OBJECTIVE Previous studies have demonstrated a close association between an altered immune system and major depressive disorders,and inhibition of neuroinflammation may represent an alternative mechanism to treat depr...OBJECTIVE Previous studies have demonstrated a close association between an altered immune system and major depressive disorders,and inhibition of neuroinflammation may represent an alternative mechanism to treat depression.Recently,the anti-inflammatory activ⁃ity of ibrutinib has been reported.However,the effect of ibrutinib on neuroinflammation-induced depression and its underlying mechanism has not been comprehensively studied.Therefore,we aimed to elucidate the potential anti-depres⁃sive role and mechanism of ibrutinib against neu⁃roinflammation-induced depression and synaptic defects.METHODS AND RESULTS Ibrutinib treatment significantly reduced lipopolysaccha⁃ride(LPS)-induced depressive-like behaviors and neuroinflammation via inhibiting NF-κB acti⁃vation,decreasing proinflammatory cytokine levels,and normalizing redox signaling and its downstream components,including Nrf2,HO-1,and SOD2,as well as glial cell activation mark⁃ers,such as Iba-1 and GFAP.Further,ibrutinib treatment inhibited LPS-activated inflammasome activation by targeting NLRP3/P38/caspase-1 signaling.Interestingly,LPS reduced the number of dendritic spines and expression of BDNF,and synaptic-related markers,including PSD95,snap25,and synaptophysin,were improved by ibrutinib treatment in the hippocampal area of the mouse brain.CONCLUSION Ibrutinib can allevi⁃ate neuroinflammation and synaptic defects,sug⁃gesting it has antidepressant potential against LPS-induced neuroinflammation and depression.展开更多
OBJECTIVE Alzheimer disease(AD)is the most common type of dementia and is featured by the accumulation ofβ-amyloid peptide(Aβ)in the brain.The Alpha 7 nicotinic acetylcholine receptor family(α7 nAChR)was widely con...OBJECTIVE Alzheimer disease(AD)is the most common type of dementia and is featured by the accumulation ofβ-amyloid peptide(Aβ)in the brain.The Alpha 7 nicotinic acetylcholine receptor family(α7 nAChR)was widely considered to interact with that Aβ,mediate neuroprotection and improve cognitive performance.However,the mechanisms underlying these interactions remain elusive.The present study aimed to determine how this interaction contribute to AD pathology.METHODS In vitro model of AD(primary culture of mice hippocampus treated with Aβ)and in vivo,a mouse model of AD(APPswe/PSEN1 d E9 double transgenic mice,APP/PS1_DT mice)were used to study to the possible inter-action ofα7 nAChR and Aβin the pathogenesis of AD.In vitro experiments,the primary hippocampal neurons cell was exposed to Aβ1-42 peptides in combination with PNU.In vivo experiments,different drugs/operations was applied to APP/PS1_DT mice for setting up of the following groups:WP group,wild-type C57 mice treated with PNU(α7 nAChR specific agonist);AP group,APP/PS1_DT mice treated with PNU;APP/PS1 group,the APP/PS1_DT mice injected intraperitoneally with the same amount of normal saline for 5 d;Control group,wild-type C57 mice injected intraperitoneally with the same amount of normal saline for 5 d.A transmission electron microscope was used to observed the synaptic morphological changes of hippocampal neurons.Reverse transcription quantitative PCR(RT-q PCR)and Western blot analysis were used to detect the expression levels of synaptic-associated proteins(SYN,SNAP25 etc).The learning and memory abilities of mice were detected by Morris water maze.RESULTS In vitro,it was found thatα7 nAChR acts as an anti-Aβ-induced synaptic injury to nerve cell by increased the expression of synaptic-associated proteins and attenuated apoptosis induced by Aβoligomers.In vivo,α7 nAChR attenuated synaptic loss induced by Aβ1-42,reduced the deposition of Aβ1-42 in the hippocampus and maintained the integrity of synaptic structures in the hippocampus.Furthermore,in the Morris water maze test,α7 nAChR improved the learning and memory ability of the APP/PS1_DT mice.CONCLUSION Theα7 nAChR attenuate the toxic effect of Aβin vivo and in vitro,eg reduced the deposition of Aβin the hippocampus,prevented the synaptic loss,partially restored the expression levels of synaptic-associated proteins,and improved the learning and memory abilities of APP/PS1_DT mice.Our results also suggested that theα7 nAChR interacted with Aβby mediated by Ca M-Ca MKⅡ-CREB signalling pathway,which was imbalanced by deposition of Aβ.展开更多
OBJECTIVE To investigate whether electroacupuncture(EA)ameliorates abnormal trigeminal neuralgia(TN)orofacial pain and anxiety-like behavior by altering synaptic plasticity in the hippocampus CA1.METHODS A mouse infra...OBJECTIVE To investigate whether electroacupuncture(EA)ameliorates abnormal trigeminal neuralgia(TN)orofacial pain and anxiety-like behavior by altering synaptic plasticity in the hippocampus CA1.METHODS A mouse infraorbital nerve transection model(pTION)of neuropathic pain was established,and EA or sham EA was used to treat ipsilateral acu⁃puncture points(GV20-Baihui and ST7-Xia⁃guan).Golgi-Cox staining and transmission elec⁃tron microscopy(TEM)were administrated to observe the changes of synaptic plasticity in the hippocampus CA1.RESULTS Stable and persistent orofacial allodynia and anxiety-like behav⁃iors induced by pT-ION were related to changes in hippocampal synaptic plasticity.Golgi stain⁃ings showed a decrease in the density of dendritic spines,especially mushroom-type dendritic spines,in hippocampal CA1 neurons of pT-ION mice.TEM results showed that the density of synapses,membrane thickness of the postsynaptic density,and length of the synaptic active zone were decreased,whereas the width of the synaptic cleft was increased in pTION mice.EA attenu⁃ated pT-ION-induced orofacial allodynia and anx⁃iety-like behaviors and effectively reversed the abnormal changes in dendritic spines and syn⁃apse of the hippocampal CA1 region.CONCLU⁃SION EA modulates synaptic plasticity of hippo⁃campal CA1 neurons,and reduces abnormal oro⁃facial pain and anxiety-like behavior,providing evidence for a TN treatment strategy.展开更多
OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depre...OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.展开更多
Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists...Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6herbs including Dihuang[prepared root of Rehmannia glutinosa(Gaertn) DC], Shanyao(rhizome of Dioscorea polystachya Turcz), Shanzhuyu(fruit of Cornus officinalis Siebold Zucc), Mudanpi(root bark of Paeonia × suffruticosa Andrews),Zexie(rhizome of Alisma plantago-aquatica L) and Fuling(scleorotia of Wolfiporia extensa(Peck) Ginns)LW-active fraction combination(LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. There are 3 fractions in LW-AFC, a polysaccharide fraction(LWB-B), a glycoside fraction(LWD-b) and an oligosaccharide fraction(CA-30). Our previous results indicate that LW-AFC has similar pharmacological effects to LW, modulating the balance of the NIM network. LW-AFC has positive effects in many animal models of kidney deficiency or disturbance of the NIM network. LW-AFC could improve the cognitive ability in Alzheimer′s disease(AD) animal models(APP/PS1, SAMP8), where modulating immune function and balancing the NIM network may play an important role in its cognition improving effects. Our study also showed that LW-AFC had protective effects on stress-induced disturbances of the NIM network. However, the underlying mechanisms remain elusive and need further investigation. OBJECTIVE This study evaluated the effects of LW-AFC and the active fractions(polysaccharide, LWB-B;glycoside, LWD-b;oligosaccharide,CA-30) on corticosterone(Cort)-induced long-term potentiation(LTP) impairment in vivo. METHODS LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration(ig, ip, 7 d) or single administration(icv, ig, ip). Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS) to induce LTP impairment. Moreover, in order to research on the possible effective pathways, an antibiotic cocktail and an immunosuppressant were also used. RESULTS Chronic administration(ig) of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Single administration(icv, ig, ip) of any of the active fractions had no effect on Cort-induced LTP impairment, while chronic administration(ig, ip) of LWB-B or LWD-b showed positive effects against Cort. Interestingly, CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition, when the intestinal microbiota was disrupted by application of the antibiotic cocktail, CA-30 showed little protective effects against Cort. The effects of LW-AFC were also abolished when the immune function was inhibited. In the hippocampal tissue, Cort treatment increased corticosterone and glutamate, and LW-AFC could inhibit the Cort-induced elevation of corticosterone and glutamate;there was little change in D-serine in Cort-treated animals, but LW-AFC could increase the D-serine levels. CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Their protective effects are unlikely by a direct way, and immune modulation might be the common pathway. CA-30 could protect LTP from impairment via modulating the intestinal microbiota. Decreasing corticosterone and glutamate and increasing D-serine in the Cort-treated animals’ hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC. Further study is needed to understand the underlying mechanisms.展开更多
Memristor with memory properties can be applied to connection points(synapses)between cells in a cellular neural network(CNN).This paper highlights memristor crossbar-based multilayer CNN(MCM-CNN)and its application t...Memristor with memory properties can be applied to connection points(synapses)between cells in a cellular neural network(CNN).This paper highlights memristor crossbar-based multilayer CNN(MCM-CNN)and its application to edge detection.An MCM-CNN is designed by adopting a memristor crossbar composed of a pair of memristors.MCM-CNN based on the memristor crossbar with changeable weight is suitable for edge detection of a binary image and a color image considering its characteristics of programmablization and compactation.Figure of merit(FOM)is introduced to evaluate the proposed structure and several traditional edge detection operators for edge detection results.Experiment results show that the FOM of MCM-CNN is three times more than that of the traditional edge detection operators.展开更多
The motor cortex plays a key role in motor control as its output directly generates movement.However,it is known that the motor cortex also exhibits a high degree of plasticity that may be important in both health and...The motor cortex plays a key role in motor control as its output directly generates movement.However,it is known that the motor cortex also exhibits a high degree of plasticity that may be important in both health and disease.Here I provide evidence to support that dopaminergic innervation arising from the midbrain plays critical roles in the process of acquiring novel motor skills as well as recovery of motor functions after ischemic stroke.Based on extracel ular multi-unit recordings from conscious freely moving rats,we investigated the dynamics of neurons in the output layer 5b(L5b)of the primary motor cortex during the training of a forelimb reaching for food task.We found a subpopulation of task-recruited layer 5b neurons that not only became more movement-encoding during motor learning,but their activities were also more temporally aligned to motor execution.These phenomena were accompanied by the emergence of reproducibleneurodynamics of the L5b neuronal ensemble and traininginduced long-term synaptic plasticity of inputs to these neurons,but were highly disrupted by local denervation of dopaminergic inputs originating from the ventral tegmental area.In another series of experiments based on rodent models of focal ischemic stroke,administration of L-DOPA,the precursor of dopamine,significantly promoted motor function recovery.Morphological and biochemical examination of the perilesioned area provided evidence that neuroplasticity markers,dendritic arborisation and synaptic plasticity were increased by the treatment.Further examination of neuronal activity through in vivo recording revealed that motor cortical regions adjacent to the infarct had restored capability for synaptic plasticity.Finally,pharmacological blockade of either D1 or D2 receptors at the perilesioned region abolished the beneficial effects.Together,our findings highlight the importance of the plasticity of the motor cortex in health and disease that are mediated by the mesocortical dopaminergic pathway.展开更多
OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS)are the...OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS)are the most common infantile seizures,yet its pathological progress is largely unknown.METHODS Mice pups(postnatal 8-10 d)were posted to 43℃hyperthermia condition to develop FS,and then the latency and threshold of seizures were determined.The displacement of synapses was observed through immunofluorescence staining.We researched whether microglial displacement of GABAergic synapses will influence complex FS-induced increase in GABAergic neurotransmission and neuronal excitability with patch-clamp electrophysiology.Moreover,we used the CD11 bD TR mice to selective ablation of microglia or pharmacological inhibition of microglia to observe their effects on susceptibility to FS and synaptic stripping.RESULTS GABAergic presynaptic terminals surrounding neuronal soma and GABAergic transmissions were increased in complex FS.Meanwhile,the activated microglia ensheathe glutamatergic neuronal soma to displace,but do not phagocytize,GABAergic presynaptic terminals.Patch-clamp electrophysiology established that the microglial displacement of GABAergic synapses reduced complex FS-induced increase in GABAergic neurotransmission and neuronal excitability,while GABA exerts excitatory action in this immature stage.Moreover,pharmacological inhibition of microglial displacement of GABAergic synapses or selective ablation of microglia in CD11 bDTR mice promoted the generation of complex FS.CONCLUSION Displacement of GABAergic synapses by microglia is a protective event in the pathological progress of complex FS.展开更多
OBJECTIVE Exposure to stressful events can be differently perceived by individuals depending on the level of stress resilience or vulnerability.The neural processes that underlie such clinical y and social y important...OBJECTIVE Exposure to stressful events can be differently perceived by individuals depending on the level of stress resilience or vulnerability.The neural processes that underlie such clinical y and social y important differences are largely unknown.As insula cortex is important in emotional processing,we have examined whether the changes in synaptic plasticity in the insula cortex involved in stress resilience or vulnerability.METHODS Mice were divided into two groups:control and stress group.Stress group was treated by foot electric shock twice daily(0.8 mA,2 s,ten times in 1 min) in continuous two weeks.Then we used fear conditioning test to detect re-experiencing of traumatic experience,open field test to detect avoidance,pre-pulse inhibition experiment to detect hyper arousal.The changes of synaptic plasticity in the insular cortex were recorded by the multiple channels electrophysiology and whole cell patch.RESULTS According to the behavioral scores,it was divided into resilient and vulnerable group.In the fear conditioning test,the vulnerable group showed the significant freezing time decreased than that of the resilient group(P<0.01).In the open field test,the time that enter the center zone of vulnerable group is increased than that resilient group(P<0.01);In the pre-pulse inhibition experiment,there are not significant difference of PPI value in both groups(P=0.4239).And then electrophysiological experiments are performed to detect the synaptic plasticity of the insular cortex.Compared with the resilient group,the LTP level was decreased(P<0.05) and the mEPSC was increased(P<0.01) in vulnerable group.CONCLUSION The impairment of synaptic plasticity in the insular cortex may be one of the neural mechanisms for the vulnerability to chronic stress.展开更多
As a structural protein, the physiological function of tau proteins is to promote microtu-bule assembly and maintain the stability of the microtubules, so that to build up the tracks for axonal transport of the neuron...As a structural protein, the physiological function of tau proteins is to promote microtu-bule assembly and maintain the stability of the microtubules, so that to build up the tracks for axonal transport of the neurons. Recent studies suggest that tau is also actively involved in regulation of cell viability and enzymatic reaction. In Alzheimer disease (AD) and other tauopathies, tau proteins are abnormally hyperphosphorylated or cleaved, or the gene mutated, which result in intracellular tau accumulation and formation of neurofibrillary tangles in the degenerated neurons. In addition to hyperphosphorylation, many other types of tau posttranslational modifications have been identified in the brains of AD patients and/or the transgenic mouse models. To date, it is not clear how the abnormality of tau causes neurodegeneration and memory deficits. By overexpressing human full-length wildtype tau to mimic tau abnormality as seen in the brain of sporadic AD patients, we found that tau accumulation activated JAK2 to phosphorylate STAT1 at Tyr701 leading to STAT1 dimerization, nuclear translocation and its activation. STAT1 activation suppressed expression of NMDAR through direct binding to the specific GAS element of Glu N1, Glu N2A and Glu N2B promoters, while knockdown STAT1 by AAV-Cre in STAT1 flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescued tau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance.These findings indicate that tau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, which reveals a novel mechanism for tau-associated synapse and memory deficits in AD and other tauopathies.展开更多
Hyperphosphorylated tau in the form of paired helical filament is the major protein component of neurofibrillary tangle,which is positively correlated with the degree of dementia in patients with Alzheimer disease(AD)...Hyperphosphorylated tau in the form of paired helical filament is the major protein component of neurofibrillary tangle,which is positively correlated with the degree of dementia in patients with Alzheimer disease(AD),the most common cause of dementia in the elderly.Activation of protein kinases or/and inhibition of protein phosphatases is responsible for tau hyperphosphorylation.Among various kinases,glycogen展开更多
OBJECTIVE LW-AFC is extracted from the classical traditional Chinese medicinal prescription-Liuwei Dihuang Decoction.Previous studies have showed that LW-AFC could improve learning&memory ability in amny animal mo...OBJECTIVE LW-AFC is extracted from the classical traditional Chinese medicinal prescription-Liuwei Dihuang Decoction.Previous studies have showed that LW-AFC could improve learning&memory ability in amny animal models.In this study,we focused on evaluating the effect of several main active components fromLW-AFC(B-B;loganin,LOG;morroniside,MOR;paeoniflorin,PF and stachyose,STA)on LTP.METHODS In vivo recording of LTP was used in this study to evaluate the effects of LW-AFC and it′s active components on coticorsterone(Cort)induced LTP impairment.RESULTS The results showed that LW-AFC could ameliorate Cort-induced LTP impairment.The effect of LW-AFC was abolished when the immune function was inhibited.Single administration(ig,ip,icv)of any of the components had no effect on Cort-induced LTP impairment.Consecutively intragastric administration or intraperitoneal injections(chronic administration)of B-B,LOG,MOR or PF for 7 d showed protective effect on Cort-induced LTP impairment.Intragastric administration of STA for 7 d protected LTP from impairment induced by Cort,while there was little improving effect when STA was administrated via intraperitoneal injection.In addition,when the intestinal microbiota was disrupted by applying the antibiotic cocktail,STA showed little protective effect against Cort.CONCLUSION In conclusion,LW-AFC and it′s components showed positive effects against cort induced LTP impairment,it seems that all displayed protective effects via indirectly,immune modulation might be the common pathway for all components;the exact pathways are different in each component,B-B,LOG,MOR and PF could be absorbed into the bloods tream and then modulate the peripheral immune function,while STA could not be absorbed and modulates the immune function via modulating intestinal microbiota.Further studies are needed to invesgate the underlying mechanisms and the synergetic effects of all components.展开更多
OBJECTIVE Liuwei Dihuang Decoction(LW)-active fraction combination(LW-AFC,consist of 3 fractions polysaccharide,LWB-B;glycoside,LWD-b;oligosaccharide,CA-30)is extracted from LW,it is effective for the treatment of kid...OBJECTIVE Liuwei Dihuang Decoction(LW)-active fraction combination(LW-AFC,consist of 3 fractions polysaccharide,LWB-B;glycoside,LWD-b;oligosaccharide,CA-30)is extracted from LW,it is effective for the treatment of kidney yin deficiency in many animal models.This study evaluated the effects and mechanisms of LW-AFC and the active fractions on corticosterone(Cort)-induced long-term potentiation(LTP)impairment in vivo.METHODS LTP was used to evaluate the synaptic plasticity.LW-AFC was orally administered for seven days.The active fractions were given by either chronic administration(ig,ip,7 d)or single administration(icv,ig,ip).Cort was injected subcutaneously 1h before the high-frequency stimulation(HFS)to induce LTP impairment.Moreover,in order to research on the possible effective pathways,an antibiotic cocktail and an immunosuppressant were also used.RESULTS Chronic administration(ig)of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment.Single administration(icv,ig,ip)of any of the active fractions had no effect on Cort-induced LTP impairment,while chronic administration(ig,ip)of LWB-B or LWD-b showed positive effects against Cort.Interestingly,CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition,when the intestinal microbiota was disrupted by application of the antibiotic cocktail,CA-30 showed little protective effects against Cort.The effects of LW-AFC were also abolished when the immune function was inhibited.In the hippocampal tissue,Cort treatment increased Cort and glutamate,and LW-AFC could inhibit the Cort-induced elevation of Cort and glutamate;there was little change in D-serine in Cort-treated animals,but LW-AFC could increase the D-serine levels.CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment.Their protective effects are unlikely by a direct way,and immune modulation might be the common pathway.CA-30 could protect LTP from impairment via modulating the intestinal microbiota.Decreasing Cort and glutamate and increasing D-serine in the Cort-treated animals'hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC.Further study is needed to understand the underlying mechanisms.展开更多
文摘OBJECTIVE Previous studies have demonstrated a close association between an altered immune system and major depressive disorders,and inhibition of neuroinflammation may represent an alternative mechanism to treat depression.Recently,the anti-inflammatory activ⁃ity of ibrutinib has been reported.However,the effect of ibrutinib on neuroinflammation-induced depression and its underlying mechanism has not been comprehensively studied.Therefore,we aimed to elucidate the potential anti-depres⁃sive role and mechanism of ibrutinib against neu⁃roinflammation-induced depression and synaptic defects.METHODS AND RESULTS Ibrutinib treatment significantly reduced lipopolysaccha⁃ride(LPS)-induced depressive-like behaviors and neuroinflammation via inhibiting NF-κB acti⁃vation,decreasing proinflammatory cytokine levels,and normalizing redox signaling and its downstream components,including Nrf2,HO-1,and SOD2,as well as glial cell activation mark⁃ers,such as Iba-1 and GFAP.Further,ibrutinib treatment inhibited LPS-activated inflammasome activation by targeting NLRP3/P38/caspase-1 signaling.Interestingly,LPS reduced the number of dendritic spines and expression of BDNF,and synaptic-related markers,including PSD95,snap25,and synaptophysin,were improved by ibrutinib treatment in the hippocampal area of the mouse brain.CONCLUSION Ibrutinib can allevi⁃ate neuroinflammation and synaptic defects,sug⁃gesting it has antidepressant potential against LPS-induced neuroinflammation and depression.
文摘OBJECTIVE Alzheimer disease(AD)is the most common type of dementia and is featured by the accumulation ofβ-amyloid peptide(Aβ)in the brain.The Alpha 7 nicotinic acetylcholine receptor family(α7 nAChR)was widely considered to interact with that Aβ,mediate neuroprotection and improve cognitive performance.However,the mechanisms underlying these interactions remain elusive.The present study aimed to determine how this interaction contribute to AD pathology.METHODS In vitro model of AD(primary culture of mice hippocampus treated with Aβ)and in vivo,a mouse model of AD(APPswe/PSEN1 d E9 double transgenic mice,APP/PS1_DT mice)were used to study to the possible inter-action ofα7 nAChR and Aβin the pathogenesis of AD.In vitro experiments,the primary hippocampal neurons cell was exposed to Aβ1-42 peptides in combination with PNU.In vivo experiments,different drugs/operations was applied to APP/PS1_DT mice for setting up of the following groups:WP group,wild-type C57 mice treated with PNU(α7 nAChR specific agonist);AP group,APP/PS1_DT mice treated with PNU;APP/PS1 group,the APP/PS1_DT mice injected intraperitoneally with the same amount of normal saline for 5 d;Control group,wild-type C57 mice injected intraperitoneally with the same amount of normal saline for 5 d.A transmission electron microscope was used to observed the synaptic morphological changes of hippocampal neurons.Reverse transcription quantitative PCR(RT-q PCR)and Western blot analysis were used to detect the expression levels of synaptic-associated proteins(SYN,SNAP25 etc).The learning and memory abilities of mice were detected by Morris water maze.RESULTS In vitro,it was found thatα7 nAChR acts as an anti-Aβ-induced synaptic injury to nerve cell by increased the expression of synaptic-associated proteins and attenuated apoptosis induced by Aβoligomers.In vivo,α7 nAChR attenuated synaptic loss induced by Aβ1-42,reduced the deposition of Aβ1-42 in the hippocampus and maintained the integrity of synaptic structures in the hippocampus.Furthermore,in the Morris water maze test,α7 nAChR improved the learning and memory ability of the APP/PS1_DT mice.CONCLUSION Theα7 nAChR attenuate the toxic effect of Aβin vivo and in vitro,eg reduced the deposition of Aβin the hippocampus,prevented the synaptic loss,partially restored the expression levels of synaptic-associated proteins,and improved the learning and memory abilities of APP/PS1_DT mice.Our results also suggested that theα7 nAChR interacted with Aβby mediated by Ca M-Ca MKⅡ-CREB signalling pathway,which was imbalanced by deposition of Aβ.
基金the National Natural Science Foundation of China(82001190)Natural Sci⁃ence Foundation of Shandong Province(ZR2021LZY016)+1 种基金Natural Science Foundation of Shandong Province(ZR2020MH348)Science and Technology Foundation of Shandong Traditional Chinese Medicine(2020Q035)。
文摘OBJECTIVE To investigate whether electroacupuncture(EA)ameliorates abnormal trigeminal neuralgia(TN)orofacial pain and anxiety-like behavior by altering synaptic plasticity in the hippocampus CA1.METHODS A mouse infraorbital nerve transection model(pTION)of neuropathic pain was established,and EA or sham EA was used to treat ipsilateral acu⁃puncture points(GV20-Baihui and ST7-Xia⁃guan).Golgi-Cox staining and transmission elec⁃tron microscopy(TEM)were administrated to observe the changes of synaptic plasticity in the hippocampus CA1.RESULTS Stable and persistent orofacial allodynia and anxiety-like behav⁃iors induced by pT-ION were related to changes in hippocampal synaptic plasticity.Golgi stain⁃ings showed a decrease in the density of dendritic spines,especially mushroom-type dendritic spines,in hippocampal CA1 neurons of pT-ION mice.TEM results showed that the density of synapses,membrane thickness of the postsynaptic density,and length of the synaptic active zone were decreased,whereas the width of the synaptic cleft was increased in pTION mice.EA attenu⁃ated pT-ION-induced orofacial allodynia and anx⁃iety-like behaviors and effectively reversed the abnormal changes in dendritic spines and syn⁃apse of the hippocampal CA1 region.CONCLU⁃SION EA modulates synaptic plasticity of hippo⁃campal CA1 neurons,and reduces abnormal oro⁃facial pain and anxiety-like behavior,providing evidence for a TN treatment strategy.
文摘OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.
文摘Liuwei Dihuang decoction(LW), a classic formula in traditional Chinese medicine(TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6herbs including Dihuang[prepared root of Rehmannia glutinosa(Gaertn) DC], Shanyao(rhizome of Dioscorea polystachya Turcz), Shanzhuyu(fruit of Cornus officinalis Siebold Zucc), Mudanpi(root bark of Paeonia × suffruticosa Andrews),Zexie(rhizome of Alisma plantago-aquatica L) and Fuling(scleorotia of Wolfiporia extensa(Peck) Ginns)LW-active fraction combination(LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. There are 3 fractions in LW-AFC, a polysaccharide fraction(LWB-B), a glycoside fraction(LWD-b) and an oligosaccharide fraction(CA-30). Our previous results indicate that LW-AFC has similar pharmacological effects to LW, modulating the balance of the NIM network. LW-AFC has positive effects in many animal models of kidney deficiency or disturbance of the NIM network. LW-AFC could improve the cognitive ability in Alzheimer′s disease(AD) animal models(APP/PS1, SAMP8), where modulating immune function and balancing the NIM network may play an important role in its cognition improving effects. Our study also showed that LW-AFC had protective effects on stress-induced disturbances of the NIM network. However, the underlying mechanisms remain elusive and need further investigation. OBJECTIVE This study evaluated the effects of LW-AFC and the active fractions(polysaccharide, LWB-B;glycoside, LWD-b;oligosaccharide,CA-30) on corticosterone(Cort)-induced long-term potentiation(LTP) impairment in vivo. METHODS LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration(ig, ip, 7 d) or single administration(icv, ig, ip). Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS) to induce LTP impairment. Moreover, in order to research on the possible effective pathways, an antibiotic cocktail and an immunosuppressant were also used. RESULTS Chronic administration(ig) of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Single administration(icv, ig, ip) of any of the active fractions had no effect on Cort-induced LTP impairment, while chronic administration(ig, ip) of LWB-B or LWD-b showed positive effects against Cort. Interestingly, CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition, when the intestinal microbiota was disrupted by application of the antibiotic cocktail, CA-30 showed little protective effects against Cort. The effects of LW-AFC were also abolished when the immune function was inhibited. In the hippocampal tissue, Cort treatment increased corticosterone and glutamate, and LW-AFC could inhibit the Cort-induced elevation of corticosterone and glutamate;there was little change in D-serine in Cort-treated animals, but LW-AFC could increase the D-serine levels. CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Their protective effects are unlikely by a direct way, and immune modulation might be the common pathway. CA-30 could protect LTP from impairment via modulating the intestinal microbiota. Decreasing corticosterone and glutamate and increasing D-serine in the Cort-treated animals’ hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC. Further study is needed to understand the underlying mechanisms.
基金supported by the Research Fund for International Young Scientists of the National Natural Science Foundation of China(61550110248)the Research on Fundamental Theory of Shared Intelligent Street Lamp for New Scene Service(H04W200495)+1 种基金Sichuan Science and Technology Program(2019YFG0190)the Research on Sino-Tibetan Multi-source Information Acquisition,Fusion,Data Mining and its Application(H04W170186).
文摘Memristor with memory properties can be applied to connection points(synapses)between cells in a cellular neural network(CNN).This paper highlights memristor crossbar-based multilayer CNN(MCM-CNN)and its application to edge detection.An MCM-CNN is designed by adopting a memristor crossbar composed of a pair of memristors.MCM-CNN based on the memristor crossbar with changeable weight is suitable for edge detection of a binary image and a color image considering its characteristics of programmablization and compactation.Figure of merit(FOM)is introduced to evaluate the proposed structure and several traditional edge detection operators for edge detection results.Experiment results show that the FOM of MCM-CNN is three times more than that of the traditional edge detection operators.
基金The project supported by NSFC grant(SZRIA0314025)SRFDP-HKRGC grant(2900703)+1 种基金HKGRF grant(2140903)HMRF grant(02130976)
文摘The motor cortex plays a key role in motor control as its output directly generates movement.However,it is known that the motor cortex also exhibits a high degree of plasticity that may be important in both health and disease.Here I provide evidence to support that dopaminergic innervation arising from the midbrain plays critical roles in the process of acquiring novel motor skills as well as recovery of motor functions after ischemic stroke.Based on extracel ular multi-unit recordings from conscious freely moving rats,we investigated the dynamics of neurons in the output layer 5b(L5b)of the primary motor cortex during the training of a forelimb reaching for food task.We found a subpopulation of task-recruited layer 5b neurons that not only became more movement-encoding during motor learning,but their activities were also more temporally aligned to motor execution.These phenomena were accompanied by the emergence of reproducibleneurodynamics of the L5b neuronal ensemble and traininginduced long-term synaptic plasticity of inputs to these neurons,but were highly disrupted by local denervation of dopaminergic inputs originating from the ventral tegmental area.In another series of experiments based on rodent models of focal ischemic stroke,administration of L-DOPA,the precursor of dopamine,significantly promoted motor function recovery.Morphological and biochemical examination of the perilesioned area provided evidence that neuroplasticity markers,dendritic arborisation and synaptic plasticity were increased by the treatment.Further examination of neuronal activity through in vivo recording revealed that motor cortical regions adjacent to the infarct had restored capability for synaptic plasticity.Finally,pharmacological blockade of either D1 or D2 receptors at the perilesioned region abolished the beneficial effects.Together,our findings highlight the importance of the plasticity of the motor cortex in health and disease that are mediated by the mesocortical dopaminergic pathway.
基金National Natural Science Foundation of China(8163000388).
文摘OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS)are the most common infantile seizures,yet its pathological progress is largely unknown.METHODS Mice pups(postnatal 8-10 d)were posted to 43℃hyperthermia condition to develop FS,and then the latency and threshold of seizures were determined.The displacement of synapses was observed through immunofluorescence staining.We researched whether microglial displacement of GABAergic synapses will influence complex FS-induced increase in GABAergic neurotransmission and neuronal excitability with patch-clamp electrophysiology.Moreover,we used the CD11 bD TR mice to selective ablation of microglia or pharmacological inhibition of microglia to observe their effects on susceptibility to FS and synaptic stripping.RESULTS GABAergic presynaptic terminals surrounding neuronal soma and GABAergic transmissions were increased in complex FS.Meanwhile,the activated microglia ensheathe glutamatergic neuronal soma to displace,but do not phagocytize,GABAergic presynaptic terminals.Patch-clamp electrophysiology established that the microglial displacement of GABAergic synapses reduced complex FS-induced increase in GABAergic neurotransmission and neuronal excitability,while GABA exerts excitatory action in this immature stage.Moreover,pharmacological inhibition of microglial displacement of GABAergic synapses or selective ablation of microglia in CD11 bDTR mice promoted the generation of complex FS.CONCLUSION Displacement of GABAergic synapses by microglia is a protective event in the pathological progress of complex FS.
基金National Natural Science Foundation of China(81402912).
文摘OBJECTIVE Exposure to stressful events can be differently perceived by individuals depending on the level of stress resilience or vulnerability.The neural processes that underlie such clinical y and social y important differences are largely unknown.As insula cortex is important in emotional processing,we have examined whether the changes in synaptic plasticity in the insula cortex involved in stress resilience or vulnerability.METHODS Mice were divided into two groups:control and stress group.Stress group was treated by foot electric shock twice daily(0.8 mA,2 s,ten times in 1 min) in continuous two weeks.Then we used fear conditioning test to detect re-experiencing of traumatic experience,open field test to detect avoidance,pre-pulse inhibition experiment to detect hyper arousal.The changes of synaptic plasticity in the insular cortex were recorded by the multiple channels electrophysiology and whole cell patch.RESULTS According to the behavioral scores,it was divided into resilient and vulnerable group.In the fear conditioning test,the vulnerable group showed the significant freezing time decreased than that of the resilient group(P<0.01).In the open field test,the time that enter the center zone of vulnerable group is increased than that resilient group(P<0.01);In the pre-pulse inhibition experiment,there are not significant difference of PPI value in both groups(P=0.4239).And then electrophysiological experiments are performed to detect the synaptic plasticity of the insular cortex.Compared with the resilient group,the LTP level was decreased(P<0.05) and the mEPSC was increased(P<0.01) in vulnerable group.CONCLUSION The impairment of synaptic plasticity in the insular cortex may be one of the neural mechanisms for the vulnerability to chronic stress.
文摘As a structural protein, the physiological function of tau proteins is to promote microtu-bule assembly and maintain the stability of the microtubules, so that to build up the tracks for axonal transport of the neurons. Recent studies suggest that tau is also actively involved in regulation of cell viability and enzymatic reaction. In Alzheimer disease (AD) and other tauopathies, tau proteins are abnormally hyperphosphorylated or cleaved, or the gene mutated, which result in intracellular tau accumulation and formation of neurofibrillary tangles in the degenerated neurons. In addition to hyperphosphorylation, many other types of tau posttranslational modifications have been identified in the brains of AD patients and/or the transgenic mouse models. To date, it is not clear how the abnormality of tau causes neurodegeneration and memory deficits. By overexpressing human full-length wildtype tau to mimic tau abnormality as seen in the brain of sporadic AD patients, we found that tau accumulation activated JAK2 to phosphorylate STAT1 at Tyr701 leading to STAT1 dimerization, nuclear translocation and its activation. STAT1 activation suppressed expression of NMDAR through direct binding to the specific GAS element of Glu N1, Glu N2A and Glu N2B promoters, while knockdown STAT1 by AAV-Cre in STAT1 flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescued tau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance.These findings indicate that tau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, which reveals a novel mechanism for tau-associated synapse and memory deficits in AD and other tauopathies.
文摘Hyperphosphorylated tau in the form of paired helical filament is the major protein component of neurofibrillary tangle,which is positively correlated with the degree of dementia in patients with Alzheimer disease(AD),the most common cause of dementia in the elderly.Activation of protein kinases or/and inhibition of protein phosphatases is responsible for tau hyperphosphorylation.Among various kinases,glycogen
文摘OBJECTIVE LW-AFC is extracted from the classical traditional Chinese medicinal prescription-Liuwei Dihuang Decoction.Previous studies have showed that LW-AFC could improve learning&memory ability in amny animal models.In this study,we focused on evaluating the effect of several main active components fromLW-AFC(B-B;loganin,LOG;morroniside,MOR;paeoniflorin,PF and stachyose,STA)on LTP.METHODS In vivo recording of LTP was used in this study to evaluate the effects of LW-AFC and it′s active components on coticorsterone(Cort)induced LTP impairment.RESULTS The results showed that LW-AFC could ameliorate Cort-induced LTP impairment.The effect of LW-AFC was abolished when the immune function was inhibited.Single administration(ig,ip,icv)of any of the components had no effect on Cort-induced LTP impairment.Consecutively intragastric administration or intraperitoneal injections(chronic administration)of B-B,LOG,MOR or PF for 7 d showed protective effect on Cort-induced LTP impairment.Intragastric administration of STA for 7 d protected LTP from impairment induced by Cort,while there was little improving effect when STA was administrated via intraperitoneal injection.In addition,when the intestinal microbiota was disrupted by applying the antibiotic cocktail,STA showed little protective effect against Cort.CONCLUSION In conclusion,LW-AFC and it′s components showed positive effects against cort induced LTP impairment,it seems that all displayed protective effects via indirectly,immune modulation might be the common pathway for all components;the exact pathways are different in each component,B-B,LOG,MOR and PF could be absorbed into the bloods tream and then modulate the peripheral immune function,while STA could not be absorbed and modulates the immune function via modulating intestinal microbiota.Further studies are needed to invesgate the underlying mechanisms and the synergetic effects of all components.
文摘OBJECTIVE Liuwei Dihuang Decoction(LW)-active fraction combination(LW-AFC,consist of 3 fractions polysaccharide,LWB-B;glycoside,LWD-b;oligosaccharide,CA-30)is extracted from LW,it is effective for the treatment of kidney yin deficiency in many animal models.This study evaluated the effects and mechanisms of LW-AFC and the active fractions on corticosterone(Cort)-induced long-term potentiation(LTP)impairment in vivo.METHODS LTP was used to evaluate the synaptic plasticity.LW-AFC was orally administered for seven days.The active fractions were given by either chronic administration(ig,ip,7 d)or single administration(icv,ig,ip).Cort was injected subcutaneously 1h before the high-frequency stimulation(HFS)to induce LTP impairment.Moreover,in order to research on the possible effective pathways,an antibiotic cocktail and an immunosuppressant were also used.RESULTS Chronic administration(ig)of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment.Single administration(icv,ig,ip)of any of the active fractions had no effect on Cort-induced LTP impairment,while chronic administration(ig,ip)of LWB-B or LWD-b showed positive effects against Cort.Interestingly,CA-30 only showed protective effects via ig administration,and there was little effect when CA-30 was administered ip In addition,when the intestinal microbiota was disrupted by application of the antibiotic cocktail,CA-30 showed little protective effects against Cort.The effects of LW-AFC were also abolished when the immune function was inhibited.In the hippocampal tissue,Cort treatment increased Cort and glutamate,and LW-AFC could inhibit the Cort-induced elevation of Cort and glutamate;there was little change in D-serine in Cort-treated animals,but LW-AFC could increase the D-serine levels.CONCLUSION LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment.Their protective effects are unlikely by a direct way,and immune modulation might be the common pathway.CA-30 could protect LTP from impairment via modulating the intestinal microbiota.Decreasing Cort and glutamate and increasing D-serine in the Cort-treated animals'hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC.Further study is needed to understand the underlying mechanisms.
