP pain
.

 The results of this study lay the foundation for further research on the mechanisms of ACC-related loops involved in hyperalgesia and anxiety caused by CP
.

Original link: https://link.
springer.
com/article/10.
1007%2Fs12264-021-00800-x Professor Li Yunqing of Liang Qianju Brain Research Center of PLA Air Force Military Medical University is the corresponding author of this article, and Bai Yang’s attending physician is the co-corresponding author.
Graduate students Ren Dan, Li Jiani, Qiu Xintong and Wan Faping are the co-first authors
.

This research is supported by the National Natural Science Foundation of China (No.
81620108008, No.
31971112); Shaanxi Province Innovation Capability Support Program (No.
2021TD-57) and other funds
.

Corresponding author Professor Li Yunqing (photo provided from Li Yunqing’s laboratory) Selected previous articles [1] EMBO Rep｜Kang Jiuhong's research group discovered a new mechanism for lncRNA SOX1-OT to regulate human ESC neurogenesis [2] Neuron︱ Li Yulong’s laboratory developed a new type Fluorescent probes are used to detect the temporal and spatial dynamic changes of extracellular ATP [3] Neurosci BullGuangyin Xu’s research group reveals a new mechanism for targeting the combination of GATA1 and P2x7r in spinal astrocytes through DNA methylation to relieve visceral pain [4 】Nat Rev Neurosci Opinion Article︱Probabilistic Model of Alzheimer’s Disease: Modification of the Amyloid Cascade Hypothesis【5】J Neurosci︱Wan Xiaohong's research group reveals the general and specific neural representations of the brain’s task of decision-making uncertainty [6] eLife︱ Huang Zhili’s research team discovered that the paraventricular nucleus of the hypothalamic nucleus regulates wakefulness and sleepiness [7] Nat Commun︱ women are more likely to drink alcohol? New discovery of neural circuit to alleviate alcoholism and anxiety behaviors of men and women: paraventricular nucleus of thalamus-stria terminal nucleus [8] Nature Comm︱Song Jianren's research group discovered a new target to promote neural circuit reconstruction after spinal cord injury [9] Frontier review interpretation ︱Research progress of the basal layer in neurodegenerative diseases [10] Nat Neurosci︱The semantic representation of vision and language overlaps at the edge of the human visual cortex.
High-quality scientific research and training courses are recommended.
[1] Single-cell sequencing and spatial transcriptomics data analysis seminar References (slide up and down to view) [1] Olesen SS, Krauss T, Demir IE, Wilder-Smith OH, Ceyhan GO, Pasricha PJ, et al.
Towards a neurobiological understanding of pain in chronic pancreatitis: Mechanisms and implications for treatment.
Pain Rep 2017, 2: e625.
[2] Berthoud HR, Neuhuber WL.
Functional and chemical anatomy of the afferent vagal system.
Auton Neurosci 2000, 85: 1-17.