Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladapt...Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladaptive plasticity upon injury,which is assumed to underlie pain hypersensitivity and cognitive deficits.However,much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes.Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix(ECM)and decreases ECM rigidity in the dHPC.Despite this,it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits.Laminin,a key element of the ECM,consists ofα-,β-,andγ-chains and has been implicated in several pathophysiological processes.Here,we showed that peripheral nerve injury downregulates lamininβ1(LAMB1)in the dHPC.Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction.Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrinβ1,leading to decreased Ca2+levels in pyramidal neurons,which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits.In this study,we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits,and reveal a mechanism that conveys extracellular alterations to intracellular plasticity.Moreover,we identified hippocampal LAMB1/integrinβ1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.展开更多
Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key...Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.展开更多
Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown ...Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.展开更多
Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments ...Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.展开更多
Optogenetics,a technique that employs light for neuromodulation,has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type spe...Optogenetics,a technique that employs light for neuromodulation,has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type specificity.However,visible light,particularly blue and green light,commonly used in conventional optogenetics,has limited penetration in biological tissue.This limitation necessitates the implantation of optical fibers for light delivery,especially in deep brain regions,leading to tissue damage and experimental constraints.To overcome these challenges,the use of orange-red and infrared light with greater tissue penetration has emerged as a promising approach for tetherless optical neuromodulation.In this review,we provide an overview of the development and applications of tetherless optical neuromodulation methods with long wavelengths.We first discuss the exploration of orange-red wavelength-responsive rhodopsins and their performance in tetherless optical neuromodulation.Then,we summarize two novel tetherless neuromodulation methods using near-infrared light:upconversion nanoparticle-mediated optogenetics and photothermal neuromodulation.In addition,we discuss recent advances in mid-infrared optical neuromodulation.展开更多
Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene ...Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene encoding Ttyh1,we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice,along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey(PAG)in the basal state.More importantly,the peripheral inflammationevoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice.Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release.Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief.Thus,in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.展开更多
Parvalbumin interneurons belong to the major types of GABAergic interneurons.Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied,the distribution and vulne...Parvalbumin interneurons belong to the major types of GABAergic interneurons.Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied,the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated.Through the Cre recombinase-reporter system,we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain.We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions,among which the cortex and thalamus exhibited the most intense parvalbumin signals.In regions such as the striatum and optic tract,even long-range thick parvalbumin projections were detected.Furthermore,in mouse models of temporal lobe epilepsy and Parkinson’s disease,parvalbumin fibers suffered both massive and subtle morphological alterations.Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.展开更多
Background Depressive symptoms often occur in patients with Alzheimer’s disease(AD)and exacerbate the pathogenesis of AD.However,the neural circuit mechanisms underlying the AD-associated depression remain unclear.Th...Background Depressive symptoms often occur in patients with Alzheimer’s disease(AD)and exacerbate the pathogenesis of AD.However,the neural circuit mechanisms underlying the AD-associated depression remain unclear.The serotonergic system plays crucial roles in both AD and depression.Methods We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches,chemogenetic manipulations,optogenetic manipulations,pharmacological methods,behavioral testing,and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model.Results We found that the activity of dorsal raphe nucleus serotonin neurons(DR^(N5-HT))and their projections to the dorsal hippocampal CA1(dCA1)terminals(DR^(N5-HT)-dCA1^(CaMKII))both decreased in brains of early 5×FAD mice.Chemogenetic or optogenetic activation of the DR^(N5-HT)-dCA1^(CaMKII) neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B(5-HT_(1B)R)and 4(5-HT_(4)R).Pharmaco-logical activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DR^(N5-HT)-dCA1^(CaMKII) neural circuit to improve synaptic plasticity.Conclusions These findings provide a new mechanistic connection between depression and AD and provide poten-tial pharmaceutical prevention targets for AD.展开更多
基金supported by the National Key Research and Development Program of China(2024YFC2510102)the National Natural Science Foundation of China(NSFC)grants(82330036 and 82221001)+9 种基金STI2030-Major Projects(2021ZD0203100(2021ZD0203104))the Innovation Teams in Priority Areas Accredited by Shaanxi Science and Technology(2022TD-49)to C.L.NSFC grant(82201370)China Postdoctoral Science Foundation grant(2021MD703955)to F.W.NSFC grants(82101293,82221001)to W.J.H.and S.X.W.NSFC grant(82201368)China Postdoctoral Science Foundation grant(2022M713847)to Z.Z.L.STI2030-Major Projects(2021ZD0203205)NSFC grants(82171212,82371225)to R.G.X.grant from Joint Founding Project of Innovation Research Institute,Xijing Hospital(LHJJ24JH08)Shaanxi Province Sanqin Talent Program to C.L.
文摘Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladaptive plasticity upon injury,which is assumed to underlie pain hypersensitivity and cognitive deficits.However,much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes.Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix(ECM)and decreases ECM rigidity in the dHPC.Despite this,it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits.Laminin,a key element of the ECM,consists ofα-,β-,andγ-chains and has been implicated in several pathophysiological processes.Here,we showed that peripheral nerve injury downregulates lamininβ1(LAMB1)in the dHPC.Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction.Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrinβ1,leading to decreased Ca2+levels in pyramidal neurons,which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits.In this study,we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits,and reveal a mechanism that conveys extracellular alterations to intracellular plasticity.Moreover,we identified hippocampal LAMB1/integrinβ1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203205 and 2021ZD0203104)the National Natural Science Foundation of China(82371225,82171212,82571386,82330036 and 82221001)+2 种基金National Key Research and Development Program of China(2024YFC2510102)the Excellent Youth Science Foundation of Shaanxi Province(2025JC-JCQN-103)Shaanxi Province Sanqin Talent Program.
文摘Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.
基金supported by grants from the National Natural Science Foundation of China(31400949,81502102,31471059,81371498,and 31371121)NIH R01,USA Grants(DE17794,DE22743,and NS87988)
文摘Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.
基金grants from the National Natural Science Foundation of China(81870867,31671088,31471059,and 81502102)the Natural Science Foundation of Shaanxi Province,China(2019SF-071 and 2017ZDJC-01)。
文摘Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.
基金supported by China Postdoctoral Science Foundation(2022M723356),"From 0 to 1"Original Innovation Project of the Basic Frontier Scientific Research Program of the Chinese Academy of Sciences(29J20-015-Ⅲ)Chinese Academy of Sciences 100 Talents Project:Research on Task oriented Functional Brain Development of Infants(29J20-052-Ⅲ)Natural Science Basic Research Plan in Shaanxi Province of China(2022JQ544).
文摘Optogenetics,a technique that employs light for neuromodulation,has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type specificity.However,visible light,particularly blue and green light,commonly used in conventional optogenetics,has limited penetration in biological tissue.This limitation necessitates the implantation of optical fibers for light delivery,especially in deep brain regions,leading to tissue damage and experimental constraints.To overcome these challenges,the use of orange-red and infrared light with greater tissue penetration has emerged as a promising approach for tetherless optical neuromodulation.In this review,we provide an overview of the development and applications of tetherless optical neuromodulation methods with long wavelengths.We first discuss the exploration of orange-red wavelength-responsive rhodopsins and their performance in tetherless optical neuromodulation.Then,we summarize two novel tetherless neuromodulation methods using near-infrared light:upconversion nanoparticle-mediated optogenetics and photothermal neuromodulation.In addition,we discuss recent advances in mid-infrared optical neuromodulation.
基金the National Natural Science Foundation of China(31671088 and 31730041)the Natural Science Foundation of Shaanxi Province,China(2017ZDJC-01)。
文摘Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene encoding Ttyh1,we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice,along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey(PAG)in the basal state.More importantly,the peripheral inflammationevoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice.Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release.Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief.Thus,in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.
基金supported by the Ministry of Science and Technology of China(2021ZD0201005)the National Natural Science Foundation of China(82071529 and 81974204)the Key R&D Program of Shaanxi Province(2021SF-238).
文摘Parvalbumin interneurons belong to the major types of GABAergic interneurons.Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied,the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated.Through the Cre recombinase-reporter system,we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain.We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions,among which the cortex and thalamus exhibited the most intense parvalbumin signals.In regions such as the striatum and optic tract,even long-range thick parvalbumin projections were detected.Furthermore,in mouse models of temporal lobe epilepsy and Parkinson’s disease,parvalbumin fibers suffered both massive and subtle morphological alterations.Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.
基金supported by the National Natural Science Foundation of China(81925010,91849205,U1905207,92149303 to J.Z.)the National Key Research and Development Program of China(2021YFA1101402 to J.Z.)+1 种基金the Key laboratory of Neural and Vascular Biology,Ministry of Education of China(NV20230010,NV20230014)the Project of Sichuan Department of Science and Technology(2021YFS0385).
文摘Background Depressive symptoms often occur in patients with Alzheimer’s disease(AD)and exacerbate the pathogenesis of AD.However,the neural circuit mechanisms underlying the AD-associated depression remain unclear.The serotonergic system plays crucial roles in both AD and depression.Methods We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches,chemogenetic manipulations,optogenetic manipulations,pharmacological methods,behavioral testing,and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model.Results We found that the activity of dorsal raphe nucleus serotonin neurons(DR^(N5-HT))and their projections to the dorsal hippocampal CA1(dCA1)terminals(DR^(N5-HT)-dCA1^(CaMKII))both decreased in brains of early 5×FAD mice.Chemogenetic or optogenetic activation of the DR^(N5-HT)-dCA1^(CaMKII) neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B(5-HT_(1B)R)and 4(5-HT_(4)R).Pharmaco-logical activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DR^(N5-HT)-dCA1^(CaMKII) neural circuit to improve synaptic plasticity.Conclusions These findings provide a new mechanistic connection between depression and AD and provide poten-tial pharmaceutical prevention targets for AD.
