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: The results suggest that the NMDA receptor is regulated by protein kinase C, and that the intracellular level of protein Kinase C may determine the threshold for induction of long‐term potentiation.
Abstract: Using intracellular and extracellular recordings in rat hippocampal slices, we have investigated the interactions between the quisqualate metabotropic receptor (QP) and currents mediated by N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). We found that trans-(t)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) and 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) potentiated NMDA but not AMPA-mediated currents. Intracellular injections of selective protein kinase C inhibitors prevented the up-regulation of the NMDA response. The physiological consequence of the up-regulation by ACPD of the NMDA response on the threshold of long-term potentiation induction was tested. We found that a subthreshold train of electrical stimulation that produced short-term potentiation generated long-term potentiation when coupled with ACPD application, an effect which was not produced by AMPA or NMDA. This effect was blocked by an inhibitor of protein kinase C. These results demonstrate for the first time that one subtype of glutamate receptor (QP) can regulate another subtype of glutamate receptor (NMDA) through the activation of protein kinase C. Our results also suggest that the NMDA receptor is regulated by protein kinase C, and that the intracellular level of protein kinase C may determine the threshold for induction of long-term potentiation.
207 citations
"Loss of long-term depression in the..." refers background in this paper
...NMDA receptor- or prior synaptic activity-induced subsequent LTP inhibition and LTD facilitation [63,78], mGluRs-mediated LTP enhancement [64,74,79] and inhibition of chemically- or electrically-induced LTD initiation [65,80]....
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...Also, the function of the NMDA receptor can be regulated through PKC-mediated signaling pathways [74,83,84]....
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...Nevertheless, the current literature mainly indicates the metaplastic role of mGluRs in facilitation of hippocampal LTP induction, with less emphasis placed upon their effect on LTD in cortical areas [59,60,74,75]....
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TL;DR: In this article, subjective and videotaped behavioural responses to 4160 cortical stimulations using intracerebral electrodes implanted in all cortical lobes were carried out over 12 years during the presurgical evaluation of epilepsy in 164 consecutive patients.
Abstract: 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.
182 citations
TL;DR: Reorganization of the primary somatosensory cortex was associated with increased habitual phantom limb pain, telescoping, non-painful stump sensations and painful referred sensation induced by painful stimulation.
182 citations
"Loss of long-term depression in the..." refers background in this paper
...Mechanistically, limb amputation has been shown to cause dramatic cortical reorganization in humans and primates [28-31], the amount of which correlates well with the extent of phantom pain in some reports [32-34]....
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TL;DR: The results suggest that rapid enhancement of sensory responses can be observed in the ACC after amputation and that enhanced neuronal responses to subsequent somatosensory stimuli may contribute to phantom‐limb pain.
Abstract: The anterior cingulate cortex (ACC) is important for processing different types of information, including sensory inputs. In the present study on anaesthetised rats, we recorded in vivo sensory responses of the ACC to peripheral electrical shocks. Peripheral electrical stimulation at high intensities sufficient to activate nociceptive sensory fibres elicited EPSPs within the ACC. Digit amputation caused long-lasting potentiation of ACC responses to peripheral electrical stimulation. Evoked field EPSPs remained enhanced for at least 120 min after the amputation. Because electrical shocks were delivered to the normal hindpaw, it is likely that plastic changes occur centrally in the spinal cord or the supraspinal structures following amputation. We also recorded field EPSPs of the ACC in response to focal cortical stimulation within the ACC. Like the sensory responses, field EPSPs produced by focal cortical stimulation within the ACC were potentiated after digit amputation, suggesting that long-lasting changes occurred locally within the ACC. Local blockade of peripheral activity by QX-314 at the amputated hindpaw 120 min after amputation did not significantly affect sensory responses induced within the ACC. Thus, peripheral ongoing inputs do not play an important role in maintaining potentiation within the ACC. Two pulses of hindpaw stimulation caused paired-pulse depression in the ACC. Local stimulation within the ACC also caused depression of sensory responses to hindpaw stimulation, suggesting that the population of synapses activated by local stimulation may overlap with that activated by peripheral hindpaw stimulation. Our results suggest that rapid enhancement of sensory responses can be observed in the ACC after amputation and that enhanced neuronal responses to subsequent somatosensory stimuli may contribute to phantom-limb pain.
176 citations
"Loss of long-term depression in the..." refers background in this paper
...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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TL;DR: In this paper, the anterior cingulate cortex (ACC) was analyzed from mice with chronic pain induced by hindpaw injection of complete Freund's adjuvant (CFA) in vitro whole-cell patch-clamp recordings revealed a significant enhancement in neurotransmitter release probability in ACC synapses.
Abstract: The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in learning and memory Recent studies show that painful stimuli activate the prefrontal cortex and that brain chemistry is altered in this area in patients with chronic pain Components of the CNS that are involved in pain transmission and modulation, from the spinal cord to the ACC, are very plastic and undergo rapid and long-term changes after injury Patients suffering from chronic pain often complain of memory and concentration difficulties, but little is known about the neural circuitry underlying these deficits To address this question, we analyzed synaptic transmission in the ACC from mice with chronic pain induced by hindpaw injection of complete Freund's adjuvant (CFA) In vitro whole-cell patch-clamp recordings revealed a significant enhancement in neurotransmitter release probability in ACC synapses from mice with chronic pain Trace fear memory, which requires sustained attention and the activity of the ACC, was impaired in CFA-injected mice Using knock-out mice, we found that calmodulin-stimulated adenylyl cyclases, AC1 and/or AC8, were crucial in mediating the long-lasting enhanced presynaptic transmitter release in the ACC of mice with chronic pain Our findings provide strong evidence that presynaptic alterations caused by peripheral inflammation contribute to memory impairments after injury
175 citations