RESUMEN
Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re â LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re â LS â LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.
Asunto(s)
Ansiedad , Neuronas GABAérgicas , Área Hipotalámica Lateral , Prurito , Animales , Ratones , Neuronas GABAérgicas/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Núcleos Talámicos de la Línea Media/metabolismo , Masculino , Conducta Animal , Vías Nerviosas , Plasticidad Neuronal , Núcleos SeptalesRESUMEN
Pain and itch are two closely related but essentially distinct sensations that elicit different behavioral responses. However, it remains mysterious how pain and itch information is encoded in the brain to produce differential perceptions. Here, we report that nociceptive and pruriceptive signals are separately represented and processed by distinct neural ensembles in the prelimbic (PL) subdivision of the medial prefrontal cortex (mPFC) in mice. Pain- and itch-responsive cortical neural ensembles were found to significantly differ in electrophysiological properties, input-output connectivity profiles, and activity patterns to nociceptive or pruriceptive stimuli. Moreover, these two groups of cortical neural ensembles oppositely modulate pain- or itch-related sensory and emotional behaviors through their preferential projections to specific downstream regions such as the mediodorsal thalamus (MD) and basolateral amygdala (BLA). These findings uncover separate representations of pain and itch by distinct prefrontal neural ensembles and provide a new framework for understanding somatosensory information processing in the brain.
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Complejo Nuclear Basolateral , Corteza Prefrontal , Ratones , Animales , Corteza Prefrontal/fisiología , Vías Nerviosas/fisiología , Tálamo/fisiología , DolorRESUMEN
Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACCâVTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.
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Giro del Cíngulo , Prurito , Ratones , Animales , Giro del Cíngulo/fisiología , Prurito/patología , Mesencéfalo , Corteza Cerebral/patología , Neuronas/patologíaRESUMEN
Threat and extinction memories are crucial for organisms' survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.
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Extinción Psicológica , Miedo , Animales , Extinción Psicológica/fisiología , Miedo/fisiología , Masculino , Ratones , Neuronas/fisiología , Núcleo Accumbens/fisiología , Corteza Prefrontal/fisiologíaRESUMEN
Acid-sensing ion channels (ASICs), the main H+ receptors in the central nervous system, sense extracellular pH fluctuations and mediate cation influx. ASIC1a, the major subunit responsible for acid-activated current, is widely expressed in brain neurons, where it plays pivotal roles in diverse functions including synaptic transmission and plasticity. However, the underlying molecular mechanisms for these functions remain mysterious. Using extracellular epitope tagging and a novel antibody recognizing the hASIC1a ectodomain, we examined the membrane targeting and dynamic trafficking of hASIC1a in cultured cortical neurons. Surface hASIC1a was distributed throughout somata and dendrites, clustered in spine heads, and co-localized with postsynaptic markers. By extracellular pHluorin tagging and fluorescence recovery after photobleaching, we detected movement of hASIC1a in synaptic spine heads. Single-particle tracking along with use of the anti-hASIC1a ectodomain antibody revealed long-distance migration and local movement of surface hASIC1a puncta on dendrites. Importantly, enhancing synaptic activity with brain-derived neurotrophic factor accelerated the trafficking and lateral mobility of hASIC1a. With this newly-developed toolbox, our data demonstrate the synaptic location and high dynamics of functionally-relevant hASIC1a on the surface of excitatory synapses, supporting its involvement in synaptic functions.
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Canales Iónicos Sensibles al Ácido , Neuronas , Canales Iónicos Sensibles al Ácido/metabolismo , Neuronas/metabolismo , Sinapsis/metabolismo , Transmisión SinápticaRESUMEN
Nerve injury in somatosensory pathways may lead to neuropathic pain, which affects the life quality of â¼8% of people. Long-term enhancement of excitatory synaptic transmission along somatosensory pathways contributes to neuropathic pain. Caspase 3 (Casp3) plays a non-apoptotic role in the hippocampus and regulates internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. Whether Casp3-AMPAR interaction is involved in the maintenance of peripheral hypersensitivity after nerve injury remained unknown. Here, we show that nerve injury suppresses long-term depression (LTD) and downregulates Casp3 in the anterior cingulate cortex (ACC). Interfering with interactions between Casp3 and AMPAR subunits or reducing Casp3 activity in the ACC suppresses LTD induction and causes peripheral hypersensitivity. Overexpression of Casp3 restores LTD and reduces peripheral hypersensitivity after nerve injury. We reveal how Casp3 is involved in the maintenance of peripheral hypersensitivity. Our findings suggest that restoration of LTD via Casp3 provides a therapeutic strategy for neuropathic pain management.
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Caspasa 3/metabolismo , Depresión/genética , Giro del Cíngulo/fisiopatología , Neuralgia/fisiopatología , HumanosRESUMEN
Mutations in the macroautophagy/autophagy gene WDR45 cause ß-propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in several brain regions. Immunohistochemistry analysis showed loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in prefrontal cortex, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis showed accumulation of endoplasmic reticulum (ER) proteins in KO mouse. At the cellular level, accumulation of ER proteins due to WDR45 deficiency resulted in increased ER stress and impaired ER quality control. The unfolded protein response (UPR) was elevated through ERN1/IRE1 or EIF2AK3/PERK pathway, and eventually led to neuronal apoptosis. Suppression of ER stress or activation of autophagy through MTOR inhibition alleviated cell death. Thus, the loss of WDR45 cripples macroautophagy machinery in neurons and leads to impairment in organelle autophagy, which provides a mechanistic understanding of cause of BPAN and a potential therapeutic strategy to treat this genetic disorder.Abbreviations: 7-ADD: 7-aminoactinomycin D; ASD: autistic spectrum disorder; ATF6: activating transcription factor 6; ATG: autophagy-related; BafA1: bafilomycin A1; BCAP31: B cell receptor associated protein 31; BPAN: ß-propeller protein-associated neurodegeneration; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CDIPT: CDP-diacylglycerol-inositol 3-phosphatidyltransferase (phosphatidylinositol synthase); DDIT3/CHOP: DNA-damage inducible transcript 3; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HIP: hippocampus; HSPA5/GRP78: heat shock protein family A (HSP70) member 5; KO: knockout; LAMP1: lysosomal-associated membrane 1; mEPSCs: miniature excitatory postsynaptic currents; MG132: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal; MIB: mid-brain; MTOR: mechanistic target of rapamycin kinase; PCR: polymerase chain reaction; PFA: paraformaldehyde; PFC: prefrontal cortex; PRM: parallel reaction monitoring; RBFOX3/NEUN: RNA binding protein, fox-1 homolog [C. elegans] 3; RTN3: reticulon 3; SEC22B: SEC22 homolog B, vesicle trafficking protein; SEC61B: SEC61 translocon beta subunit; SEM: standard error of the mean; SNR: substantia nigra; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; Tm: tunicamycin; TMT: tandem mass tag; TUDCA: tauroursodeoxycholic acid; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UPR: unfolded protein response; WDR45: WD repeat domain 45; WT: wild type; XBP1: X-box binding protein 1.
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Proteínas Portadoras/metabolismo , Retículo Endoplásmico/metabolismo , Homeostasis , Degeneración Nerviosa/patología , Neuronas/patología , Animales , Apoptosis , Autofagia , Secuencia de Bases , Encéfalo/patología , Muerte Celular , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/patología , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Lisosomas/metabolismo , Ratones Noqueados , Degeneración Nerviosa/complicaciones , Neuronas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Mapas de Interacción de Proteínas , ProteolisisRESUMEN
Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C λ-mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.
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Canales Iónicos Sensibles al Ácido/biosíntesis , Giro del Cíngulo/metabolismo , Isoenzimas/deficiencia , Neuralgia/metabolismo , Plasticidad Neuronal/fisiología , Dimensión del Dolor/métodos , Proteína Quinasa C/deficiencia , 6-Ciano 7-nitroquinoxalina 2,3-diona/administración & dosificación , Canales Iónicos Sensibles al Ácido/genética , Animales , Células Cultivadas , Giro del Cíngulo/efectos de los fármacos , Isoenzimas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microinyecciones/métodos , Neuralgia/genética , Neuralgia/prevención & control , Plasticidad Neuronal/efectos de los fármacos , Técnicas de Cultivo de Órganos , Dimensión del Dolor/efectos de los fármacos , Proteína Quinasa C/genéticaRESUMEN
Itch is an aversive sensation that evokes a desire to scratch. Paradoxically, scratching the itch also produces a hedonic experience. The specific brain circuits processing these different aspects of itch, however, remain elusive. Here, we report that GABAergic (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) are activated with different temporal patterns during acute and chronic itch. DA neuron activation lags behind GABA neurons and is dependent on scratching of the itchy site. Optogenetic manipulations of VTA GABA neurons rapidly modulated scratching behaviors through encoding itch-associated aversion. In contrast, optogenetic manipulations of VTA DA neurons revealed their roles in sustaining recurrent scratching episodes through signaling scratching-induced reward. A similar dichotomy exists for the role of VTA in chronic itch. These findings advance understanding of circuit mechanisms of the unstoppable itch-scratch cycles and shed important insights into chronic itch therapy.
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Conducta Animal , Neuronas Dopaminérgicas/metabolismo , Neuronas GABAérgicas/metabolismo , Prurito/metabolismo , Recompensa , Área Tegmental Ventral/metabolismo , Animales , Señalización del Calcio , Cloroquina/farmacología , Neuronas Dopaminérgicas/fisiología , Fenómenos Electrofisiológicos , Neuronas GABAérgicas/fisiología , Histamina/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Mesencéfalo , Ratones , Optogenética , Prurito/inducido químicamente , Área Tegmental Ventral/citologíaRESUMEN
Cognitive flexibility is an important aspect of executive function. The cholinergic system, an important component of cognition, has been shown to modulate cognitive flexibility mainly through the striatum and prefrontal cortex. The role of M1 muscarinic receptors (M1 mAChRs), an important therapeutic target in the cholinergic system, in hippocampus-dependent cognitive flexibility is unclarified. In the present study, we demonstrated that selective activation of M1 mAChRs promoted extinction of initial learned response and facilitated acquisition of reversal learning in the Morris water maze, a behavior test that is mainly dependent on the hippocampus. However, these effects were abolished in GluA2 mutant mice with deficiency in phosphorylation of Ser880 by protein kinase C (PKC). Further long-term depression (LTD) in the hippocampal CA1 area induced by M1 mAChR activation was shown to be dependent on AMPA receptor subunit GluA2 but not GluA1. M1 mAChRs increased GluA2 endocytosis through phosphorylation of Ser880 by PKC. Inhibition of PKC blocked M1 mAChR-mediated LTD, memory switching and reversal learning facilitation. Moreover, the slow memory extinction observed in GluA2 mutant mice and PKC inhibitor-treated mice appeared to affect the consolidation and retrieval of reversal learning. Thus, these results demonstrate that M1 mAChRs mainly facilitate acquisition in spatial reversal learning and further elucidate that such an effect is dependent on the phosphorylation of GluA2 by PKC. The study helps clarify the role of M1 mAChRs in cognitive flexibility and may prompt the earlier prevention of cognitive inflexibility.
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Receptor Muscarínico M1/efectos de los fármacos , Receptor Muscarínico M1/metabolismo , Receptores AMPA/metabolismo , Aprendizaje Inverso/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Cognición/fisiología , Hipocampo , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosforilación , Piperidinas , Proteína Quinasa C/antagonistas & inhibidores , Quinolonas , Receptor Muscarínico M1/agonistas , Receptores AMPA/deficienciaRESUMEN
Anterior cingulate cortex (ACC) is known to play important roles in key brain functions such as pain perception, cognition, and emotion. Different forms of homosynaptic plasticity such as long-term potentiation (LTP) and long-term depression have been studied in ACC synapses. However, heterosynaptic plasticity such as synaptic tagging has not been reported. Here, we demonstrate synaptic tagging in the ACC of adult male mice by using a 64-channel multielectrode array recording system. Weak theta burst stimulation (TBS), normally inducing early-phase LTP or No-LTP in most of the activated channels, produced late phase-LTP (L-LTP) in a majority of channels when a strong TBS was applied earlier to a separate input within a certain time window. Similar to hippocampus, synaptic tagging in the ACC depends on the synthesis of new proteins. Tail amputation-induced peripheral injury caused a loss of this heterosynaptic L-LTP and occluded strong TBS-evoked L-LTP as well. Together, we provide the first report of the synaptic tagging-like phenomenon in the ACC of adult mice, and the loss of synaptic tagging to amputation may contribute to injury-related cognitive changes and phantom limb sensation and pain.SIGNIFICANCE STATEMENT ACC is an important cortical region involved in many brain functions. Previous studies have dissected the molecular mechanism of multiple types of homosynaptic plasticity of ACC synapses. Here, we report a novel form of heterosynaptic plasticity occurring in the ACC. This newly identified, protein synthesis-dependent neocortical synaptic tagging is sensitive to peripheral tail amputation injury and may provide basic mechanisms for synaptic pathophysiology of phantom pain and related cognitive changes.
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Amputación Quirúrgica , Giro del Cíngulo/fisiología , Potenciación a Largo Plazo/fisiología , Traumatismos de los Nervios Periféricos/fisiopatología , Sinapsis/fisiología , Cola (estructura animal) , Animales , Estimulación Eléctrica , RatonesRESUMEN
Acid-sensing ion channel 1a (ASIC1a) has been shown to play important roles in synaptic plasticity, learning and memory. Here we identify a crucial role for ASIC1a in long-term depression (LTD) at mouse insular synapses. Genetic ablation and pharmacological inhibition of ASIC1a reduced the induction probability of LTD without affecting that of long-term potentiation in the insular cortex. The disruption of ASIC1a also attenuated the extinction of established taste aversion memory without altering the initial associative taste learning or its long-term retention. Extinction of taste aversive memory led to the reduced insular synaptic efficacy, which precluded further LTD induction. The impaired LTD and extinction learning in ASIC1a null mice were restored by virus-mediated expression of wild-type ASIC1a, but not its ion-impermeable mutant, in the insular cortices. Our data demonstrate the involvement of an ASIC1a-mediated insular synaptic depression mechanism in extinction learning, which raises the possibility of targeting ASIC1a to manage adaptive behaviours.
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Canales Iónicos Sensibles al Ácido/metabolismo , Corteza Cerebral/metabolismo , Condicionamiento Clásico , Extinción Psicológica , Potenciación a Largo Plazo , Gusto/fisiología , Canales Iónicos Sensibles al Ácido/deficiencia , Secuencia de Aminoácidos , Animales , Reacción de Prevención/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Estimulación Eléctrica , Extinción Psicológica/efectos de los fármacos , Glutamatos/metabolismo , Glicina/análogos & derivados , Glicina/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Péptidos/química , Resorcinoles/farmacología , Transducción de Señal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Gusto/efectos de los fármacosRESUMEN
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.
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Canales Iónicos Sensibles al Ácido/fisiología , Región CA1 Hipocampal/fisiología , Potenciación a Largo Plazo , Canales Iónicos Sensibles al Ácido/genética , Animales , Estimulación Eléctrica , Depresión Sináptica a Largo Plazo , Ratones , Ratones Noqueados , Receptores de N-Metil-D-AspartatoRESUMEN
It has been reported that activated microglia plays important roles in chronic pain-related sensory signaling at the spinal cord dorsal horn. Less is known about the possible contribution of microglia to cortical plasticity that has been found to be important for chronic pain. In the present study, we used a 64-channel multi-electrode array recording system to investigate the role of microglia in cortical plasticity of the anterior cingulate cortex (ACC) in normal adult mice. We found that bath application of minocycline, an inhibitor of microglial activation, had no effect on postsynaptic LTP (post-LTP) induced by theta burst stimulation in the ACC. Furthermore, presynaptic LTP (pre-LTP) induced by the combination of low-frequency stimulation with a GluK1-containing kainate receptor agonist was also not affected. The spatial distribution of post-LTP or pre-LTP among the cingulate network is also unaltered by minocycline. Our results suggest that minocycline does not affect cingulate plasticity and neurons are the major player in pain-related cortical plasticity.
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Envejecimiento/fisiología , Giro del Cíngulo/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Minociclina/farmacología , Animales , Electrodos , Giro del Cíngulo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BLRESUMEN
Fragile X syndrome is a common inherited form of mental impairment. Fragile X mental retardation protein (FMRP) plays important roles in the regulation of synaptic protein synthesis, and loss of FMRP leads to deficits in learning-related synaptic plasticity and behavioral disability. Previous studies mostly focus on postsynaptic long-term potentiation (LTP) in Fmr1 knock-out (KO) mice. Here, we investigate the role of FMRP in presynaptic LTP (pre-LTP) in the adult mouse anterior cingulate cortex (ACC). Low-frequency stimulation induced LTP in layer II/III pyramidal neurons under the voltage-clamp mode. Paired-pulse ratio, which is a parameter for presynaptic changes, was decreased after the low-frequency stimulation in Fmr1 wild-type (WT) mice. Cingulate pre-LTP was abolished in Fmr1 KO mice. We also used a 64-electrode array system for field EPSP recording and found that the combination of low-frequency stimulation paired with a GluK1-containing kainate receptor agonist induced NMDA receptor-independent and metabotropic glutamate receptor-dependent pre-LTP in the WT mice. This potentiation was blocked in Fmr1 KO mice. Biochemical experiments showed that Fmr1 KO mice displayed altered translocation of protein kinase A subunits in the ACC. Our results demonstrate that FMRP plays an important role in pre-LTP in the adult mouse ACC, and loss of this pre-LTP may explain some of the behavioral deficits in Fmr1 KO mice.
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Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Giro del Cíngulo/metabolismo , Potenciación a Largo Plazo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Potenciales Postsinápticos Excitadores , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Giro del Cíngulo/citología , Giro del Cíngulo/fisiología , Masculino , Ratones , Ratones Noqueados , Células Piramidales/metabolismo , Células Piramidales/fisiología , Receptores de Ácido Kaínico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiologíaRESUMEN
One major interest in the study of transient receptor potential vanilloid type 1 (TRPV1) in sensory system is that it may serve as a drug target for treating chronic pain. While the roles of TRPV1 in peripheral nociception and sensitization have been well documented, less is known about its contribution to pain-related cortical plasticity. Here, we used 64 multi-electrode array recording to examine the potential role of TRPV1 in two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the anterior cingulate cortex (ACC). We found that pharmacological blockade of TRPV1 with either [(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide] (AMG9810, 10 µM) or N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791, 20 µM) failed to affect LTP induced by strong theta burst stimulation in the ACC of adult mice. Similarly, neither AMG9810 nor SB366791 blocked the cingulate LTD induced by low-frequency stimulation. Analysis of the results from different layers of the ACC obtained the same conclusions. Spatial distribution of LTP or LTD-showing channels among the ACC network was also unaltered by the TRPV1 antagonists. Since cortical LTP and LTD in the ACC play critical roles in chronic pain triggered by inflammation or nerve injury, our findings suggest that TRPV1 may not be a viable target for treating chronic pain, especially at the cortical level.
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Giro del Cíngulo/fisiología , Potenciación a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Canales Catiónicos TRPV/metabolismo , Acrilamidas/farmacología , Anilidas/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cinamatos/farmacología , Giro del Cíngulo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in â¼75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.
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Síndrome del Cromosoma X Frágil/fisiopatología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/fisiopatología , Potenciación a Largo Plazo , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Masculino , Ratones , Ratones Noqueados , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiopatologíaRESUMEN
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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Amputación Quirúrgica , Corteza Cerebral/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Cola (estructura animal)/cirugía , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Corteza Cerebral/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Estimulación Eléctrica , Glicina/análogos & derivados , Glicina/farmacología , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa C/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Resorcinoles/farmacología , Transmisión Sináptica/efectos de los fármacosRESUMEN
Affective disorders and cognitive deficits are common comorbidities of chronic pain in the clinical setting, which severely affect the quality of life of pain patients and impose a great difficulty upon clinical pain therapy. Despite large numbers of human studies examining this issue, there are surprisingly few reports investigating the comorbidities of chronic pain in animal models. This review summarizes and integrates previous reports of animal studies on pain and comorbidity, covering pain-evoked anxiety, depression, attentional deficits, cognitive impairment and locomotor dysfunction in rodents. Moreover, pain-induced alterations in synaptic plasticity are also discussed in terms of long-term potentiation and long-term depression, synaptic transmission, neuronal excitability and structural correlates in 'pain matrix'. Finally, we conclude this review by pointing out some unresolved problems and future research directions.
Asunto(s)
Trastornos del Conocimiento/fisiopatología , Trastornos del Humor/fisiopatología , Dolor/fisiopatología , Animales , Encéfalo/fisiopatología , Trastornos del Conocimiento/epidemiología , Comorbilidad , Modelos Animales de Enfermedad , Humanos , Trastornos del Humor/epidemiologíaRESUMEN
Voltage gated calcium channels (VGCCs) are well known for its importance in synaptic transmission in the peripheral and central nervous system. However, the role of different VGCCs in the anterior cingulate cortex (ACC) has not been studied. Here, we use a multi-electrode array recording system (MED64) to study the contribution of different types of calcium channels in glutamatergic excitatory synaptic transmission in the ACC. We found that only the N-type calcium channel blocker ω-conotoxin-GVIA (ω-Ctx-GVIA) produced a great inhibition of basal synaptic transmission, especially in the superficial layer. Other calcium channel blockers that act on L-, P/Q-, R-, and T-type had no effect. We also tested the effects of several neuromodulators with or without ω-Ctx-GVIA. We found that N-type VGCC contributed partially to (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid- and (R)-Baclofen-induced synaptic inhibition. By contrast, the inhibitory effects of 2-Chloroadenosine and carbamoylcholine chloride did not differ with or without ω-Ctx-GVIA, indicating that they may act through other mechanisms. Our results provide strong evidence that N-type VGCCs mediate fast synaptic transmission in the ACC.