Loss of long-term depression in the insular cortex after tail amputation in adult mice
TL;DR: It is 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, and it is suggested that restoration of insular LTD may represent a novel therapeutic strategy against the synaptic dysfunctions underlying the pathophysiology of phantom pain.
Abstract: 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.
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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.
76 citations
Cites background from "Loss of long-term depression in the..."
...Peripheral nerve injury or tail amputation produces long-term upregulation or activation of the synaptic NMDARs (Zhuo, 1998; Qiu et al., 2013) or loss of long-term depression in the insular cortex (Liu and Zhuo, 2014)....
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..., 2013) or loss of long-term depression in the insular cortex (Liu and Zhuo, 2014)....
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TL;DR: LTP of glutamatergic transmission in pain related cortical areas serves as a key mechanism for chronic pain.
65 citations
TL;DR: There is strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission and basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain are provided.
Abstract: Long-term potentiation (LTP) is a key cellular mechanism for pathological pain in the central nervous system. LTP contains at least two different phases: early-phase LTP (E-LTP) and late-phase LTP (L-LTP). Among several major cortical areas, the anterior cingulate cortex (ACC) is a critical brain region for pain perception and its related emotional changes. Periphery tissue or nerve injuries cause LTP of excitatory synaptic transmission in the ACC. Our previous studies have demonstrated that genetic deletion of calcium-stimulated adenylyl cyclase 1 (AC1) or pharmacological application of a selective AC1 inhibitor NB001 blocked E-LTP in the ACC. However, the effect of AC1 on L-LTP, which requires new protein synthesis and is important for the process of chronic pain, has not been investigated. Here we tested the effects of NB001 on the ACC L-LTP and found that bath application of NB001 (0.1 μM) totally blocked the induction of L-LTP and recruitment of cortical circuitry without affecting basal excitatory transmission. In contrast, gabapentin, a widely used analgesic drug for neuropathic pain, did not block the induction of L-LTP and circuitry recruitment even at a high concentration (100 μM). Gabapentin non-selectively decreased basal synaptic transmission. Our results provide strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission. It also provides basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain.
41 citations
Cites background from "Loss of long-term depression in the..."
...in sensory and emotion-related cortical areas such as the insular cortex (IC) and anterior cingulate cortex (ACC), both E-LTP and L-LTP have been recently reported in adult mice [11-14]....
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TL;DR: It is found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region.
Abstract: The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain.
39 citations
TL;DR: Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.
Abstract: Commercial pigs are frequently exposed to tail mutilations in the form of preventive husbandry procedures (tail docking) or as a result of abnormal behaviour (tail biting). Although tissue and nerve injuries are well-described causes of pain hypersensitivity in humans and in rodent animal models, there is no information on the changes in local pain sensitivity induced by tail injuries in pigs. To determine the temporal profile of sensitisation, pigs were exposed to surgical tail resections and mechanical nociceptive thresholds (MNT) were measured in the acute (one week post-operatively) and in the long-term (either eight or sixteen weeks post-surgery) phase of recovery. The influence of the degree of amputation on MNTs was also evaluated by comparing three different tail-resection treatments (intact, 'short tail', 'long tail'). A significant reduction in MNTs one week following surgery suggests the occurrence of acute sensitisation. Long-term hypersensitivity was also observed in tail-resected pigs at either two or four months following surgery. Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.
35 citations
References
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TL;DR: It is demonstrated that Erk signaling pathway in the ACC is potently activated after peripheral tissue or nerve injury and proposed a synaptic model for explaining the roles of Erk activity during different phases of chronic pain.
Abstract: The extracellular signal-regulated kinase (Erk) activity contributes to synaptic plasticity, a key mechanism for learning, memory and chronic pain. Although the anterior cingulate cortex (ACC) has been reported as an important cortical region for neuronal mechanisms underlying the induction and expression of chronic pain, it has yet to be investigated whether or not Erk activity in the ACC may be affected by peripheral injury or in chronic pain state. In the present study, we use adult rat animal models of inflammatory and neuropathic pain and demonstrate that Erk signaling pathway in the ACC is potently activated after peripheral tissue or nerve injury. Furthermore, we demonstrate that mechanical allodynia significantly activated Erk activity at synaptic sites at two weeks after the injury. We propose a synaptic model for explaining the roles of Erk activity during different phases of chronic pain. Our findings suggest that cortical activation of Erk may contribute to both induction and expression of chronic pain.
75 citations
"Loss of long-term depression in the..." refers background or methods in this paper
...Specifically, we found that peripheral amputation abolished LTD and enhanced extracellular signal-regulated kinase activation in the rodent ACC at two weeks [37-39]....
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...We previously demonstrated that digit amputation in rats or tail amputation in mice triggered long-lasting plastic alterations in the anterior cingulate cortex (ACC), including an enhancement of excitatory synaptic responses in vivo [35,36], loss of long-term depression (LTD) in vitro [37,38] and activation of activity-dependent immediate early genes [37,39]....
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...In the present study, we performed electrophysiological recordings at 2 weeks after tail amputation (Figure 1A), on the basis of our previous reports showing an evident plastic change in the ACC at this time point [37-39]....
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TL;DR: In this article, the authors performed quantal analysis of excitatory synapses in the anterior cingulate cortex (ACC) with chronic pain to examine the source of these increases.
Abstract: The anterior cingulate cortex (ACC) is a forebrain structure that plays important roles in emotion, learning, memory and persistent pain. Our previous studies have demonstrated that the enhancement of excitatory synaptic transmission was induced by peripheral inflammation and nerve injury in ACC synapses. However, little information is available on their presynaptic mechanisms, since the source of the enhanced synaptic transmission could include the enhanced probability of neurotransmitter release at existing release sites and/or increases in the number of available vesicles. The present study aims to perform quantal analysis of excitatory synapses in the ACC with chronic pain to examine the source of these increases. The quantal analysis revealed that both probability of transmitter release and number of available vesicles were increased in a mouse model of peripheral inflammation, whereas only probability of transmitter release but not number of available vesicles was enhanced in a mouse model of neuropathic pain. In addition, we compared the miniature excitatory postsynaptic potentials (mEPSCs) in ACC synapses with those in other pain-related brain areas such as the amygdala and spinal cord. Interestingly, the rate and amplitude of mEPSCs in ACC synapses were significantly lower than those in the amygdala and spinal cord. Our studies provide strong evidences that chronic inflammatory pain increases both probability of transmitter release and number of available vesicles, whereas neuropathic pain increases only probability of transmitter release in the ACC synapses.
75 citations
"Loss of long-term depression in the..." refers background in this paper
...It has been previously reported that peripheral inflammation or nerve injury could trigger a long-term enhancement of excitatory synaptic transmission in various brain regions, such as ACC [51-54], amygdala [55-57], and hippocampus [58]....
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TL;DR: The mechanisms underlying phantom pain primarily relate to peripheral/spinal dysfunction, and supraspinal and central plasticity in sensorimotor body representations, and the most promising methods for managing phantom pain address the maladaptive changes at multiple levels of the neuraxis.
Abstract: Purpose of reviewPhantom pain is a frequent consequence of amputation or deafferentation. There are many possible contributing mechanisms, including stump-related pathology, spinal and cortical changes. Phantom limb pain is notoriously difficult to treat. Continued consideration of the factors assoc
75 citations
"Loss of long-term depression in the..." refers background in this paper
...Phantom pain refers to the feeling of pain in a body part that has been amputated [25-27]....
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...Phantom pain is a common form of chronic pain syndrome characterized by the feeling of pain in the missing limb following amputation or deafferentation [25-27]....
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TL;DR: The data suggest that a negative context not only has an effect on immediate pain but can modulate perception of pain in the future even without experience/conditioning.
Abstract: It is generally accepted that acute painful experience is influenced by context information shaping expectation and modulating attention, arousal, stress, and mood. However, little is known about the nature, duration, and extent of this effect, particularly regarding the negative expectation. We used a standardized longitudinal pain paradigm and painful heat test stimuli in healthy participants over a time course of 8 consecutive days, inducing nociceptive habituation over time. Thirty-eight healthy volunteers were randomly assigned to two different groups. One group received the information that the investigators expected the pain intensity to increase over time (context group). The other group was not given any information (control group). All participants rated the pain intensity of the daily standardized pain paradigm on a visual analog scale. In agreement with previous studies the pain ratings in the control group habituated over time. However, the context group reported no change of pain ratings over time. Functional imaging data showed a difference between the two groups in the right parietal operculum. These data suggest that a negative context not only has an effect on immediate pain but can modulate perception of pain in the future even without experience/conditioning. Neuronally, this process is mediated by the right opercular region.
74 citations
"Loss of long-term depression in the..." refers background in this paper
...In particular, human brain imaging studies have demonstrated the activation of IC in a broad range of pain conditions [4-6]....
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TL;DR: In this paper, a patch-clamp in rat brain slices was used to measure monosynaptic excitatory postsynaptic currents (EPSCs) and polysynaptic inhibitory currents (IPSCs) that were evoked by electrical stimulation in the basolateral amygdala (BLA).
Abstract: Neuroplasticity in the central nucleus of the amygdala (CeA), particularly its latero-capsular division (CeLC), is an important contributor to the emotional-affective aspects of pain. Previous studies showed synaptic plasticity of excitatory transmission to the CeLC in different pain models, but pain-related changes of inhibitory transmission remain to be determined. The CeLC receives convergent excitatory inputs from the parabrachial nucleus in the brainstem and from the basolateral amygdala (BLA). In addition, feedforward inhibition of CeA neurons is driven by glutamatergic projections from the BLA area to a cluster of GABAergic neurons in the intercalated cell masses (ITC). Using patch-clamp in rat brain slices we measured monosynaptic excitatory postsynaptic currents (EPSCs) and polysynaptic inhibitory currents (IPSCs) that were evoked by electrical stimulation in the BLA. In brain slices from arthritic rats, input-output functions of excitatory synaptic transmission were enhanced whereas inhibitory synaptic transmission was decreased compared to control slices from normal untreated rats. A non-NMDA receptor antagonist (NBQX) blocked the EPSCs and reduced the IPSCs, suggesting that non-NMDA receptors mediate excitatory transmission and also contribute to glutamate-driven feed-forward inhibition of CeLC neurons. IPSCs were blocked by a GABAA receptor antagonist (bicuculline). Bicuculline increased EPSCs under normal conditions but not in slices from arthritic rats, which indicates a loss of GABAergic control of excitatory transmission. A metabotropic glutamate receptor subtype 1 (mGluR1) antagonist (LY367385) reversed both the increase of excitatory transmission and the decrease of inhibitory transmission in the arthritis pain model but had no effect on basal synaptic transmission in control slices from normal rats. The inhibitory effect of LY367385 on excitatory transmission was blocked by bicuculline suggesting the involvement of a GABAergic mechanism. An mGluR5 antagonist (MTEP) inhibited both excitatory and inhibitory transmission in slices from normal and from arthritic rats. The analysis of spontaneous and miniature EPSCs and IPSCs showed that mGluR1 acted presynaptically whereas mGluR5 had postsynaptic effects. In conclusion, mGluR1 rather than mGluR5 can account for the pain-related changes of excitatory and inhibitory synaptic transmission in the CeLC through a mechanism that involves inhibition of inhibitory transmission (disinhibition).
74 citations
"Loss of long-term depression in the..." refers background in this paper
...It has been previously reported that peripheral inflammation or nerve injury could trigger a long-term enhancement of excitatory synaptic transmission in various brain regions, such as ACC [51-54], amygdala [55-57], and hippocampus [58]....
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