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Journal ArticleDOI

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

TL;DR: The 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.
Abstract: 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.
Citations
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Journal ArticleDOI
TL;DR: Increasing evidence from rodent studies that ACC activation contributes to chronic pain states is discussed and several forms of synaptic plasticity that may underlie this effect are described.
Abstract: Evidence suggests that activity in the anterior cingulate cortex (ACC) contributes to acute and chronic pain. In this article, Zhuo and colleagues review the different types of synaptic plasticity observed in the ACC and the implications of these forms of plasticity for pain processing.

428 citations

Journal ArticleDOI
TL;DR: The medial PFC (mPFC) could serve dual, opposing roles in pain: it mediates antinociceptive effects, due to its connections with other cortical areas, and as the main source of cortical afferents to the PAG for modulation of pain.
Abstract: The prefrontal cortex (PFC) is not only important in executive functions, but also pain processing. The latter is dependent on its connections to other areas of the cerebral neocortex, hippocampus, periaqueductal gray (PAG), thalamus, amygdala, and basal nuclei. Changes in neurotransmitters, gene expression, glial cells, and neuroinflammation occur in the PFC during acute and chronic pain, that result in alterations to its structure, activity, and connectivity. The medial PFC (mPFC) could serve dual, opposing roles in pain: (1) it mediates antinociceptive effects, due to its connections with other cortical areas, and as the main source of cortical afferents to the PAG for modulation of pain. This is a 'loop' where, on one side, a sensory stimulus is transformed into a perceptual signal through high brain processing activity, and perceptual activity is then utilized to control the flow of afferent sensory stimuli at their entrance (dorsal horn) to the CNS. (2) It could induce pain chronification via its corticostriatal projection, possibly depending on the level of dopamine receptor activation (or lack of) in the ventral tegmental area-nucleus accumbens reward pathway. The PFC is involved in biopsychosocial pain management. This includes repetitive transcranial magnetic stimulation, transcranial direct current stimulation, antidepressants, acupuncture, cognitive behavioral therapy, mindfulness, music, exercise, partner support, empathy, meditation, and prayer. Studies demonstrate the role of the PFC during placebo analgesia, and in establishing links between pain and depression, anxiety, and loss of cognition. In particular, losses in PFC grey matter are often reversible after successful treatment of chronic pain.

355 citations

Journal ArticleDOI
TL;DR: It is concluded that fish lack the necessary neurocytoarchitecture, microcircuitry, and structural connectivity for the neural processing required for feeling pain.
Abstract: Only humans can report feeling pain. In contrast, pain in animals is typically inferred on the basis of nonverbal behaviour. Unfortunately, these behavioural data can be problematic when the reliability and validity of the behavioural tests are questionable. The thesis proposed here is based on the bioengineering principle that structure determines function. Basic functional homologies can be mapped to structural homologies across a broad spectrum of vertebrate species. For example, olfaction depends on olfactory glomeruli in the olfactory bulbs of the forebrain, visual orientation responses depend on the laminated optic tectum in the midbrain, and locomotion depends on pattern generators in the spinal cord throughout vertebrate phylogeny, from fish to humans. Here I delineate the region of the human brain that is directly responsible for feeling painful stimuli. The principal structural features of this region are identified and then used as biomarkers to infer whether fish are, at least, anatomically capable of feeling pain. Using this strategy, I conclude that fish lack the necessary neurocytoarchitecture, microcircuitry, and structural connectivity for the neural processing required for feeling pain.

202 citations


Cites background from "GluA1 Phosphorylation Contributes t..."

  • ...Subsequent mouse knock-in experiments also revealed that increased expression of the AMPA receptor in the insular cortex was responsible for long-term potentiation of glutamate transmission during neuropathic pain (Qui et al., 2014)....

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  • ...Subsequent mouse knock-in experiments also revealed that increased expression of the AMPA receptor in the insular cortex was responsible for long term potentiation of glutamate transmission during neuropathic pain (Qui et al., 2014)....

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  • ...Neuropathic pain in a mouse model has been shown to be associated with synaptic plasticity in the insular cortex (Qui et al., 2014)....

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Journal ArticleDOI
TL;DR: This review discusses the latest data proposing that subregions of the IC are involved in isolated pain networks: the posterior sensory circuit and the anterior emotional network.
Abstract: An increasing body of neuroimaging and electrophysiological studies of the brain suggest that the insular cortex (IC) integrates multimodal salient information ranging from sensation to cognitive-affective events to create conscious interoception. Especially with regard to pain experience, the IC has been supposed to participate in both sensory-discriminative and affective-motivational aspects of pain. In this review, we discuss the latest data proposing that subregions of the IC are involved in isolated pain networks: the posterior sensory circuit and the anterior emotional network. Due to abundant connections with other brain areas, the IC is likely to serve as an interface where cross-modal shaping of pain occurs. In chronic pain, however, this mode of emotional awareness and the modulation of pain are disrupted. We highlight some of the molecular mechanisms underlying the changes of the pain modulation system that contribute to the transition from acute to chronic pain in the IC.

155 citations


Cites background from "GluA1 Phosphorylation Contributes t..."

  • ...Our previous study showed that persistent pain can bring about a series of neural plastic changes mediated by the synaptic GluA1 subunit of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) [9]....

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  • ...And this enhancement relies on an increased amount and sensitivity of the synaptic GluA1 subunit of AMPARs, but not the GluA2/3 subunit [9]....

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Journal ArticleDOI
TL;DR: It is argued that the insect brain supports functions analogous to those of the vertebrate midbrain and hence that insects may also have a capacity for subjective experience.
Abstract: To what degree are non-human animals conscious? We propose that the most meaningful way to approach this question is from the perspective of functional neurobiology. Here we focus on subjective experience, which is a basic awareness of the world without further reflection on that awareness. This is considered the most basic form of consciousness. Tellingly, this capacity is supported by the integrated midbrain and basal ganglia structures, which are among the oldest and most highly conserved brain systems in vertebrates. A reasonable inference is that the capacity for subjective experience is both widespread and evolutionarily old within the vertebrate lineage. We argue that the insect brain supports functions analogous to those of the vertebrate midbrain and hence that insects may also have a capacity for subjective experience. We discuss the features of neural systems which can and cannot be expected to support this capacity as well as the relationship between our arguments based on neurobiological mechanism and our approach to the "hard problem" of conscious experience.

109 citations

References
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Book
31 Jul 2001
TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.
Abstract: "The Mouse Brain in Stereotaxic Coordinates" is the most widely used and cited atlas of the mouse brain in print. It provides researchers and students with both accurate stereotaxic coordinates for laboratory use, and detailed delineations and indexing of structures for reference. The accompanying DVD provides drawings of brains structures that can be used as templates for making figures for publication. The 3rd edition is both a major revision and an expansion of previous editions. Delineations and photographs in the horizontal plane of section now complement the coronal and sagittal series, and all the tissue sections are now shown in high resolution digital color photography. The photographs of the sections and the intermediate sections are also provided on the accompanying DVD in high-resolution JP 2000 format. The delineations of structures have been revised, and naming conventions made consistent with Paxinos and Watson's "Rat Brain in Stereotaxic Coordinates, 6th Edition". The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use. This edition is in full color throughout. It includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material. Coronal and sagittal diagrams are completely reworked and updated. Rhombomeric borders are included in sagittal figures, for the first time in mammals. Microscopic plates are scanned with a new method in much higher quality.

15,681 citations


"GluA1 Phosphorylation Contributes t..." refers methods in this paper

  • ...The anatomical terminology is based on the atlas of Franklin and Paxinos (1997)....

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Journal ArticleDOI
TL;DR: It is found that painful and non-painful somaesthetic representations in the human insula overlap, and lateralization in the right hemisphere of sites where painful sensations were evoked is coherent with the hypothesis of a preponderant role of this hemisphere in species survival.
Abstract: We studied painful and non-painful somaesthetic sensations elicited by direct electrical stimulations of the insular cortex performed in 43 patients with drug refractory temporal lobe epilepsy, using stereotactically implanted depth electrodes. Painful sensations were evoked in the upper posterior part of the insular cortex in 14 patients, mostly in the right hemisphere. Non-painful sensations were elicited in the posterior part of the insular cortex in 16 patients, in both hemispheres. Thus, painful and non-painful somaesthetic representations in the human insula overlap. Both types of responses showed a trend toward a somatotopic organization. These results agree with previous anatomical and unit recording studies in monkeys indicating a participation of the posterior part of the insular cortex in processing both noxious and innocuous somaesthetic stimuli. In humans, both a posterior and an anterior pain-related cortical area have been described within the insular cortex using functional imaging. Our results help to define the respective functional roles of these two insular areas. Finally, lateralization in the right hemisphere of sites where painful sensations were evoked is coherent with the hypothesis of a preponderant role of this hemisphere in species survival.

519 citations


"GluA1 Phosphorylation Contributes t..." refers background in this paper

  • ...Insular cortex and neuropathic pain The insular cortex is critical in pain and sensory perception (Ostrowsky et al., 2002; Mazzola et al., 2009, 2012)....

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  • ..., 2008), and direct electrical stimulation of the insular cortex could elicit painful and somatic sensations, supporting the critical roles of the insular cortex in acute pain and sensory perception (Ostrowsky et al., 2002; Mazzola et al., 2009; Mazzola et al., 2012)....

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  • ...…stimuli (Henderson et al., 2008), and direct electrical stimulation of the insular cortex could elicit painful and somatic sensations, supporting the critical roles of the insular cortex in acute pain and sensory perception (Ostrowsky et al., 2002; Mazzola et al., 2009; Mazzola et al., 2012)....

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Journal ArticleDOI
28 Jan 2010-Neuron
TL;DR: Elevated extrasynaptic NMDAR activity is demonstrated in an animal model of neurodegenerative disease and a candidate mechanism linking several pathways previously implicated in HD pathogenesis is provided and successful early therapeutic intervention in mice is demonstrated.

477 citations


"GluA1 Phosphorylation Contributes t..." refers methods in this paper

  • ...Subcellular fractionation was conducted on tissue from C57BL/6 mice or transgenic mice using an adapted protocol (Pacchioni et al., 2009; Milnerwood et al., 2010)....

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  • ...The synaptosome was digested to yield an insoluble PSD-enriched (synaptic) membrane fraction and a soluble non-PSD enriched (peri/extrasynaptic and presynaptic) membrane fraction (Pacchioni et al., 2009; Milnerwood et al., 2010)....

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Journal ArticleDOI
15 Sep 2005-Neuron
TL;DR: It is reported that the activation of the NR2B and NR2A subunits of the NMDA receptor is critical for the induction of cingulate LTP, regardless of the induction protocol.

477 citations

Journal ArticleDOI
19 Nov 2010-Science
TL;DR: It is 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, which defines a temporal window in which fear memory can be degraded by behavioral experience.
Abstract: 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.

451 citations


"GluA1 Phosphorylation Contributes t..." refers methods in this paper

  • ...…the role of phosphorylation in the upregulation of insular GluA1 during neuropathic pain, we used two lines of mutant mice specifically lacking phosphorylation of the Ser845 site (GluA1–S845A mutants) or lacking phosphorylation of the Ser831 site (GluA1–S831A mutants; Clem and Huganir, 2010)....

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