ArticleLiterature Review

Contribution of synaptic plasticity in the insular cortex to chronic pain

August 2016
Neuroscience 338

DOI:10.1016/j.neuroscience.2016.08.014

Authors:

University of Toronto

Animal and human studies have consistently demonstrated that cortical regions are important for pain perception and pain-related emotional changes. Studies of the anterior cingulate cortex (ACC) have shown that adult cortical synapses can be modified after peripheral injuries, and long-term changes at synaptic level may contribute to long-lasting suffering in patients. It also explains why chronic pain is resistant to conventional analgesics that act by inhibiting synaptic transmission. Insular cortex (IC), another critical cortical area, is found to be highly plastic and can undergo long-term potentiation (LTP) after injury. Inhibiting IC LTP reduces behavioral sensitization caused by injury. LTP of glutamatergic transmission in pain related cortical areas serves as a key mechanism for chronic pain.

Multiple modulatory roles of serotonin in chronic pain and injury-related anxiety

Article

Full-text available

Apr 2023

Chronic pain is long-lasting pain that often persists during chronic diseases or after recovery from disease or injury. It often causes serious side effects, such as insomnia, anxiety, or depression which negatively impacts the patient’s overall quality of life. Serotonin (5-HT) in the central nervous system (CNS) has been recognized as an important neurotransmitter and neuromodulator which regulates various physiological functions, such as pain sensation, cognition, and emotions–especially anxiety and depression. Its widespread and diverse receptors underlie the functional complexity of 5-HT in the CNS. Recent studies found that both chronic pain and anxiety are associated with synaptic plasticity in the anterior cingulate cortex (ACC), the insular cortex (IC), and the spinal cord. 5-HT exerts multiple modulations of synaptic transmission and plasticity in the ACC and the spinal cord, including activation, inhibition, and biphasic actions. In this review, we will discuss the multiple actions of the 5-HT system in both chronic pain and injury-related anxiety, and the synaptic mechanisms behind them. It is likely that the specific 5-HT receptors would be new promising therapeutic targets for the effective treatment of chronic pain and injury-related anxiety in the future.

Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry

Article

Jan 2021
BRAIN RES

The insula has emerged as a critical target for electrical stimulation since it influences pathological pain states. We investigated the effects of repetitive electrical stimulation of the insular cortex (ESI) on mechanical nociception, and general locomotor activity in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. We also studied neuroplastic changes in central pain areas and the involvement of GABAergic signaling on ESI effects. CCI rats had electrodes implanted in the left agranular posterior insular cortex (pIC), and mechanical sensitivity was evaluated before and after one or five daily consecutive ESIs (15 min each, 60 Hz, 210 μs, 1 V). Five ESIs (repetitive ESI) induced sustained mechanical antinociception from the first to the last behavioral assessment without interfering with locomotor activity. A marked increase in Fos immunoreactivity in pIC and a decrease in the anterior and mid-cingulate cortex, periaqueductal gray and hippocampus were noticed after five ESIs. The intrathecal administration of the GABAA receptor antagonist bicuculline methiodide reversed the stimulation-induced antinociception after five ESIs. ESI increased GAD65 levels in pIC but did not interfere with GABA, glutamate or glycine levels. No changes in GFAP immunoreactivity were found in this work. Altogether, the results indicate the efficacy of repetitive ESI for the treatment of experimental neuropathic pain and suggest a potential influence of pIC in regulating pain pathways partially through modulating GABAergic signaling.

Cortical Potentiation in Chronic Neuropathic Pain and the Future Treatment

Article

Full-text available

Mar 2025

Pain, or the ability to feel pain and express the unpleasantness caused by peripheral injuries, are functions of the central nervous system. From peripheral sensory nerve terminals to certain cortical regions of the brain, activation of related neural networks underlies the sensory process. Recently, our knowledge of pain has been increasing dramatically, due to the advancement of scientific approaches. We no longer see the brain as a random matrix for pain but, rather, we are able to identify the step-by-step selective signaling proteins, neurons, and networks that preferentially contribute to the process of chronic pain and its related negative emotions, like anxiety and fear. However, there is still lacking the selective and effective drugs and methods for the treatment of chronic pain clinically. While first-line drugs for acute pain and mental diseases are also applied for the clinical management of chronic pain, their prolonged usage always causes serious side effects. In this short review, we will update and summarize the recent progress in this field and mainly focus on the roles of neural networks and synaptic mechanisms in chronic neuropathic pain. Furthermore, potential drug targets (such as plasticity-related signaling molecules, ionic channels, cytokines, and neuropeptides) and methods for the management of chronic neuropathic pain will be discussed as well. We hope this review can provide new, valuable insight into the treatment of chronic neuropathic pain.

Converging Effects of Chronic Pain and Binge Alcohol Consumption on Anterior Insular Cortex Neurons Projecting to the Dorsolateral Striatum in Male Mice

Article

Full-text available

Mar 2024

Chronic pain and alcohol use disorder (AUD) are highly comorbid, and patients with chronic pain are more likely to meet the criteria for AUD. Evidence suggests that both conditions alter similar brain pathways, yet this relationship remains poorly understood. Prior work shows that the anterior insular cortex (AIC) is involved in both chronic pain and AUD. However, circuit-specific changes elicited by the combination of pain and alcohol use remain understudied. The goal of this work was to elucidate the converging effects of binge alcohol consumption and chronic pain on AIC neurons that send projections to the dorsolateral striatum (DLS). Here, we used the Drinking-in-the-Dark (DID) paradigm to model binge-like alcohol drinking in mice that underwent spared nerve injury (SNI), after which whole-cell patch-clamp electrophysiological recordings were performed in acute brain slices to measure intrinsic and synaptic properties of AIC→DLS neurons. In male, but not female, mice, we found that SNI mice with no prior alcohol exposure consumed less alcohol compared with sham mice. Electrophysiological analyses showed that AIC→DLS neurons from SNI-alcohol male mice displayed increased neuronal excitability and increased frequency of miniature excitatory postsynaptic currents. However, mice exposed to alcohol prior to SNI consumed similar amounts of alcohol compared with sham mice following SNI. Together, our data suggest that the interaction of chronic pain and alcohol drinking have a direct effect on both intrinsic excitability and synaptic transmission onto AIC→DLS neurons in mice, which may be critical in understanding how chronic pain alters motivated behaviors associated with alcohol.

BDNF in Neuropathic Pain; the Culprit that Cannot be Apprehended

Article

Full-text available

Feb 2024
NEUROSCIENCE

Peter A Smith

EEG-Based Cortical Alterations in Individuals With Chronic Knee Pain Secondary to Osteoarthritis: A Cross-sectional Investigation

Article

Nov 2023
J PAIN

Different Synaptic Plasticity After Physiological and Psychological Stress in the Anterior Insular Cortex in an Observational Fear Mouse Model

Article

Full-text available

May 2022

Post-traumatic stress disorder (PTSD) can be triggered not only in people who have personally experienced traumatic events but also in those who witness them. Physiological and psychological stress can have different effects on neural activity, but little is known about the underlying mechanisms. There is ample evidence that the insular cortex, especially the anterior insular cortex (aIC), is critical to both the sensory and emotional experience of pain. It is therefore worthwhile to explore the effects of direct and indirect stress on the synaptic plasticity of the aIC. Here, we used a mouse model of observational fear to mimic direct suffering (Demonstrator, DM) and witnessing (Observer, OB) of traumatic events. After observational fear training, using a 64-channel recording system, we showed that both DM and OB mice exhibited a decreased ratio of paired-pulse with intervals of 50 ms in the superficial layers of the aIC but not in the deep layers. We found that theta-burst stimulation (TBS)–induced long-term potentiation (LTP) in OB mice was significantly higher than in DM mice, and the recruitment of synaptic responses occurred only in OB mice. Compared with naive mice, OB mice showed stronger recruitment and higher amplitude in the superficial layers of the aIC. We also used low-frequency stimulation (LFS) to induce long-term depression (LTD). OB mice showed greater LTD in both the superficial and deep layers of the aIC than naive mice, but no significant difference was found between OB and DM mice. These results provide insights into the changes in synaptic plasticity in the aIC after physiological and psychological stress, and suggest that different types of stress may have different mechanisms. Furthermore, identification of the possible causes of the differences in stress could help treat stress-related disorders.

Endogenous Opioid and Cannabinoid Systems Contribute to NSAIDs-Induced Antinociception: II. Agranular Insular Cortex

Chapter

Full-text available

Sep 2021

A growing body of literature suggests that the insula nicely demonstrates the convergence of neuroanatomy and the functional multidimensional nature of pain. The posterior (granular) insula receives inputs from pain, temperature, visceral, vestibular, and other sensory pathways; this multimodal sensory representation is further elaborated in the mid-insular (dysgranular) cortex and then conveyed to the anterior (agranular) insula, which further processes this information and interacts with areas involved in cognitive and emotional control. The insula thus provides an interface between bodily sensation, pain, and emotion, and may have a key role in perceptual awareness, social behavior, and decision making. In the second report, using the thermal withdrawal (Hargreaves) and mechanical (von Frey) tests, we provide data on the administration of NSAIDs into the agranular insular cortex in rats that reduced heat and mechanical hyperalgesia. The latter was produced by intraplantar injection of formalin, and this hyperalgesia was attenuated by pre-or post-treatment with the opioid receptor antagonists, naloxone and CTOP, and of the cannabinoid receptor (CB1) antagonist AM-251. These data support the concept that NSAID-evoked antinociception is mediated via descending endogenous opioid and cannabinoid systems inhibiting spinal paw withdrawal reflexes in rats.

Genetic overlap between multi-site chronic pain and cognition: a large-scale genome-wide cross-trait analysis

Article

Full-text available

Mar 2025

Background Different studies have consistently demonstrated a positive correlation between chronic pain and cognitive changes. This study aimed to explore the genetic factors underlying the relationship between chronic pain and cognitive traits, and to investigate whether an inherent causal connection exists between them. Method The genetic contributions of chronic multi-site pain and eight cognitive traits were investigated based on Genome-wide association studies (GWAS) data. Linkage disequilibrium score regression (LDSC) was employed to assess the genetic correlations between each pair of traits. The shared genetic components of these traits were investigated by identifying single nucleotide polymorphisms (SNPs) with pleiotropic effects using the Cross Phenotype Association (CPASSOC) method. Furthermore, enrichment analysis and transcriptome-wide association studies (TWAS) were performed to characterize the significant associations between genetic traits. The latent causal variable model (LCV) was employed to explore the potential causal relationship between both traits. Results A significant negative genetic correlation was found between chronic pain and several cognitive functions, particularly intelligence (rg = −0. 11, p = 7.77 × 10 ⁻⁶⁴ ). CPASSOC identified 150 pleiotropic loci. A co-localization analysis was conducted, which identified 20 loci exhibiting pleiotropic effects at the same genomic position. The LCV analysis indicated no causal relationship between both traits. Conclusion The present work contributed to an enhanced understanding of the complex genetic interplay between cognitive function and chronic pain.

Allosteric modulation and direct activation of glycine receptors by a tricyclic sulfonamide

Article

Full-text available

Feb 2025

Ionotropic glycine receptors (GlyRs) are chloride-permeable ligand-gated ion channels expressed in the nervous system. Alterations to glycinergic inhibition and the generation of dysfunctional GlyRs have been linked to chronic pain, a widely prevalent disease. Positive allosteric modulators (PAMs) targeting GlyRs exerted analgesic effects, motivating research on glycinergic PAMs as potential pain therapies. Rationally designed tricyclic sulfonamides are novel glycinergic PAMs with analgesic activity. However, detailed electrophysiological studies on these PAMs are still limited, and the GlyR binding site structural data has not been yet validated by mutational studies. Here, we combined electrophysiology and bioinformatics to systematically study the AM-1488 actions, a prototypical tricyclic sulfonamide, on recombinant GlyRs. We determined that AM-1488 is a potent, non-selective PAM of mammalian GlyR subtypes. In addition, the compound displayed agonistic activity, with partial preference for α1GlyRs. Single channel assays revealed that the compound increased the channel open probability without changing conductance. Mutational analyses on the tricyclic sulfonamide site confirm the molecular determinants contributing to functional activity. Our findings further define the mechanistic framework underlying the GlyR modulation by this PAM class, suggesting that further structure-driven exploration within the tricyclic sulfonamide site may originate novel glycinergic modulators for future development.

Supraspinal facilitation of painful stimuli by glutamatergic innervation from the retrosplenial to the anterior cingulate cortex

Article

Full-text available

Jan 2025
PLOS BIOL

The anterior cingulate cortex (ACC) is recognized as a pivotal cortical region involved in the perception of pain. The retrosplenial cortex (RSC), located posterior to the ACC, is known to play a significant role in navigation and memory processes. Although the projections from the RSC to the ACC have been found, the specifics of the synaptic connections and the functional implications of the RSC-ACC projections remain less understood. In this study, we employed a combination of whole-brain imaging, in vitro electrophysiology, and two-photon calcium imaging techniques to confirm the presence of direct excitatory glutamatergic projections from the RSC to the ACC in mice. This excitatory transmission is predominantly mediated by the postsynaptic AMPA receptors. Furthermore, the activation of the RSC-ACC projections through opto-/chemogenetics significantly facilitated the behavioral responses to both mechanical and thermal nociceptive stimuli in adult mice. Notably, this activation did not influence spinal nociceptive responses in the tail-flick test, nor did it affect anxiety-like or aversive behaviors. These findings indicate that the RSC-ACC glutamatergic pathway modulates nociceptive perception primarily at the supraspinal cortical level. We have identified a novel cortico-cortical facilitatory pathway that contributes to nociceptive processing in the cingulate cortex. The RSC-ACC pathway probably serves to integrate memory engrams with pain perception in both humans and animals.

Whole-brain mapping of afferents to the anterior cingulate cortex in adult mice

Article

Full-text available

Nov 2024
MOL PAIN

The anterior cingulate cortex (ACC) is critical for pain perception, emotion and cognition. Previous studies showed that the ACC has a complex network architecture, which can receive some projection fibers from many brain regions, including the thalamus, the cerebral cortex and other brain regions. However, there was still a lack of whole-brain mapping of the ACC in adult mice. In the present study, we utilized a rabies virus-based retrograde trans-monosynaptic tracing system to map whole-brain afferents to the unilateral ACC in adult mice. We also combined with a new high-throughput, high-speed and high-resolution VISoR imaging technique to generate a three-dimensional whole-brain reconstruction. Our results showed that several principal groups of brain structures send direct monosynaptic inputs to the ACC, including the cerebral cortex, amygdala, striatum, the thalamus, and the brainstem. We also found that cortical neurons in the ACC mainly receive ipsilateral monosynaptic projections. Some cortical areas and forebrain regions also bilaterally projected to the ACC. These findings provide a complete analysis of the afferents to the ACC in adult mice, and whole-brain mapping of ACC afferents would provide important anatomic evidence for the study of pain, memory, and cognition.

The Role of the Insular Cortex and Serotonergic System in the Modulation of Long-Lasting Nociception

Article

Full-text available

Oct 2024

The insular cortex (IC) is a brain region that both receives relevant sensory information and is responsible for emotional and cognitive processes, allowing the perception of sensory information. The IC has connections with multiple sites of the pain matrix, including cortico-cortical interactions with the anterior cingulate cortex (ACC) and top-down connections with sites of descending pain inhibition. We explored the changes in the extracellular release of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), after inflammation was induced by carrageenan injection. Additionally, we explored the role of 5HT receptors (the 5HT1A, 5HT2A, and 5HT3 receptors) in the IC after inflammatory insult. The results showed an increase in the extracellular levels of 5HT and 5-HIAA during the inflammatory process compared to physiological levels. Additionally, the 5HT1A receptor was overexpressed. Finally, the 5HT1A, 5HT2A, and 5HT3 receptor blockade in the IC had antinociceptive effects. Our results highlight the role of serotonergic neurotransmission in long-lasting inflammatory nociception within the IC.

Cortical nitric oxide required for presynaptic long-term potentiation in the insular cortex

Article

Full-text available

Jun 2024
PHILOS T R SOC B

Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is required for kainate receptor (KAR)-dependent presynaptic form of LTP (pre-LTP) in the adult insular cortex (IC). In the IC, we found that inhibition of NO synthase erased the maintenance of pre-LTP, while the induction of pre-LTP required the activation of KAR. Furthermore, NO is essential for pre-LTP induced between two pyramidal cells in the IC using the double patch-clamp recording. These results suggest that NO is required for homosynaptic pre-LTP in the IC. Our results present strong evidence for the critical roles of NO in pre-LTP in the IC. This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats

Article

Full-text available

May 2024
J HEADACHE PAIN

Background Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. Methods The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. Results The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. Conclusions Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Impaired neuronal macroautophagy in the prelimbic cortex contributes to comorbid anxiety-like behaviors in rats with chronic neuropathic pain

Article

Full-text available

Mar 2024

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors.Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.

Investigating the brain functional abnormalities underlying pain hypervigilance in chronic neck and shoulder pain: a resting-state fMRI study

Article

Full-text available

Feb 2024
NEURORADIOLOGY

Purpose To investigate pain hypervigilance in individuals suffering from chronic neck and shoulder pain (CNSP) and its underlying brain mechanism. Methods The evaluation of pain vigilance was conducted through the utilization of pain vigilance and awareness questionnaires. Voxel-wise regional homogeneity (ReHo) from 60 CNSP patients and 60 healthy controls (HCs) using resting-state fMRI data. Voxel-wise two-sample T-test was conducted to reveal the ReHo variations between CNSP and HC. Correlation analyses were utilized to reveal the connection between brain abnormalities and medical measurements. Furthermore, a mediation analysis was conducted to elucidate the pathway-linking changes in brain function with medical measurements. Results Our present study revealed three main findings. Firstly, patients with CSNP demonstrated a heightened vigilance of pain in comparison to healthy adults, a common occurrence among individuals with chronic pain conditions. Secondly, we observed brain abnormalities in various brain regions in CSNP patients, and these alterations were associated with the extent of pain vigilance. Lastly, the pain hypervigilance impact on the severity of pain was found to be controlled by regional neural activity in the anterior cingulate cortex (ACC) in subjects with CSNP. Conclusion Our findings suggested that long-term repetitive nociceptive input caused by chronic pain further aggravates the pain intensity by impairing the vigilance-related pain processing within the anterior cingulate cortex in CNSP patients.

Symptom effects and central mechanism of acupuncture in patients with functional gastrointestinal disorders: a systematic review based on fMRI studies

Article

Full-text available

Jan 2024
BMC GASTROENTEROL

Background Functional gastrointestinal disorders (FGIDs) are closely related to disorders of brain-gut interaction. FGIDs are the dominant disease of acupuncture treatment, which can improve the symptoms and emotional state. Aim To evaluate the results and quality of the available clinical evidence and to summarize the central mechanism and effect of acupuncture on FGIDs. Methods PubMed, EMBASE, Web of science, Cochrane Library, China National Knowledge Infrastructure (CNKI) were searched by computer to collect the randomized controlled trials (RCTs), which contained central mechanisms via fMRI research of acupuncture in the treatment of FGIDs patients. The search time limit was from the establishment of the database to June 22, 2022. Two researchers independently screened the literature, extracted data, and evaluated the quality. Results Ten RCTs involving fMRI data were included in this study, including 4 Functional dyspepsia (FD) studies, 3 irritable bowel syndrome (IBS) studies, and 3 functional constipation (FC) studies. The score of improvements in both gastrointestinal symptoms and psychological symptoms showed that acupuncture could significantly improve the clinical symptoms of FGIDs patients, including abdominal pain, abdominal distension, frequency of defecation, and stool characteristics, and could relieve anxiety and depression symptoms of patients. Acupuncture could regulate brain functional connections and functional activity in FGIDs patients, mainly including insula, anterior cingulate cortex, prefrontal cortex, thalamus, hippocampus, amygdala and other brain regions. Conclusion Acupuncture can improve gastrointestinal symptoms and psychological status in FGIDs patients, and regulate functional connectivity and activity of brain regions such as insula, ACC, PFC, thalamus, HIPP, amygdala, etc. These changes in brain activity may related to visceral sensation, pain regulation, emotion, but further studies of high quality are still necessary.

Assessing brain function in stressed healthy individuals following the use of a combination of green tea, Rhodiola, magnesium, and B vitamins: an fMRI study

Article

Full-text available

Aug 2023

Introduction This randomized, controlled, single-blinded trial assessed the effect of magnesium (Mg)-Teadiola (Mg, vitamins B6, B9, B12, Rhodiola, and green tea/L-theanine) versus placebo on the brain response to stressful thermal stimulus in chronically stressed, but otherwise healthy subjects. Impacts on stress-related quality-of-life parameters (depression, anxiety, sleep, and perception of pain) were also explored. Methods The study recruited a total of 40 adults (20 per group), suffering from stress for more than 1 month and scaling ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire at the time of inclusion. Individuals received oral Mg-Teadiola or placebo for 28 days (D). fMRI analysis was used to visualize the interplay between stress and pain cerebral matrices, using thermal stress model, at baseline (D0) and after D28. Results Based on blood-oxygen-level-dependent (BOLD) signal variations during the stress stimulation (before pain perception), a significantly increased activation between D0 and D28 was observed for left and right frontal area (p = 0.001 and p = 0.002, respectively), left and right anterior cingulate cortex (ACC) (p = 0.035 and p = 0.04, respectively), and left and right insula (p = 0.034 and p = 0.0402, respectively) in Mg-Teadiola versus placebo group. During thermal pain stimulation, a significantly diminished activation of the pain matrix was observed between D0 and D28, for left and right prefrontal area (both p = 0.001), left and right insula (p = 0.008 and p = 0.019, respectively), and left and right ventral striatum (both p = 0.001) was observed in Mg-Teadiola versus placebo group. These results reinforce the clinical observations, showing a perceived benefit of Mg-Teadiola on several parameters. After 1 month of treatment, DASS-42 stress score significantly decreased in Mg-Teadiola group [effect size (ES) −0.46 (−0.91; −0.01), p = 0.048]. Similar reductions were observed on D14 (p = 0.011) and D56 (p = 0.008). Sensitivity to cold also improved from D0 to D28 for Mg-Teadiola versus placebo [ES 0.47 (0.02; 0.92) p = 0.042]. Conclusion Supplementation with Mg-Teadiola reduced stress on D28 in chronically stressed but otherwise healthy individuals and modulated the stress and pain cerebral matrices during stressful thermal stimulus.

Nociplastic pain in research and practice : Overview of biopsychosocial principles, possibilities and difficulties

Article

Jul 2023
SCHMERZ

Traditionally, two mechanistic pain categories were distinguished: nociceptive and neuropathic pain. After the definitions of these two mechanistic descriptors were refined more precisely in the International Association for the Study of Pain (IASP) taxonomy in 2011, a large group of patients remained whose pain could not be assigned to either of the two categories. Nociplastic pain was therefore proposed as a third mechanistic descriptor in 2016. This review article presents the current state of the integration of nociplastic pain into research and clinical practice. In particular, the possibilities and difficulties of applying this concept are addressed from a human and animal experimental research perspective.

Proanthocyanidins induce analgesic and anxiolytic effects in spared nerve injured mice by decreasing in vivo firing rate of pyramidal cells in the insular cortex

Article

Full-text available

Jun 2023

Neuropathic pain is one of the most common symptoms of clinical pain that often accompanied by severe emotional changes such as anxiety. However, the treatment for comorbidity of chronic pain and anxiety is limited. Proanthocyanidins (PACs), a group of polyphenols enriched in plants and foods, have been reported to cause pain-alleviating effects. However, whether and how PACs induce analgesic and anxiolytic effects in the central nervous system remain obscure. In the present study, we observed that microinjection of PACs into the insular cortex (IC) inhibited mechanical and spontaneous pain sensitivity and anxiety-like behaviors in mice with spared nerve injury. Meanwhile, PACs application exclusively reduced the FOS expression in the pyramidal cells but not interneurons in the IC. In vivo electrophysiological recording of the IC further showed that PACS application inhibited the firing rate of spikes of pyramidal cells of IC in neuropathic pain mice. In summary, PACs induce analgesic and anxiolytic effects by inhibiting the spiking of pyramidal cells of the IC in mice with neuropathic pain, which should provide new evidence of PACs as the potential clinical treatment of chronic pain and anxiety comorbidity.

Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice

Article

Full-text available

Jun 2023
MOL NEUROBIOL

Chronic pain conditions within clinical populations are correlated with a high incidence of depression, and researchers have reported their high rate of comorbidity. Clinically, chronic pain worsens the prevalence of depression, and depression increases the risk of chronic pain. Individuals suffering from chronic pain and depression respond poorly to available medications, and the mechanisms underlying the comorbidity of chronic pain and depression remain unknown. We used spinal nerve ligation (SNL) in a mouse model to induce comorbid pain and depression. We combined behavioral tests, electrophysiological recordings, pharmacological manipulation, and chemogenetic approaches to investigate the neurocircuitry mechanisms of comorbid pain and depression. SNL elicited tactile hypersensitivity and depression-like behavior, accompanied by increased and decreased glutamatergic transmission in dorsal horn neurons and midbrain ventrolateral periaqueductal gray (vlPAG) neurons, respectively. Intrathecal injection of lidocaine, a sodium channel blocker, and gabapentin ameliorated SNL-induced tactile hypersensitivity and neuroplastic changes in the dorsal horn but not depression-like behavior and neuroplastic alterations in the vlPAG. Pharmacological lesion of vlPAG glutamatergic neurons induced tactile hypersensitivity and depression-like behavior. Chemogenetic activation of the vlPAG-rostral ventromedial medulla (RVM) pathway ameliorated SNL-induced tactile hypersensitivity but not SNL-elicited depression-like behavior. However, chemogenetic activation of the vlPAG-ventral tegmental area (VTA) pathway alleviated SNL-produced depression-like behavior but not SNL-induced tactile hypersensitivity. Our study demonstrated that the underlying mechanisms of comorbidity in which the vlPAG acts as a gating hub for transferring pain to depression. Tactile hypersensitivity could be attributed to dysfunction of the vlPAG-RVM pathway, while impairment of the vlPAG-VTA pathway contributed to depression-like behavior. Graphical Abstract

A Critical Involvement of Glutamatergic Neurons in the Anterior Insular Cortex for Subdiaphragmatic Vagotomy-induced Analgesia

Article

Full-text available

Apr 2023

Subdiaphragmatic vagotomy (SDV) is known to produce analgesic effect in various pain conditions including not only visceral pain but also somatic pain. We aimed to determine brain mechanisms by which SDV induces analgesic effect in somatic pain condition by using formalin-induced acute inflammatory pain model. We identified brain regions that mediate SDV-induced analgesic effect on acute inflammatory pain by analyzing c-Fos expression in the whole brain. We found that c-Fos expression was specifically increased in the anterior insular cortex (aIC) among subregions of the insular cortex in acute inflammatory pain, which was reversed by SDV. These results were not mimicked in female mice, indicating sexual-dimorphism in SDV-induced analgesia. SDV decreased c-Fos expressions more preferentially in glutamatergic neurons rather than GABAergic neurons in the aIC, and pharmacological activation of glutamatergic neurons with NMDA in the aIC inhibited SDV-induced analgesic effect. Furthermore, chemogenetic activation of glutamatergic neurons in the aIC reversed SDV-induced analgesia. Taken together, our results suggest that the decrease in the neuronal activity of glutamatergic neurons in the aIC mediates SDV-induced analgesic effect, potentially serving as an important therapeutic target to treat inflammatory pain.

Cortical synaptic basis of consciousness

Preprint

Apr 2023

Min Zhuo

Consciousness is one of final questions for humans to tackle in neuroscience. Due to the lack of understanding of the basic brain network and mechanisms of functions, our knowledge of consciousness remains at the theoretical level. Recent studies using brain imaging in humans and modern neuroscience techniques in animal studies reveal a basic brain network for consciousness. The projection from the thalamus to different cortical regions form a network of activities to maintain consciousness in human and animals. These feedback and feedforward circuits maintain the consciousness even in certain brain injury conditions. Proteins and ion channels that contribute to these circuit neural activities are targets for drugs and manipulations that affect consciousness, such as anesthetic agents. Synaptic plasticity that trains synapses during learning and information recall, modify circuits and contribute to a high level of consciousness in certain populations.

The Role of the Insular Cortex in Pain

Article

Full-text available

Mar 2023
INT J MOL SCI

Charalampos Labrakakis

The transition from normal to chronic pain is believed to involve alterations in several brain areas that participate in the perception of pain. These plastic changes are then responsible for aberrant pain perception and comorbidities. The insular cortex is consistently found activated in pain studies of normal and chronic pain patients. Functional changes in the insula contribute to chronic pain; however, the complex mechanisms by which the insula is involved in pain perception under normal and pathological conditions are still not clear. In this review, an overview of the insular function is provided and findings on its role in pain from human studies are summarized. Recent progress on the role of the insula in pain from preclinical experimental models is reviewed, and the connectivity of the insula with other brain regions is examined to shed new light on the neuronal mechanisms of the insular cortex’s contribution to normal and pathological pain sensation. This review underlines the need for further studies on the mechanisms underlying the involvement of the insula in the chronicity of pain and the expression of comorbid disorders.

Comparative investigation of analgesic tolerance to taurine, sodium salicylate and morphine: Involvement of peripheral muscarinic receptors

Article

Dec 2022
NEUROSCI LETT

Nowadays various analgesic medications are used for the management of acute and chronic pain. Among these opioid and non-steroidal anti-inflammatory drugs stand in the first line of therapy, however, prolonged administration of these substance is generally challenged by development of analgesic tolerance in patients. Therefore, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. In this respect, Taurine, a free amino acid, has been shown to induce significant analgesia at both spinal and peripheral levels through cholinergic mechanisms. In the present study, we used hot-plate analgesic test to investigate how taurine either as a single medication or in combination with sodium salicylate and morphine may affect both acute response to pain and development of analgesic tolerance. The effect of taurine was also tested on morphine withdrawal syndrome. Hyoscine butyl bromide was used to assess the role of muscarinic receptors in taurine-mediated effects. Finally, biochemical assay was done to reveal how the activity of brain acetylcholinesterase may change in relation with muscarinic receptor activity. Results indicated that acute administration of taurine-sodium salicylate combination causes more potent analgesia compared to the use of tau (but not SS alone) and this seems to be mediated via activity of muscarinic receptors in peripheral nervous system. Furthermore, the effect of this combination undergoes less analgesic tolerance during time. Combination of taurine and morphine is an effective strategy to attenuate both morphine analgesic tolerance and dependence and this also seems to depend on activity of muscarinic receptors, however through differential cellular mechanisms.

Electrical stimulation of the posterior insular cortex induces opioid and cannabinoid-dependent antinociception and regulates glial cells in the spinal cord

Article

Full-text available

Nov 2022

BACKGROUND AND OBJECTIVES Half of neuropathic pain patients still end up failing clinical treatments. Electrical stimulation of the posterior insular cortex (ESI) modulates sensory and nociceptive circuits. This study evaluated the effects of a range of frequencies of ESI proposed to improve neuropathic pain. METHODS Male Sprague Dawley rats, 280-340 g, submitted to the chronic constriction of the right sciatic nerve were tested for mechanical sensitivity using the paw pressure and von Frey flaments tests, and for thermal sensitivity using the hot plate test. The rats were submitted to ESI 10, 60 or 100 Hz (one, five or seven ESI, 15 min, 210 µs, 1V), applied to the posterior insular cortex, and were evaluated in the tests before and after ESI, or in follow-up of 48, 72 and 168h. The open field evaluated general activity after ESI 5. The involvment of opioid and cannabinoid testes were evaluated through treatment with naloxone and SR1416A - antagonist and inverse agonist/antagonist of the receptors, respectively, after ESI 5, while activation of astrocytes, marked by glial fibrillary acid protein (GFAP), and of microglia, marked by IBA-1 (glial marker), in the spinal cord evaluated by immunohistochemistry. RESULTS Data demonstrate that 10, 60, and 100 Hz ESIs modulate mechanical and thermal sensitivity. ESI 5 increased immunoreactivity of GFAP in the spinal cord, without altering IBA-1 (glial marker). Naloxone and SR141716A reversed the antinociception of 60 Hz ESI 5. 60 Hz ESI 7 induced antinociception up to 72h. CONCLUSION 60 Hz ESI induces opioid and cannabinoid-dependent antinociception and regulates glia. HIGHLIGHTS • 60 Hz-delivered ESI was the best analgesic protocol for the insular stimulation. • Data showed a prolonged analgesic effect up to 72h after repetitive ESI. • ESI regulates glia activation in pain modulatory system.

CGRP physiology, pharmacology, and therapeutic targets: Migraine and beyond

Article

Dec 2022
PHYSIOL REV

Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. Its two isoforms (α and β) are widely expressed throughout the body in sensory neurons, as well as in other cell types, such as motor neurons and neuroendocrine cells. CGRP acts via at least two G protein-coupled receptors that form unusual complexes with receptor activity-modifying proteins. These are the CGRP receptor and the AMY1 receptor; in rodents, additional receptors come into play. Although CGRP is known to produce many effects, the precise molecular identity of the receptor(s) that mediate CGRP effects is seldom clear. Despite the many enigmas still in CGRP biology, therapeutics that target the CGRP axis to treat or prevent migraine are a bench to bedside success story. This review provides a contextual background on the regulation and sites of CGRP expression and CGRP receptor pharmacology. The physiological actions of CGRP in the nervous system are discussed, along with updates on CGRP actions in the cardiovascular, pulmonary, gastrointestinal, immune, hematopoietic, and reproductive systems, and metabolic effects of CGRP in muscle and adipose tissues. We cover how CGRP in these systems is associated with disease states, most notably migraine. In this context, we discuss how CGRP actions in both the peripheral and central nervous systems provide a basis for therapeutic targeting of CGRP in migraine. Finally, we highlight potentially fertile ground for the development of additional therapeutics and combinatorial strategies that could be designed to modulate CGRP signaling for migraine and other diseases.

Central sensitization: clinical utility of a physiological concept for the International Statistical Classification of Diseases and Related Health Problems and for nociplastic pain

Article

Full-text available

Sep 2022

Nowe leczenie skojarzone zmniejsza obiektywne i subiektywne wskaźniki stresu

Article

Full-text available

Jan 2022

Lionel Noah

Zredukowanie szkodliwego stresu jest kluczowym wyzwaniem, aby móc zachować dobre samopoczucie. Niedawne badanie przeprowadzone metodą podwójnie ślepej próby, z randomizacją i grupą kontrolną placebo u zdrowych dorosłych odczuwających umiarkowany stres (Clinicaltrials.gov: NCT03262376; 25/0817) wykazało korzystny wpływ stosowania połączenia magnezu, witamin z grupy B (B6, B9, B12) oraz ekstraktów z różeńca i zielonej herbaty na obiektywne i subiektywne wskaźniki stresu. Połączenie to było skuteczniejsze niż stosowanie któregokolwiek z ekstraktów oddzielnie.

Chronic musculoskeletal pain: traps and pitfalls in classification and management of a major global disease burden

Article

Full-text available

Aug 2022

Rolf-Detlef Treede

Mary-Ann Fitzcharles et al. propose to introduce “regional fibromyalgia” as a new diagnosis. This commentary summarizes why this term is misleading but nonetheless the article may pave the way towards useful concepts for myofascial pains.

Chronic pain domains and their relationship to personality, abilities, and brain networks

Article

Apr 2022

Chronic pain is a multidimensional pathological state. Recent evidence suggests that specific brain properties and patients’ psychological and physical traits are distorted in chronic pain patients. However, the relationship between these alterations and pain dimensions remains poorly understood. Here we first evaluated multiple dimensions of chronic pain by assessing a broad battery of pain-related questionnaire scores (23 outcomes) of 107 chronic low back pain (CBP) patients, we identified three distinct chronic pain domains: magnitude, affect & disability, and quality. Second, we investigated the pain domains relationship with measures of personality, social interaction, psychological traits, and ability traits (77 biopsy&ab outcomes). Pain magnitude (OOS r2=0.33) associated with emotional control, attention and working memory; with higher pain scores showing lower capacity to regulate and adapt behaviorally. Pain affect & disability (OOS r2=0.79) associated with anxiety, catastrophizing and social relationships dysfunction. Pain quality did not relate significantly to biopsy&ab variables. Third, we mapped these three pain domains to brain functional connectivity. Pain magnitude mainly associated with the sensorimotor and the cingulo-opercular networks (OOS r2=0.41). Pain affect & disability related to frontoparietal and default mode networks (OOS r2=0.35). Pain quality integrated sensorimotor, auditory, and cingulo-opercular networks (OOS r2=0.43). Mediation analysis could link functional connectivity and biopsy&ab models to respective pain domains. Our results provide a global overview of the complexity of chronic pain, showing how underlying distinct domains of the experience map to different biopsy&ab correlates and underlie unique brain network signatures.

Abnormal reward system network in primary dysmenorrhea

Article

Nov 2021
MOL PAIN

Neuroimaging studies have demonstrated that reward system is associated with chronic pain diseases. In addition, previous studies have also demonstrated abnormal functional and structural brain regions in primary dysmenorrhea. However, the relation of reward system and primary dysmenorrhea is still unknown. Using the resting state functional magnetic resonance imaging, we aimed to investigate the functional connectivity changes of reward system during periovulatory phase in primary dysmenorrhea. Forty-one primary dysmenorrhea patients and 39 matched female healthy controls participated in this study. Compared to healthy controls, primary dysmenorrhea patients showed decreased connectivity of left nucleus accumbens with the bilateral anterior insula and the left amygdala and decreased connectivity of right nucleus accumbens with ventral tegmental area, the left hippocampus, the right orbital frontal cortex, and the right anterior insula. In addition, the decreased functional connectivity between the right nucleus accumbens-ventral tegmental area negatively correlated with the level of prostaglandin F2 alpha. Our findings provide neuroimaging evidence in support of the abnormal reward system connectivity in primary dysmenorrhea patients, which might contribute to a better understanding of the cerebral pathophysiology of primary dysmenorrhea.

Cellular and synaptic mechanisms for Parkinson’s disease-related chronic pain

Article

Full-text available

Mar 2021
MOL PAIN

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. Chronic pain is experienced by the vast majority of patients living with Parkinson’s disease. The degeneration of dopaminergic neuron acts as the essential mechanism of Parkinson’s disease in the midbrain dopaminergic pathway. The impairment of dopaminergic neurons leads to dysfunctions of the nociceptive system. Key cortical areas, such as the anterior cingulate cortex (ACC) and insular cortex (IC) that receive the dopaminergic projections are involved in pain transmission. Dopamine changes synaptic transmission via several pathway, for example the D2-adenly cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway and D1-G protein-coupled receptor kinase 2 (GRK2)-fragile X mental retardation protein (FMRP) pathway. The management of Parkinson’s disease-related pain implicates maintenance of stable level of dopaminergic drugs and analgesics, however a more selective drug targeting at key molecules in Parkinson’s disease-related pain remains to be investigated.

Cortical Modulation of Nociception

Article

Jan 2021
NEUROSCIENCE

Nociception is the neuronal process of encoding noxious stimuli and could be modulated at peripheral, spinal, brainstem, and cortical levels. At cortical levels, several areas including the anterior cingulate cortex, prefrontal cortex, ventrolateral orbital cortex, insular cortex, motor cortex, and somatosensory cortices are involved in nociception modulation through two main mechanisms: (i) a descending modulatory effect at spinal level by direct corticospinal projections or mostly by activation of brainstem structures (i.e. periaqueductal grey matter, locus coeruleus, the nucleus of raphe and rostroventral medulla); and by (ii) cortico-cortical or cortico-subcortical interactions. This review summarizes evidence related to the participation of the aforementioned cortical areas in nociception modulation and different neurotransmitters or neuromodulators that have been studied in each area. Besides, we point out the importance of considering intracortical neuronal populations and receptors expression, as well as, nociception-induced cortical changes, both functional and connectional, to better understand this modulatory effect. Finally, we discuss the possible mechanisms that could potentiate the use of cortical stimulation as a promising procedure in pain alleviation.

Common neural correlates of chronic pain – A systematic review and meta-analysis of resting-state fMRI studies

Article

Mar 2025
PROG NEURO-PSYCHOPH

Deciphering distinct spatial alterations in N-glycan expression profiles in the spinal cord and brain of male rats in a neuropathic pain model

Article

Mar 2025
CELL MOL BIOL LETT

Background Neuropathic pain is a complex condition resulting from damage or disease in the somatosensory nervous system, causing significant physical and emotional distress. Despite its profound impact, the underlying causes and treatment methods of neuropathic pain remain poorly understood. Methods To better understand this condition, we conducted the first study examining the spatial distribution and dynamic expression changes of N-glycan molecules that play a crucial role in nervous system function and sustainable pain signal transmission across multiple regions of the spinal cord and brain in an experimentally induced neuropathic pain model, using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). Results Our findings revealed that neuropathic pain induces dynamic changes in N-glycan expression across various regions of the spinal cord and brain. Notably, we discovered distinct glycan profiles between the spinal cord and brain, with N-glycans downregulated in the spinal cord and upregulated in the brain at a time when mechanical allodynia is sustained following spinal nerve ligation (SNL). Significant changes in N-glycan expression were observed in the dorsal laminae IV/V/VI and the ventral horn of the spinal cord. Additionally, marked changes were detected in the contralateral regions of the primary sensory cortex (S1) and the primary sensory cortex hindlimb area (S1HL). Furthermore, we observed significant upregulation of N-glycan expression in the thalamus, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC) in both ipsilateral and contralateral regions of the brain. Conclusions Given that N-glycans are implicated in pain processing yet their precise role remains unclear, our study highlights the need to explore N-glycosylation with a more nuanced focus on both the spinal cord and brain. This research provides new insights into the mechanisms of persistent neuropathic pain and lays the groundwork for future studies and the development of targeted therapeutic strategies. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s11658-025-00709-7.

Serotonin circuits act cooperatively with pathophysiology of opioid use disorder

Article

Full-text available

Nov 2024

Cortical Tagged Synaptic Long-Term Depression in the Anterior Cingulate Cortex of Adult Mice

Article

Jul 2024

The anterior cingulate cortex (ACC) is a key cortical region for pain perception and emotion. Different forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), have been reported in the ACC. Synaptic tagging of LTP plays an important role in hippocampus-related associative memory. In this study, we demonstrate that synaptic tagging of LTD is detected in the ACC of adult male and female mice. This form of tagged LTD requires the activation of metabotropic glutamate receptor subtype 1 (mGluR1). The induction of tagged LTD is time-related with the strongest tagged LTD appearing when the interval between two independent stimuli is 30 min. Inhibitors of mGluR1 blocked the induction of tagged LTD; however, blocking N-methyl-d-aspartate receptors did not affect the induction of tagged LTD. Nimodipine, an inhibitor of L-type voltage–gated calcium channels, also blocked tagged LTD. In an animal model of amputation, we found that tagged LTD was either reduced or completely blocked. Together with our previous report of tagged LTP in the ACC, this study strongly suggests that excitatory synapses in the adult ACC are highly plastic. The biphasic tagging of synaptic transmission provides a new form of heterosynaptic plasticity in the ACC which has functional and pathophysiological significance in phantom pain.

Recruitment of cortical silent responses by forskolin in the anterior cingulate cortex of adult mice

Article

May 2024
MOL PAIN

Recent studies using different experimental approaches demonstrate that silent synapses may exist in adult cortex including the sensory cortex and anterior cingulate cortex (ACC). Postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.

Insular cortex stimulation alleviates neuropathic pain through changes in the expression of collapsin response mediator protein 2 involved in synaptic plasticity

Article

Mar 2024
NEUROBIOL DIS

P2X receptor- and postsynaptic NMDA receptor-mediated long-lasting facilitation of inhibitory synapses in the rat insular cortex

Article

Dec 2023
NEUROPHARMACOLOGY

Cortical synaptic basis of consciousness

Article

Nov 2023
EUR J NEUROSCI

Min Zhuo

Consciousness is one of final questions for humans to tackle in neuroscience. Due to a lack of understanding of basic brain networks and mechanisms of functions, our knowledge of consciousness mainly stays at a theoretical level. Recent studies using brain imaging in humans and modern neuroscience techniques in animal studies reveal the basic brain network for consciousness. The projection from the thalamus to different cortical regions forms a network of activities to maintain consciousness in humans and animals. These feedback and feedforward circuits maintain consciousness even in certain brain injury conditions. Pterions and ion channels that contribute to these circuit neural activities are targets for drugs and manipulations that affect consciousness such as anesthetic agents. Synaptic plasticity that trains synapses during learning and information recall modified the circuits and contributes to a high level of consciousness in a certain population.

Neuropathic pain; what we know and what we should do about it

Article

Full-text available

Sep 2023

Peter A Smith

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve injury promotes Schwann cell activation and invasion of immunocompetent cells into the site of injury, spinal cord and higher sensory structures such as thalamus and cingulate and sensory cortices. Various cytokines, chemokines, growth factors, monoamines and neuropeptides effect two-way signalling between neurons, glia and immune cells. This promotes sustained hyperexcitability and spontaneous activity in primary afferents that is crucial for onset and persistence of pain as well as misprocessing of sensory information in the spinal cord and supraspinal structures. Much of the current understanding of pain aetiology and identification of drug targets derives from studies of the consequences of peripheral nerve injury in rodent models. Although a vast amount of information has been forthcoming, the translation of this information into the clinical arena has been minimal. Few, if any, major therapeutic approaches have appeared since the mid 1990's. This may reflect failure to recognise differences in pain processing in males vs. females, differences in cellular responses to different types of injury and differences in pain processing in humans vs. animals. Basic science and clinical approaches which seek to bridge this knowledge gap include better assessment of pain in animal models, use of pain models which better emulate human disease, and stratification of human pain phenotypes according to quantitative assessment of signs and symptoms of disease. This can lead to more personalized and effective treatments for individual patients. Significance statement: There is an urgent need to find new treatments for neuropathic pain. Although classical animal models have revealed essential features of pain aetiology such as peripheral and central sensitization and some of the molecular and cellular mechanisms involved, they do not adequately model the multiplicity of disease states or injuries that may bring forth neuropathic pain in the clinic. This review seeks to integrate information from the multiplicity of disciplines that seek to understand neuropathic pain; including immunology, cell biology, electrophysiology and biophysics, anatomy, cell biology, neurology, molecular biology, pharmacology and behavioral science. Beyond this, it underlines ongoing refinements in basic science and clinical practice that will engender improved approaches to pain management.

Nitric oxide synthase contributes to the maintenance of LTP in the oxytocin– mRFP1 neuron of the rat hypothalamus

Article

Sep 2023

Background Oxytocin (OXT) is a neuropeptide hormone that plays a critical role in nociception. Long‐term potentiation (LTP) is a major form of synaptic plasticity in the central nervous system. Recently, LTP has been reported in the hypothalamus; however, data on LTP in hypothalamic OXT‐ergic neurons are unclear. Furthermore, the signalling pathways for hypothalamic OXT‐ergic neuronal LTP and its physiological significance remain unknown. Methods Herein, we aimed to investigate the induction of hypothalamic OXT‐ergic neuronal LTP and its synaptic mechanism using OXT‐monomeric red fluorescent protein 1 transgenic rats to visualize and record from OXT‐ergic neurons. Results The hypothalamic paraventricular nucleus (PVN) OXT‐ergic neuronal LTP induced by the pairing protocol was dependent on N‐methyl‐D‐aspartate receptor (NMDAR). Furthermore, nitric oxide synthase (NOS) is required to maintain the LTP regardless of the NMDARs. In addition, hypothalamic OXT‐ergic neuronal LTP was not induced in the adjuvant arthritis rat model but increased excitatory postsynaptic currents were detected. Conclusion LTP in hypothalamic OXT‐ergic neurons in the PVN in the presence of NOS may be involved in neuronal changes during OXT synthesis in chronic inflammation. This article is protected by copyright. All rights reserved.

Silent synapses in pain-related anterior cingulate cortex

Article

May 2023
MOL PAIN

Min Zhuo

Synaptic plasticity such as Long-term potentiation (LTP) is a key mechanism for learning in central synapses including the cortex. There are two least two major forms of LTPs: presynaptic LTP and postsynaptic LTP. For postsynaptic LTP, the potentiation of AMPA receptor-mediated responses through protein phosphorylation is thought to be a key mechanism. Silent synapses have been reported in the hippocampus, but it is thought to be mainly present in the cortex during early development, and may contribute to maturation of the cortical circuit. However, recent several lines of evidence demonstrate that silent synapses may exist in mature synapses of adult cortex, and they can be recruited by LTP-inducing protocols, as well as chemical-induced LTP. In pain-related cortical regions, silent synapses may not only contribute to cortical excitation after peripheral injury, but also the recruitment of new cortical circuits as well. Thus, it is proposed that silent synapses and modification of functional AMPA receptors and NMDA receptors may play important roles in chronic pain, including phantom pain.

Supraspinal facilitation of nociception by glutamatergic innervation from the retrosplenial cortex to anterior cingulate cortex

Preprint

Full-text available

Feb 2023

Anterior cingulate cortex (ACC) is critical for pain perception; while the retrosplenial cortex (RSC) plays an important role in navigation and memory. It is known that RSC projects to ACC, less is known about the function of this projection. Here we used integrative approaches to show that there is direct excitatory glutamatergic projections from the RSC to the ACC, and postsynaptic excitatory responses are mediated by AMPA receptors. Activation of RSC-ACC by optogenetics significantly facilitated behavioral responses to nociceptive stimuli (mechanical and thermal) in freely moving mice. By contrast, spinal nociceptive tail-flick and anxiety-like activities were not affected. Our results suggest that RSC to ACC projection preferentially affects nociceptive process in supraspinal cortical region. Our results have identified a new facilitatory cortico-cortical circuit for sensory nociceptive process, and this pathway serves to link memory ‘engram’ to pain perception in humans and animals.

Differential roles of NMDAR subunits 2A and 2B in mediating peripheral and central sensitization contributing to orofacial neuropathic pain

Article

Aug 2022
BRAIN BEHAV IMMUN

The spinal N-methyl-D-aspartate receptor (NMDAR), particularly their subtypes NR2A and NR2B, plays pivotal roles in neuropathic and inflammatory pain. However, the roles of NR2A and NR2B in orofacial pain and the exact molecular and cellular mechanisms mediating nervous system sensitization are still poorly understood. Here, we exhaustively assessed the regulatory effect of NMDAR in mediating peripheral and central sensitization in orofacial neuropathic pain. Von-Frey filament tests showed that the inferior alveolar nerve (IANX) induced ectopic allodynia behavior in the whisker pad of mice. Interestingly, mechanical allodynia was reversed in mice lacking NR2A and NR2B. IANX also promoted the production of peripheral sensitization-related molecules, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, brain-derived neurotrophic factor (BDNF), and chemokine upregulation (C-C motif) ligand 2 (CCL2), and decreased the inward potassium channel (Kir) 4.1 on glial cells in the trigeminal ganglion, but NR2A conditional knockout (CKO) mice prevented these alterations. In contrast, NR2B CKO only blocked the changes in Kir4.1, IL-1β, and TNF-α and further promoted the production of CCL2. Central sensitization-related c-fos, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) were promoted and Kir4.1 was reduced in the spinal trigeminal caudate nucleus by IANX. Differential actions of NR2A and NR2B in mediating central sensitization were also observed. Silencing of NR2B was effective in reducing c-fos, GFAP, and Iba-1 but did not affect Kir4.1. In contrast, NR2A CKO only altered Iba-1 and Kir4.1 and further increased c-fos and GFAP. Gain-of-function and loss-of-function approaches provided insight into the differential roles of NR2A and NR2B in mediating peripheral and central nociceptive sensitization induced by IANX, which may be a fundamental basis for advancing knowledge of the neural mechanisms’ reaction to nerve injury.

Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain

Article

Apr 2022
NEURON

Empathic pain has attracted the interest of a substantial number of researchers studying the social transfer of pain in the sociological, psychological, and neuroscience fields. However, the neural mechanism of empathic pain remains elusive. Here, we establish a long-term observational pain model in mice and find that glutamatergic projection from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for the formation of observational pain. The selective activation or inhibition of the IC-BLA projection pathway strengthens or weakens the intensity of observational pain, respectively. The synaptic molecules are screened, and the upregulated synaptotagmin-2 and RIM3 are identified as key signals in controlling the increased synaptic glutamate transmission from the IC to the BLA. Together, these results reveal the molecular and synaptic mechanisms of a previously unidentified neural pathway that regulates observational pain in mice.

NMDA receptors and synaptic plasticity in the anterior cingulate cortex

Article

Aug 2021
NEUROPHARMACOLOGY

The anterior cingulate cortex (ACC) plays an important role in pain modulation, and pain-related emotional disorders. In the ACC, two major forms of long-term potentiation (LTP) coexist in excitatory synapses and lay the basis of chronic pain and pain-related emotional disorders. The induction of postsynaptic LTP is dependent on the activation of postsynaptic NMDA receptors (NMDARs), while the presynaptic LTP is NMDAR-independent. Long-term depression (LTD) can also be divided into two types according to the degree of sensitivity to the inhibition of NMDARs. NMDAR heteromers containing GluN2A and GluN2B act as key molecules in both the NMDAR-dependent postsynaptic LTP and LTD. Additionally, NMDARs also exist in presynaptic terminals and modulate the evoked and spontaneous transmitter release. From a translational point of view, inhibiting subtypes of NMDARs and/or downstream signaling proteins may provide potential drug targets for chronic pain and its related emotional disorders. This article is part of the special Issue on ‘Glutamate Receptors –NMDA receptors’.

Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC

Article

Full-text available

Dec 2015

Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely moving mice. We found that selective activation of pyramidal neurons rapidly and acutely reduced nociceptive thresholds and that this effect was occluded in animals made hypersensitive using Freund's Complete Adjuvant (CFA). Conversely, inhibition of ACC pyramidal neurons rapidly and acutely reduced hypersensitivity induced by CFA treatment. A similar analgesic effect was induced by activation of parvalbumin (PV) expressing interneurons, whereas activation of somatostatin (SOM) expressing interneurons had no effect on pain thresholds. Our results provide direct evidence of the pivotal role of ACC excitatory neurons, and their regulation by PV expressing interneurons, in nociception. Electronic supplementary material The online version of this article (doi:10.1186/s13041-015-0170-6) contains supplementary material, which is available to authorized users.

Article

Full-text available

Sep 2015
Neural Plast

The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ (PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζ in the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. After ζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ (p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζ were decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζ and that ZIP has potential applications for relieving chronic pain.

GluA1 Phosphorylation Contributes to Postsynaptic Amplification of Neuropathic Pain in the Insular Cortex

Article

Full-text available

Oct 2014

Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex. The synaptic GluA1 subunit of AMPAR, but not the GluA2/3 subunit, was increased after nerve ligation. Genetic knock-in mice lacking phosphorylation of the Ser845 site, but not that of the Ser831 site, blocked the enhancement of the synaptic GluA1 subunit, indicating that GluA1 phosphorylation at the Ser845 site by protein kinase A (PKA) was critical for this upregulation after nerve injury. Furthermore, A-kinase anchoring protein 79/150 (AKAP79/150) and PKA were translocated to the synapses after nerve injury. Genetic deletion of adenylyl cyclase subtype 1 (AC1) prevented the translocation of AKAP79/150 and PKA, as well as the upregulation of synaptic GluA1-containing AMPARs. Pharmacological inhibition of calcium-permeable AMPAR function in the insular cortex reduced behavioral sensitization caused by nerve injury. Our results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.

A novel bispecific antibody targeting tumor necrosis factor α and ED-B fibronectin effectively inhibits the progression of established collagen-induce arthritis

Article

Full-text available

Jun 2014
J BIOTECHNOL

Specific delivery of TNF-α antagonist to the inflamed site can increase its efficacy and reduce the side effects. In this study, we constructed a bispecific diabody (BsDb) that targets TNF-α and ED-B-containing fibronectin (B-FN), a fibronectin isoform specifically expressed in the pannus of the inflamed joint in rheumatoid arthritis. BsDb was produced in E. coli as inclusion bodies, purified to homogeneity, and refolded to the functional form. Our data demonstrate that BsDb could simultaneously bind to human TNF-α and B-FN and neutralize TNF-α action. In the collagen-induced arthritis mouse model, we compared the biodistrubtion and therapeutic efficacy of BsDb with those of the anti-TNF-α scFv (TNF-scFv). Similar to TNF-scFv, BsDb penetrated into the synovial tissue quickly, showing a rapid clearance from blood and normal organs. In contrast, BsDb could selectively accumulate and retain in arthritic joints of mice for a long period time, resulting in a much stronger inhibition of arthritis progression in mice than TNF-scFv. The findings described herein indicate that BsDb has a good specificity to the inflamed joint, with low toxicity to normal organs and seems to be an ideal biological agent for the treatment of RA and other chronic inflammatory disease.

Effects of NB001 and gabapentin on irritable bowel syndrome-induced behavioral anxiety and spontaneous pain

Article

Full-text available

Jun 2014

Irritable bowel syndrome (IBS) is characterized by recurrent abdominal discomfort, spontaneous pain, colorectal hypersensitivity and bowel dysfunction. Patients with IBS also suffer from emotional anxiety and depression. However, few animal studies have investigated IBS-induced spontaneous pain and behavioral anxiety. In this study, we assessed spontaneous pain and anxiety behaviors in an adult mouse model of IBS induced by zymosan administration. By using Fos protein as a marker, we found that sensory and emotion related brain regions were activated at day 7 after the treatment with zymosan; these regions include the prefrontal cortex, anterior cingulate cortex, insular cortex and amygdala. Behaviorally, zymosan administration triggered spontaneous pain (decreased spontaneous activities in the open field test) and increased anxiety-like behaviors in three different tests (the open field, elevated plus maze and light/dark box tests). Intraperitoneal injection of NB001, an adenylyl cyclase 1 (AC1) inhibitor, reduced spontaneous pain but had no significant effect on behavioral anxiety. In contrast, gabapentin reduced both spontaneous pain and behavioral anxiety. These results indicate that NB001 and gabapentin may inhibit spontaneous pain and anxiety-like behaviors through different mechanisms.

Loss of Long-Term Depression in the Insular Cortex after Tail Amputation in Adult Mice

Article

Full-text available

Jan 2014
MOL PAIN

The insular cortex (IC) is an important forebrain structure involved in pain perception and taste memory formation. Using a 64-channel multi-electrode array system, we recently identified and characterized two major forms of synaptic plasticity in the adult mouse IC: long-term potentiation (LTP) and long-term depression (LTD). In this study, we investigate injury-related metaplastic changes in insular synaptic plasticity after distal tail amputation. We found that tail amputation in adult mice produced a selective loss of low frequency stimulation-induced LTD in the IC, without affecting (RS)-3,5-dihydroxyphenylglycine (DHPG)-evoked LTD. The impaired insular LTD could be pharmacologically rescued by priming the IC slices with a lower dose of DHPG application, a form of metaplasticity which involves activation of protein kinase C but not protein kinase A or calcium/calmodulin-dependent protein kinase II. These findings provide important insights into the synaptic mechanisms of cortical changes after peripheral amputation and suggest that restoration of insular LTD may represent a novel therapeutic strategy against the synaptic dysfunctions underlying the pathophysiology of phantom pain.

Long-term potentiation in the anterior cingulate cortex and chronic pain

Article

Full-text available

Jan 2014
PHILOS T R SOC B

Min Zhuo

Glutamate is the primary excitatory transmitter of sensory transmission and perception in the central nervous system. Painful or noxious stimuli from the periphery 'teach' humans and animals to avoid potentially dangerous objects or environments, whereas tissue injury itself causes unnecessary chronic pain that can even last for long periods of time. Conventional pain medicines often fail to control chronic pain. Recent neurobiological studies suggest that synaptic plasticity taking place in sensory pathways, from spinal dorsal horn to cortical areas, contributes to chronic pain. Injuries trigger long-term potentiation of synaptic transmission in the spinal cord dorsal horn and anterior cingulate cortex, and such persistent potentiation does not require continuous neuronal activity from the periphery. At the synaptic level, potentiation of excitatory transmission caused by injuries may be mediated by the enhancement of glutamate release from presynaptic terminals and potentiated postsynaptic responses of AMPA receptors. Preventing, 'erasing' or reducing such potentiation may serve as a new mechanism to inhibit chronic pain in patients in the future.

Cognitive and emotional control of pain and its disruption in chronic pain

Article

Full-text available

May 2013

Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache and arthritis. To address this growing problem, many people are turning to mind-body therapies, including meditation, yoga and cognitive behavioural therapy. This article will review the neural mechanisms underlying the modulation of pain by cognitive and emotional states - important components of mind-body therapies. It will also examine the accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic.

Long-term potentiation of synaptic transmission in the adult mouse insular cortex: Multielectrode array recordings

Article

Full-text available

May 2013
J NEUROPHYSIOL

The insular cortex (IC) is widely believed to be an important forebrain structure involved in cognitive and sensory processes such as memory and pain. However, little work has been performed at the cellular level to investigate the synaptic basis of IC-related brain functions. To bridge the gap, the present study was designed to characterize the basic synaptic mechanisms for insular long-term potentiation (LTP). Using a 64-channel recording system, we found that an enduring form of late-phase LTP (L-LTP) could be reliably recorded for at least 3 h in different layers of the IC slices following theta burst stimulation. The induction of insular LTP is protein synthesis-dependent and requires activation of both GluN2A and GluN2B subunits of the NMDA receptor, L-type voltage-gated calcium channels, and metabotropic glutamate receptor 1. The paired-pulse facilitation ratio was unaffected by insular L-LTP induction, and expression of insular L-LTP requires the recruitment of postsynaptic calcium-permeable AMPA receptors. Our results provide the first in vitro report of long-term multi-channel recordings of L-LTP in the IC from adult mice, and suggest its potential important roles in insular-related memory and chronic pain.

Expression of NMDA receptor-dependent LTP in the hippocampus: Bridging the divide

Article

Full-text available

Jan 2013

A consensus has famously yet to emerge on the locus and mechanisms underlying the expression of the canonical NMDA receptor-dependent form of LTP. An objective assessment of the evidence leads us to conclude that both presynaptic and postsynaptic expression mechanisms contribute to this type of synaptic plasticity.

Characterization of Fyn-mediated Tyrosine Phosphorylation Sites on GluRepsilon 2 (NR2B) Subunit of the N-Methyl-D-aspartate Receptor

Article

Full-text available

Jan 2001

The N-methyl-d-aspartate (NMDA) receptors play critical roles in synaptic plasticity, neuronal development, and excitotoxicity. Tyrosine phosphorylation of NMDA receptors by Src-family tyrosine kinases such as Fyn is implicated in synaptic plasticity. To precisely address the roles of NMDA receptor tyrosine phosphorylation, we identified Fyn-mediated phosphorylation sites on the GluRε2 (NR2B) subunit of NMDA receptors. Seven out of 25 tyrosine residues in the C-terminal cytoplasmic region of GluRε2 were phosphorylated by Fyn in vitro. Of these 7 residues, Tyr-1252, Tyr-1336, and Tyr-1472 in GluRε2 were phosphorylated in human embryonic kidney fibroblasts when co-expressed with active Fyn, and Tyr-1472 was the major phosphorylation site in this system. We then generated rabbit polyclonal antibodies specific to Tyr-1472-phosphorylated GluRε2 and showed that Tyr-1472 of GluRε2 was indeed phosphorylated in murine brain using the antibodies. Importantly, Tyr-1472 phosphorylation was greatly reduced infyn mutant mice. Moreover, Tyr-1472 phosphorylation became evident when hippocampal long term potentiation started to be observed, and its magnitude became larger in murine brain. Finally, Tyr-1472 phosphorylation was significantly enhanced after induction of long term potentiation in the hippocampal CA1 region. These data suggest that Tyr-1472 phosphorylation of GluRε2 is important for synaptic plasticity.

Memory maintenance by PKM an evolutionary perspective

Article

Full-text available

Sep 2012

Todd Charlton Sacktor

Long-term memory is believed to be maintained by persistent modifications of synaptic transmission within the neural circuits that mediate behavior. Thus, long-term potentiation (LTP) is widely studied as a potential physiological basis for the persistent enhancement of synaptic strength that might sustain memory. Whereas the molecular mechanisms that initially induce LTP have been extensively characterized, the mechanisms that persistently maintain the potentiation have not. Recently, however, a candidate molecular mechanism linking the maintenance of LTP and the storage of long-term memory has been identified. The persistent activity of the autonomously active, atypical protein kinase C (aPKC) isoform, PKMzeta, is both necessary and sufficient for maintaining LTP. Furthermore, blocking PKMzeta activity by pharmacological or dominant negative inhibitors disrupts previously stored long-term memories in a variety of neural circuits, including spatial and trace memories in the hippocampus, aversive memories in the basolateral amygdala, appetitive memories in the nucleus accumbens, habit memory in the dorsal lateral striatum, and elementary associations, extinction, and skilled sensorimotor memories in the neocortex. During LTP and memory formation, PKMzeta is synthesized de novo as a constitutively active kinase. This molecular mechanism for memory storage is evolutionarily conserved. PKMzeta formation through new protein synthesis likely originated in early vertebrates ~500 million years ago during the Cambrian period. Other mechanisms for forming persistently active PKM from aPKC are found in invertebrates, and inhibiting this atypical PKM disrupts long-term memory in the invertebrate model systems Drosophila melanogaster and Aplysia californica. Conversely, overexpressing PKMzeta enhances memory in flies and rodents. PKMzeta persistently enhances synaptic strength by maintaining increased numbers of AMPA receptors at postsynaptic sites, a mechanism that might have evolved from the general function of aPKC in trafficking membrane proteins to the apical compartment of polarized cells. This mechanism of memory may have had adaptive advantages because it is both stable and reversible, as demonstrated by the downregulation of experience-dependent, long-term increases in PKMzeta after extinction and reconsolidation blockade that attenuate learned behavior. Thus, PKMzeta, the "working end" of LTP, is a component of an evolutionarily conserved molecular mechanism for the persistent, yet flexible storage of long-term memory.

Anterior insular cortex is necessary for empathetic pain perception

Article

Full-text available

Sep 2012
BRAIN

Empathy refers to the ability to perceive and share another person's affective state. Much neuroimaging evidence suggests that observing others' suffering and pain elicits activations of the anterior insular and the anterior cingulate cortices associated with subjective empathetic responses in the observer. However, these observations do not provide causal evidence for the respective roles of anterior insular and anterior cingulate cortices in empathetic pain. Therefore, whether these regions are 'necessary' for empathetic pain remains unknown. Herein, we examined the perception of others' pain in patients with anterior insular cortex or anterior cingulate cortex lesions whose locations matched with the anterior insular cortex or anterior cingulate cortex clusters identified by a meta-analysis on neuroimaging studies of empathetic pain perception. Patients with focal anterior insular cortex lesions displayed decreased discrimination accuracy and prolonged reaction time when processing others' pain explicitly and lacked a typical interference effect of empathetic pain on the performance of a pain-irrelevant task. In contrast, these deficits were not observed in patients with anterior cingulate cortex lesions. These findings reveal that only discrete anterior insular cortex lesions, but not anterior cingulate cortex lesions, result in deficits in explicit and implicit pain perception, supporting a critical role of anterior insular cortex in empathetic pain processing. Our findings have implications for a wide range of neuropsychiatric illnesses characterized by prominent deficits in higher-level social functioning.

The Role of Protein Phosphorylation in the Gustatory Cortex and Amygdala During Taste Learning

Article

Full-text available

Jun 2012

Protein phosphorylation and dephosphorylation form a major post-translation mechanism that enables a given cell to respond to ever-changing internal and external environments. Neurons, similarly to any other cells, use protein phosphorylation/dephosphorylation to maintain an internal homeostasis, but they also use it for updating the state of synaptic and intrinsic properties, following activation by neurotransmitters and growth factors. In the present review we focus on the roles of several families of kinases, phosphatases, and other synaptic-plasticity-related proteins, which activate membrane receptors and various intracellular signals to promote transcription, translation and protein degradation, and to regulate the appropriate cellular proteomes required for taste memory acquisition, consolidation and maintenance. Attention is especially focused on the protein phosphorylation state in two forebrain areas that are necessary for taste-memory learning and retrieval: the insular cortex and the amygdala. The various temporal phases of taste learning require the activation of appropriate waves of biochemical signals. These include: extracellular signal regulated kinase I and II (ERKI/II) signal transduction pathways; Ca(2+)-dependent pathways; tyrosine kinase/phosphatase-dependent pathways; brain-derived neurotrophicfactor (BDNF)-dependent pathways; cAMP-responsive element bindingprotein (CREB); and translation-regulation factors, such as initiation and elongation factors, and the mammalian target of rapamycin (mTOR). Interestingly, coding of hedonic and aversive taste information in the forebrain requires activation of different signal transduction pathways.

Kainate receptor-mediated synaptic transmissions in the adult rodent insular cortex

Article

Full-text available

Jul 2012
J NEUROPHYSIOL

Kainate (KA) receptors are expressed widely in the central nervous system and regulate both excitatory and inhibitory synaptic transmission. KA receptors play important roles in fear memory, anxiety, and pain. However, little is known about their function in synaptic transmission in the insular cortex (IC), a critical region for taste, memory, and pain. Using whole cell patch-clamp recordings, we have shown that KA receptors contribute to fast synaptic transmission in neurons in all layers of the IC. In the presence of the GABA(A) receptor antagonist picrotoxin, the NMDA receptor antagonist AP-5, and the selective AMPA receptor antagonist GYKI 53655, KA receptor-mediated excitatory postsynaptic currents (KA EPSCs) were revealed. We found that KA EPSCs are ∼5-10% of AMPA/KA EPSCs in all layers of the adult mouse IC. Similar results were found in adult rat IC. KA EPSCs had a significantly slower rise time course and decay time constant compared with AMPA receptor-mediated EPSCs. High-frequency repetitive stimulations at 200 Hz significantly facilitated the summation of KA EPSCs. In addition, genetic deletion of GluK1 or GluK2 subunit partially reduced postsynaptic KA EPSCs, and exposure of GluK2 knockout mice to the selective GluK1 antagonist UBP 302 could significantly reduce the KA EPSCs. These data suggest that both GluK1 and GluK2 play functional roles in the IC. Our study may provide the synaptic basis for the physiology and pathology of KA receptors in the IC-related functions.

The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB

Article

Full-text available

May 2012

Eric R. Kandel

The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory.

Astrocyte signaling controls spike timing-dependent depression at neocortical synapses

Article

Full-text available

Mar 2012
NAT NEUROSCI

Endocannabinoid mediated spike timing-dependent depression (t-LTD) is crucially involved in the development of the sensory neocortex. t-LTD at excitatory synapses in the developing rat barrel cortex requires cannabinoid CB(1) receptor (CB(1)R) activation, as well as activation of NMDA receptors located on the presynaptic terminal, but the exact signaling cascade leading to t-LTD remains unclear. We found that astrocytes are critically involved in t-LTD. Astrocytes gradually increased their Ca(2+) signaling specifically during the induction of t-LTD in a CB(1)R-dependent manner. In this way, astrocytes might act as a memory buffer for previous coincident neuronal activity. Following activation, astrocytes released glutamate, which activated presynaptic NMDA receptors to induce t-LTD. Astrocyte stimulation coincident with afferent activity resulted in long-term depression, indicating that astrocyte activation is sufficient for the induction of synaptic depression. Taken together, our findings describe the retrograde signaling cascade underlying neocortical t-LTD. The critical involvement of astrocytes in this process highlights their importance for experience-dependent sensory remodeling.

Acute Cannabinoids Impair Working Memory through Astroglial CB1 Receptor Modulation of Hippocampal LTD

Article

Full-text available

Mar 2012

Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.

Molecular Mechanisms Underlying Memory Consolidation of Taste Information in the Cortex

Article

Full-text available

Jan 2012

The senses of taste and odor are both chemical senses. However, whereas an organism can detect an odor at a relatively long distance from its source, taste serves as the ultimate proximate gatekeeper of food intake: it helps in avoiding poisons and consuming beneficial substances. The automatic reaction to a given taste has been developed during evolution and is well adapted to conditions that may occur with high probability during the lifetime of an organism. However, in addition to this automatic reaction, animals can learn and remember tastes, together with their positive or negative values, with high precision and in light of minimal experience. This ability of mammalians to learn and remember tastes has been studied extensively in rodents through application of reasonably simple and well defined behavioral paradigms. The learning process follows a temporal continuum similar to those of other memories: acquisition, consolidation, retrieval, relearning, and reconsolidation. Moreover, inhibiting protein synthesis in the gustatory cortex (GC) specifically affects the consolidation phase of taste memory, i.e., the transformation of short- to long-term memory, in keeping with the general biochemical definition of memory consolidation. This review aims to present a general background of taste learning, and to focus on recent findings regarding the molecular mechanisms underlying taste-memory consolidation in the GC. Specifically, the roles of neurotransmitters, neuromodulators, immediate early genes, and translation regulation are addressed.

Counteracting roles of metabotropic glutamate receptor subtypes 1 and 5 in regulation of pain-related spatial and temporal synaptic plasticity in rat entorhinal–hippocampal pathways

Article

Full-text available

Dec 2011

It was previously found that persistent inflammatory pain state resulted in enhancement of synaptic connections and efficacy in direct entorhinal-hippocampal (EC-HIP) pathways. In the current study, the roles of two subtypes of group I metabotropic glutamate receptors in the above processes were evaluated. Similarly, pain-related spatial and temporal synaptic enhancement model was stably achieved by the multi-electrode array (8×8) recordings in the hippocampal slices of rats pre-treated with intraplantar (i.pl.) bee venom (BV) injection. I.pl. saline injection was used as control. Inhibition of mGluR1 by a selective antagonist 7-hydroxyiminocyclopropan [b] chromen-1α-carboxylic acid ethyl ester (CPCCOEt) resulted in a dramatic increase in synaptic connections in the hippocampal slices of rats treated by BV, but not by saline. However, inhibition of mGluR5 by a selective antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) produced no spatial change from either of the two groups. Temporally, the BV-enhanced LTP could be further incremented by antagonism of mGluR1 with CPCCOEt perfusion when plateau LTP was well established. However, the BV-enhanced LTP was significantly suppressed by antagonism of mGluR5 with MPEP. Neither of the two drugs affected magnitude of LTP in rats treated by i.pl. saline. Taken together with our previous results, it is suggested that mGluR1 be involved in tonic inhibition of EC-HIP synaptic enhancement, while mGluR5 be involved in maintenance of persistent inflammatory pain-associated EC-HIP synaptic enhancement that is largely based upon activation of ionic glutamate receptors.

Induction of Activity-Dependent LTD Requires Muscarinic Receptor Activation in Medial Prefrontal Cortex

Article

Full-text available

Dec 2011
J NEUROSCI

The medial prefrontal cortex (mPFC) forms part of a neural circuit involved in the formation of lasting associations between objects and places. Cholinergic inputs from the basal forebrain innervate the mPFC and may modulate synaptic processes required for the formation of object-in-place memories. To investigate whether acetylcholine regulates synaptic function in the rat mPFC, whole-cell voltage-clamp recordings were made from pyramidal neurons in layer V. Bath application of the cholinergic agonist carbachol caused a potent and long-term depression (LTD) of synaptic responses that was blocked by the muscarinic receptor antagonist scopolamine and was mimicked, in part, by the M(1) receptor agonists McN-A-343 or AF102B. Furthermore, inhibition of PKC blocked carbachol-mediated LTD. We next determined the requirements for activity-dependent LTD in the prefrontal cortex. Synaptic stimulation that was subthreshold for producing LTD did, however, result in LTD when acetylcholine levels were enhanced by inhibition of acetylcholinesterase or when delivered in the presence of the M(1)-selective positive allosteric modulator BQCA. Increasing the levels of synaptic stimulation resulted in M(1) receptor-dependent LTD without the need for pharmacological manipulation of acetylcholine levels. These results show that synaptic stimulation of muscarinic receptors alone can be critical for plastic changes in excitatory synaptic transmission in the mPFC. In turn, these muscarinic mediated events may be important in the formation of object-in-place memories. A loss of basal forebrain cholinergic neurons is a classic hallmark of Alzheimer's dementia and our results provide a potential explanation for the loss of memory associated with the disease.

Stimulation of the human cortex and the experience of pain: Wilder Penfield's observations revisited

Article

Full-text available

Feb 2012
BRAIN

Thanks to the seminal work of Wilder Graves Penfield (1891-1976) at the Montreal Neurological Institute, electrical stimulation is used worldwide to localize the epileptogenic cortex and to map the functionally eloquent areas in the context of epilepsy surgery or lesion resections. In the functional map of elementary and experiential responses he described through >20 years of careful exploration of the human cortex via stimulation of the cortical surface, Penfield did not identify any 'pain cortical area'. We reinvestigated this issue by analysing subjective and videotaped behavioural responses to 4160 cortical stimulations using intracerebral electrodes implanted in all cortical lobes that were carried out over 12 years during the presurgical evaluation of epilepsy in 164 consecutive patients. Pain responses were scarce (1.4%) and concentrated in the medial part of the parietal operculum and neighbouring posterior insula where pain thresholds showed a rostrocaudal decrement. This deep cortical region remained largely inaccessible to the intraoperative stimulation of the cortical surface carried out by Penfield after resection of the parietal operculum. It differs also from primary sensory areas described by Penfield et al. in the sense that, with our stimulation paradigm, pain represented only 10% of responses. Like Penfield et al., we obtained no pain response anywhere else in the cortex, including in regions consistently activated by pain in most functional imaging studies, i.e. the first somatosensory area, the lateral part of the secondary somatosensory area, anterior and mid-cingulate gyri (mid-cingulate cortex), anterior frontal, posterior parietal and supplementary motor areas. The medial parietal operculum and posterior insula are thus the only areas where electrical stimulation is able to trigger activation of the pain cortical network and thus the experience of somatic pain.

Posttranslational regulation of AMPA receptor trafficking and function

Article

Full-text available

Oct 2011

In the mammalian central nervous system, the majority of fast excitatory synaptic transmission is mediated by glutamate acting on AMPA-type ionotropic glutamate receptors. The abundance of AMPA receptors at the synapse can be modulated through receptor trafficking, which dynamically regulates many fundamental brain functions, including learning and memory. Reversible posttranslational modifications, including phosphorylation, palmitoylation and ubiquitination of AMPA receptor subunits are important regulatory mechanisms for controlling synaptic AMPA receptor expression and function. In this review, we highlight recent advances in the study of AMPA receptor posttranslational modifications and discuss how these modifications regulate AMPA receptor trafficking and function at synapses.

Post-Learning Molecular Reactivation Underlies Taste Memory Consolidation

Article

Full-text available

Sep 2011

It is considered that memory consolidation is a progressive process that requires post-trial stabilization of the information. In this regard, it has been speculated that waves of receptors activation, expression of immediate early genes, and replenishment of receptor subunit pools occur to induce functional or morphological changes to maintain the information for longer periods. In this paper, we will review data related to neuronal changes in the post-acquisition stage of taste aversion learning that could be involved in further stabilization of the memory trace. In order to achieve such stabilization, evidence suggests that the functional integrity of the insular cortex (IC) and the amygdala (AMY) is required. Particularly the increase of extracellular levels of glutamate and activation of N-methyl-d-aspartate (NMDA) receptors within the IC shows a main role in the consolidation process. Additionally the modulatory actions of the dopaminergic system in the IC appear to be involved in the mechanisms that lead to taste aversion memory consolidation through the activation of pathways related to enhancement of protein synthesis such as the Protein Kinase A pathway. In summary, we suggest that post-acquisition molecular and neuronal changes underlying memory consolidation are dependent on the interactions between the AMY and the IC.

Long-term potentiation and long-term depression: A clinical perspective

Article

Full-text available

Jun 2011

Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke.

Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex

Article

Full-text available

Jul 2008
J NEUROSCI

Neuropathic pain is caused by a primary lesion or dysfunction in the nervous system. Investigations have mainly focused on the spinal mechanisms of neuropathic pain, and less is known about cortical changes in neuropathic pain. Here, we report that peripheral nerve injury triggered long-term changes in excitatory synaptic transmission in layer II/III neurons within the anterior cingulate cortex (ACC). Both the presynaptic release probability of glutamate and postsynaptic glutamate AMPA receptor-mediated responses were enhanced after injury using the mouse peripheral nerve injury model. Western blot showed upregulated phosphorylation of GluR1 in the ACC after nerve injury. Finally, we found that both presynaptic and postsynaptic changes after nerve injury were absent in genetic mice lacking calcium-stimulated adenylyl cyclase 1 (AC1). Our studies therefore provide direct integrative evidence for both long-term presynaptic and postsynaptic changes in cortical synapses after nerve injury, and that AC1 is critical for such long-term changes. AC1 thus may serve as a potential therapeutic target for treating neuropathic pain.

Caudal Granular Insular Cortex Is Sufficient and Necessary for the Long-Term Maintenance of Allodynic Behavior in the Rat Attributable to Mononeuropathy

Article

Full-text available

Apr 2011
J NEUROSCI

Mechanical allodynia, the perception of innocuous tactile stimulation as painful, is a severe symptom of chronic pain often produced by damage to peripheral nerves. Allodynia affects millions of people and remains highly resistant to classic analgesics and therapies. Neural mechanisms for the development and maintenance of allodynia have been investigated in the spinal cord, brainstem, thalamus, and forebrain, but manipulations of these regions rarely produce lasting effects. We found that long-term alleviation of allodynic manifestations is produced by discreetly lesioning a newly discovered somatosensory representation in caudal granular insular cortex (CGIC) in the rat, either before or after a chronic constriction injury of the sciatic nerve. However, CGIC lesions alone have no effect on normal mechanical stimulus thresholds. In addition, using electrophysiological techniques, we reveal a corticospinal loop that could be the anatomical source of the influence of CGIC on allodynia.

AKAP Signaling Complexes in Regulation of Excitatory Synaptic Plasticity

Article

Full-text available

Jun 2011
NEUROSCIENTIST

Plasticity at excitatory glutamatergic synapses in the central nervous system is believed to be critical for neuronal circuits to process and encode information, allowing animals to perform complex behaviors such as learning and memory. In addition, alterations in synaptic plasticity are associated with human diseases, including Alzheimer disease, epilepsy, chronic pain, drug addiction, and schizophrenia. Long-term potentiation (LTP) and depression (LTD) in the hippocampal region of the brain are two forms of synaptic plasticity that increase or decrease, respectively, the strength of synaptic transmission by postsynaptic AMPA-type glutamate receptors. Both LTP and LTD are induced by activation of NMDA-type glutamate receptors but differ in the level and duration of Ca(2+) influx through the NMDA receptor and the subsequent engagement of downstream signaling by protein kinases, including PKA, PKC, and CaMKII, and phosphatases, including PP1 and calcineurin-PP2B (CaN). This review addresses the important emerging roles of the A-kinase anchoring protein family of scaffold proteins in regulating localization of PKA and other kinases and phosphatases to postsynaptic multiprotein complexes that control NMDA and AMPA receptor function during LTP and LTD.

Identification of an Adenylyl Cyclase Inhibitor for Treating Neuropathic and Inflammatory Pain

Article

Full-text available

Jan 2011
Sci Transl Med

Neuropathic pain, often caused by nerve injury, is commonly observed among patients with different diseases. Because its basic mechanisms are poorly understood, effective medications are limited. Previous investigations of basic pain mechanisms and drug discovery efforts have focused mainly on early sensory neurons such as dorsal root ganglion and spinal dorsal horn neurons, and few synaptic-level studies or new drugs are designed to target the injury-related cortical plasticity that accompanies neuropathic pain. Our previous work has demonstrated that calcium-stimulated adenylyl cyclase 1 (AC1) is critical for nerve injury-induced synaptic changes in the anterior cingulate cortex. Through rational drug design and chemical screening, we have identified a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, we have found that NB001, when administered intraperitoneally or orally, has an analgesic effect in animal models of neuropathic pain, without any apparent side effects. Our study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.

Alleviating Neuropathic Pain Hypersensitivity by Inhibiting PKM in the Anterior Cingulate Cortex

Article

Full-text available

Dec 2010
SCIENCE

Pain in the Brain One of the major challenges in pain research is finding ways to reverse chronic pain. Synaptic long-term potentiation (LTP) at spinal or cortical levels is a cellular model of chronic pain. X.-Y. Li. et al. (p. 1400 ) studied the role of the enzyme protein kinase M zeta (PKMζ) in neurons of the anterior cingulate cortex (ACC) in the maintenance of LTP and for enhanced pain sensitivity after peripheral nerve injury in mice. Nerve injury appeared to lead to the up-regulation and phosphorylation of PKMζ. This triggered LTP at some synapses in the ACC by increasing the number of AMPA receptors. LTP was restricted to ACC neurons that were activated by nerve injury. Blocking PKMζ in the ACC days after nerve injury normalized pain behavior. Thus, PKMζ may represent a promising target for the treatment of chronic pain.

Calcium-Permeable AMPA Receptor Dynamics Mediate Fear Memory Erasure

Article

Full-text available

Oct 2010
SCIENCE

Traumatic fear memories can be inhibited by behavioral therapy for humans, or by extinction training in rodent models, but are prone to recur. Under some conditions, however, these treatments generate a permanent effect on behavior, which suggests that emotional memory erasure has occurred. The neural basis for such disparate outcomes is unknown. We found that a central component of extinction-induced erasure is the synaptic removal of calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) in the lateral amygdala. A transient up-regulation of this form of plasticity, which involves phosphorylation of the glutamate receptor 1 subunit of the AMPA receptor, defines a temporal window in which fear memory can be degraded by behavioral experience. These results reveal a molecular mechanism for fear erasure and the relative instability of recent memory.

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Handbook Exp Pharmacol

Volker Neugebauer

A limbic brain area, the amygdala plays a key role in emotional responses and affective states and disorders such as learned fear, anxiety, and depression. The amygdala has also emerged as an important brain center for the emotional-affective dimension of pain and for pain modulation. Hyperactivity in the laterocapsular division of the central nucleus of the amygdala (CeLC, also termed the "nociceptive amygdala") accounts for pain-related emotional responses and anxiety-like behavior. Abnormally enhanced output from the CeLC is the consequence of an imbalance between excitatory and inhibitory mechanisms. Impaired inhibitory control mediated by a cluster of GABAergic interneurons in the intercalated cell masses (ITC) allows the development of glutamate- and neuropeptide-driven synaptic plasticity of excitatory inputs from the brainstem (parabrachial area) and from the lateral-basolateral amygdala network (LA-BLA, site of integration of polymodal sensory information). BLA hyperactivity also generates abnormally enhanced feedforward inhibition of principal cells in the medial prefrontal cortex (mPFC), a limbic cortical area that is strongly interconnected with the amygdala. Pain-related mPFC deactivation results in cognitive deficits and failure to engage cortically driven ITC-mediated inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms.

Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain

Article

Dec 2014

Chronic pain can lead to anxiety and anxiety can enhance the sensation of pain. Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

Correlation Discrepancies between High-Grade Squamous Intraepithelial Lesions and High-Grade Cervical Intraepithelial Neoplasia: A Cytological/Histological Correlation Study from a Single-Institution Experience

Article

Dec 2013

Objective: Previous studies have demonstrated diagnostic discrepancies for the detection of high-grade cervical intraepithelial neoplasia (CIN 2/3) from previously confirmed cytological high-grade squamous intraepithelial lesions (HSILs). The goal of this study is to investigate the possible factors which may be responsible for this diagnostic discrepancy. Study design: The study included all the cytological specimens diagnosed with a HSIL by the Papanicolaou (Pap) test at Temple University Hospital (2000-2010) as well as timely follow-up cervical biopsies. The biopsy tissue types and diagnoses were subsequently categorized and analyzed. Results: Of the total 842 Pap tests with HSIL diagnosis, 96 cases (11.4%) showed non-CIN 2/3 in follow-up cervical biopsies. Among those cases, the most common biopsy diagnoses were cervicitis (27.9%) and CIN 1 (25%). Endocervical curettage (ECC) samples showed a high percentage of inadequacy for diagnosis (43.7%). Thirty-seven cases had subsequent follow-up biopsy, and CIN 2/3 was found in 15 cases. However, none of the CIN 2/3 cases was detected by ECC sampling. Conclusions: Our study indicated that the discrepant correlation between HSIL and CIN 2/3 was most likely due to tissue sampling issues during colposcopic examination. The diagnostic value of ECC remains poor for the detection and grading of cervical intraepithelial dysplasia.

Topographically Organized Projection to Posterior Insular Cortex From the Posterior Portion of the Ventral Medial Nucleus in the Long-Tailed Macaque Monkey

Article

Jan 2014
J COMP NEUROL

A.D. Craig

Prior anterograde tracing work identified somatotopically organized lamina I trigemino- and spino-thalamic terminations in a cytoarchitectonically distinct portion of posterolateral thalamus of the macaque monkey, named the posterior part of the ventral medial nucleus (VMpo; Craig, 2004b). Microelectrode recordings from clusters of selectively thermoreceptive or nociceptive neurons were used to guide precise micro-injections of various tracers in VMpo. A prior report (Craig and Zhang, 2006) described retrograde tracing results, which confirmed the selective lamina I input to VMpo and the antero-posterior (head to foot) topography. The present report describes the results of micro-injections of anterograde tracers placed at different levels in VMpo, based on the antero-posterior topographic organization of selectively nociceptive units and clusters over nearly the entire extent of VMpo. Each injection produced dense, patchy terminal labeling in a single coherent field within a distinct granular cortical area centered in the fundus of the superior limiting sulcus. The terminations were distributed with a consistent antero-posterior topography over the posterior half of the superior limiting sulcus. These observations demonstrate a specific VMpo projection area in dorsal posterior insular cortex that provides the basis for a somatotopic representation of selectively nociceptive lamina I spinothalamic activity. These results also identify the VMpo terminal area as the posterior half of interoceptive cortex; the anterior half receives input from the vagal-responsive and gustatory neurons in the basal part of the ventral medial nucleus (VMb). J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc.

An Increase in Synaptic NMDA Receptors in the Insular Cortex Contributes to Neuropathic Pain

Article

May 2013

Neurons in the insular cortex are activated by acute and chronic pain, and inhibition of neuronal activity in the insular cortex has analgesic effects. We found that in a mouse model in which peripheral nerve injury leads to the development of neuropathic pain, the insular cortex showed changes in synaptic plasticity, which were associated with a long-term increase in the amount of synaptic N-methyl-d-aspartate receptors (NMDARs), but not that of extrasynaptic NMDARs. Activation of cyclic adenosine monophosphate (cAMP)-dependent signaling enhanced the amount of synaptic NMDARs in acutely isolated insular cortical slices and increased the surface localization of NMDARs in cultured cortical neurons. We found that the increase in the amount of NMDARs required phosphorylation of the NMDAR subunit GluN2B at Tyr(1472) by a pathway involving adenylyl cyclase subtype 1 (AC1), protein kinase A (PKA), and Src family kinases. Finally, injecting NMDAR or GluN2B-specific antagonists into the insular cortex reduced behavioral responses to normally nonnoxious stimuli in the mouse model of neuropathic pain. Our results suggest that activity-dependent plasticity takes place in the insular cortex after nerve injury and that inhibiting the increase in NMDAR function may help to prevent or treat neuropathic pain.

In vivo long-term potentiation in the insular cortex: NMDA receptor dependence

Article

Feb 1998
BRAIN RES

It has been demonstrated that the insular cortex (IC) plays an important role in the acquisition and storage of different aversive motivated learning tasks like conditioned taste aversion, spatial maze and inhibitory avoidance. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here, we address this issue by examining the induction of synaptic plasticity, long-term potentiation (LTP) in in vivo preparations. The results showed that high frequency stimulation of the basolateral amygdaloid nucleus (Bla) induced LTP in the IC. The LTP induced by tetanus was blocked by application of the N-methyl-d-aspartate (NMDA) receptor antagonists CPP and MK-801, indicating that NMDA receptors were responsible for its induction. These results suggest that in vivo tetanus induced LTP of the Bla–IC projection is a possible mechanism for the memory-related functions performed by the IC.

The insular cortex. A review.

Article

Dec 2012

Rudolf Nieuwenhuys

The human insular cortex forms a distinct, but entirely hidden lobe, situated in the depth of the Sylvian fissure. Here, we first review the recent literature on the connectivity and the functions of this structure. It appears that this small lobe, taking up less than 2% of the total cortical surface area, receives afferents from some sensory thalamic nuclei, is (mostly reciprocally) connected with the amygdala and with many limbic and association cortical areas, and is implicated in an astonishingly large number of widely different functions, ranging from pain perception and speech production to the processing of social emotions. Next, we embark on a long, adventurous journey through the voluminous literature on the structural organization of the insular cortex. This journey yielded the following take-home messages: (1) The meticulous, but mostly neglected publications of Rose (1928) and Brockhaus (1940) are still invaluable for our understanding of the architecture of the mammalian insular cortex. (2) The relation of the insular cortex to the adjacent claustrum is neither ontogenetical nor functional, but purely topographical. (3) The insular cortex has passed through a spectacular progressive differentiation during hominoid evolution, but the assumption of Craig (2009) that the human anterior insula has no homologue in the rhesus monkey is untenable. (4) The concept of Mesulam and Mufson (1985), that the primate insula is essentially composed of three concentrically arranged zones, agranular, dysgranular, and granular, is presumably correct, but there is at present much confusion concerning the more detailed architecture of the anterior insular cortex. (5) The large spindle-shaped cells in the fifth layer of the insular cortex, currently known as von Economo neurons (VENs), are not only confined to large-brained mammals, such as whales, elephants, apes, and humans, but also occur in monkeys and prosimians, as well as in the pygmy hippopotamus, the Atlantic walrus, and Florida manatee. Finally, we point out that the human insula presents a unique opportunity for performing an in-depth comparative analysis of the relations between structure and function in a typical sensory and a typical cognitive cortical domain.

Targeting neuronal adenylyl cyclase for the treatment of chronic pain

Article

Jan 2012

Min Zhuo

Pain research is currently undergoing dramatic changes. In the area of basic pain research, new discoveries have been made towards the understanding of pain transmission, modulation and plasticity. However, many of these basic discoveries have not yet led to the development of new drugs for the treatment of chronic pain. One major reason for this disconnection is the lack of translational research and drug discovery based directly on the novel pain mechanism. In this review, I focus on activity-dependent potentiation in pain-related cortical areas and recent translational research on adenylyl cyclase subtype 1 (AC1) as a novel target for treating chronic pain. In particular, I discuss the AC1 inhibitor, NB001, which produces powerful analgesic effects in animal models of chronic pain by inhibiting chronic pain-related cortical potentiation.

NMDA Receptors, mGluR5, and Endocannabinoids are Involved in a Cascade Leading to Hippocampal Long-Term Depression

Article

Feb 2012
NEUROPSYCHOPHARMACOL

In the CA1 region of the rat hippocampus, metabotropic glutamate receptor-5 (mGluR5) and cannabinoid-1 receptors (CB1Rs) are believed to participate in long-term synaptic depression (LTD). How mGluRs and CB1Rs interact to promote LTD remains uncertain. In this study, we examined LTD induced by CB1R agonists, mGluR5 agonists, and low-frequency electrical stimulation (LFS) of the Schaffer collateral pathway. Synthetic CB1R agonists induced robust LTD that was mimicked by the endocannabinoid (EC), noladin ether (NLDE), but not by anandamide. 2-Arachidonylglycerol (2AG) produced only a small degree of LTD. The selective mGluR5 agonist, namely (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), also induced robust LTD, and CHPG and NLDE occluded each other's effects. Similarly, CHPG and NLDE occluded LFS-induced LTD, and LTD resulting from all three treatments was blocked by a CB1R antagonist. CHPG-LTD and NLDE-LTD were insensitive to N-methyl-D-aspartate receptor (NMDAR) block, even though LFS-LTD requires NMDARs. LTD induced by LFS or CHPG, but not NLDE-LTD, was blocked by a selective mGluR5 antagonist. (RS)-3,5-dihydroxyphenylglycine (DHPG), a less selective group I mGluR agonist, also induced LTD, but its effects were not blocked by mGluR5 or CB1R antagonists. Furthermore, DHPG-LTD was additive with LFS-LTD and CHGP-LTD. These results suggest that NMDARs, mGluR5, and CB1Rs participate in a cascade that underlies LFS-LTD and that release of an EC and CB1R activation occur downstream of NMDARs and mGluR5. Furthermore, DHPG induces a form of LTD that differs mechanistically from LFS-induced depression.

Spatiotemporal dynamics of long-term potentiation in rat insular cortex revealed by optical imaging

Article

Aug 2011
NEUROBIOL LEARN MEM

Long-term potentiation (LTP) of the gustatory cortex (GC), a part of the insular cortex (IC) around the middle cerebral artery, is a key process of gustatory learning and memory, including conditioned taste aversion learning. The rostral (rGC) and caudal GC (cGC) process different tastes; the rGC responds to hedonic and the cGC responds to aversive tastes. However, plastic changes of spatial interaction of excitatory propagation between the rGC and cGC remain unknown. The present study aimed to elucidate spatiotemporal profiles of excitatory propagation, induced by electrical stimulation (five train pulses) of the rGC/cGC before and after LTP induction, using in vivo optical imaging with a voltage-sensitive dye. We demonstrated that tetanic stimulation of the cGC induced long-lasting expansion of the excitation responding to five train stimulation of the cGC, and an increase in amplitude of optical signals in the IC. Excitatory propagation after LTP induction spread preferentially toward the rostral IC: the length constant (λ) of excitation, obtained by fitting optical signals with a monoexponential curve, was increased to 121.9% in the rostral direction, whereas λ for the caudal, dorsal, and ventral directions were 48.9%, 44.2%, and 62.5%, respectively. LTP induction was prevented by pre-application of D-APV, an NMDA receptor antagonist, or atropine, a muscarinic receptor antagonist, to the cortical surface. In contrast, rGC stimulation induced only slight LTP without direction preference. Considering the different roles of the rGC and cGC in gustatory processing, these characteristic patterns of LTP in the GC may be involved in a mechanism underlying conversion of palatability.

Central Representation of Somatic Sensations in the Parietal Operculum (SII) and Insula

Article

Dec 2004

Four subjects with small restricted cerebral cortical infarcts have been examined. One had a lesion confined to the parietal operculum (SII), while in the second the SII lesion also encroached on the posterior insula; in the third subject, both banks of the sylvian fissure and the dorsal insula were involved, while in the fourth the lesion involved the upper bank of the sylvian fissure. In all cases, the postcentral gyrus (SI) was intact. Subjects 1 and 2 had mild spontaneous pain, but subjects 3 and 4 had never had spontaneous pain. In the affected areas, none could feel mechanical (skinfold pinch) pain. The 2 subjects with spontaneous pain could not discriminate sharpness (pinprick), but this was unimpaired in the third and fourth subjects. Warmth, cold, and heat pain were impaired in the 2 subjects with spontaneous pain, but not in those without; however warm-cold difference was greater in the affected regions of all subjects. The possibility must nevertheless be considered that the presence of central pain in some way alters the cortical mechanisms for the perception of thermal stimuli. Certainly, as we had earlier observed, spontaneous pain only occurs when there is interference with thermal sensation. Functional MRI (fMRI) studies following thermal stimulation in subjects 1 and 2 showed these areas, particularly SII, to be concerned with the reception of innocuous and noxious thermal stimuli, mechanical (skinfold pinch) pain and sharpness (pinprick), implying that SI is principally concerned with the reception of low-intensity mechanical stimuli, although it was activated in 1 of our fMRI-studied subjects by innocuous cooling.

Neurons in the posterior insular cortex are responsive to gustatory stimulation of the pharyngolarynx, baroreceptor and chemoreceptor stimulation, and tail pinch in rats

Article

Feb 1998
BRAIN RES

Extracellular unit responses to gustatory stimulation of the pharyngolaryngeal region, baroreceptor and chemoreceptor stimulation, and tail pinch were recorded from the insular cortex of anesthetized and paralyzed rats. Of the 32 neurons identified, 28 responded to at least one of the nine stimuli used in the present study. Of the 32 neurons, 11 showed an excitatory response to tail pinch, 13 showed an inhibitory response, and the remaining eight had no response. Of the 32 neurons, eight responded to baroreceptor stimulation by an intravenous (i.v.) injection of methoxamine hydrochloride (Mex), four were excitatory and four were inhibitory. Thirteen neurons were excited and six neurons were inhibited by an arterial chemoreceptor stimulation by an i.v. injection of sodium cyanide (NaCN). Twenty-two neurons were responsive to at least one of the gustatory stimuli (deionized water, 1.0 M NaCl, 30 mM HCl, 30 mM quinine HCl, and 1.0 M sucrose); five to 11 excitatory neurons and three to seven inhibitory neurons for each stimulus. A large number of the neurons (25/32) received converging inputs from more than one stimulus among the nine stimuli used in the present study. Most neurons (23/32) received converging inputs from different modalities (gustatory, visceral, and tail pinch). The neurons responded were located in the insular cortex between 2.0 mm anterior and 0.2 mm posterior to the anterior edge of the joining of the anterior commissure (AC); the mean location was 1.2 mm (n=28) anterior to the AC. This indicates that most of the neurons identified in the present study seem to be located in the region posterior to the taste area and anterior to the visceral area in the insular cortex. These results indicate that the insular cortex neurons distributing between the taste area and the visceral area receive convergent inputs from gustatory, baroreceptor, chemoreceptor, and nociceptive organs.

Possible representation of somatic pain in the rat insular visceral sensory cortex: A field potential study

Article

Jan 1998
NEUROSCI LETT

Shin-ichi Ito

Vagus nerve stimulation evokes a potential in the dorsal insular cortex in rats. To determine whether this cortical visceral area, like the brainstem visceral nuclei, also receives somatic input, somatic potentials were examined. Subcutaneous electrical stimulation, regardless of the laterality and site, evoked a potential closely resembling the vagal potential in shape, surface distribution and depth profile. This somatic potential had a higher threshold and a longer latency than the potentials in the nearby somatosensory cortices, and was attributed to primary Adelta afferents based on conduction velocity measurements and the relationship to peripheral nerve activity. No Abeta afferent-related response was found. These results suggest that the insula receives convergent sensory input from both the viscera and body surface, and the latter probably conveys somatic nociceptive information.

Significance of the insula for the evolution of human awareness of feelings from the body

Article

Apr 2011
ANN NY ACAD SCI

A.D. Craig

An ascending sensory pathway that underlies feelings from the body, such as cooling or toothache, terminates in the posterior insula. Considerable evidence suggests that this activity is rerepresented and integrated first in the mid-insula and then in the anterior insula. Activation in the anterior insula correlates directly with subjective feelings from the body and, strikingly, with all emotional feelings. These findings appear to signify a posterior-to-anterior sequence of increasingly homeostatically efficient representations that integrate all salient neural activity, culminating in network nodes in the right and left anterior insulae that may be organized asymmetrically in an opponent fashion. The anterior insula has appropriate characteristics to support the proposal that it engenders a cinemascopic model of human awareness and subjectivity. This review presents the author's views regarding the principles of organization of this system and discusses a possible sequence for its evolution, as well as particular issues of historical interest.

Enhancement of Consolidated Long-Term Memory by Overexpression of Protein Kinase M in the Neocortex

Article

Mar 2011
SCIENCE

Memories are more easily disrupted than improved. Many agents can impair memories during encoding and consolidation. In contrast, the armamentarium of potential memory enhancers is so far rather modest. Moreover, the effect of the latter appears to be limited to enhancing new memories during encoding and the initial period of cellular consolidation, which can last from a few minutes to hours after learning. Here, we report that overexpression in the rat neocortex of the protein kinase C isozyme protein kinase Mζ (PKMζ) enhances long-term memory, whereas a dominant negative PKMζ disrupts memory, even long after memory has been formed.

Nociceptor sensitization in pain pathogenesis

Article

Nov 2010
NAT MED

The incidence of chronic pain is estimated to be 20-25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions for which the underlying pathology is not apparent. An intact central nervous system (CNS) is required for the conscious perception of pain, and changes in the CNS are clearly evident in chronic pain states. However, the blockage of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Accordingly, we focus here on nociceptors: their excitability, their heterogeneity and their role in initiating and maintaining pain.

Contribution of synaptic plasticity in the insular cortex to chronic pain

Abstract

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