Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the re...Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2 a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2 a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2 a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2 a interneurons also play an important role in rhythmic patterning maintenance, leftright alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2 a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2 a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2 a interneurons transplanted in spinal cord injury foci.展开更多
Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited.Although regular exercise effectively improves learning and memory functions across multiple neurological diseases,its appl...Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited.Although regular exercise effectively improves learning and memory functions across multiple neurological diseases,its application in patients with epilepsy remains controversial.Here,we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy.Cognitive assays confirmed the improvement of object and spatial memory after endurance training,and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise.Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons,probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier.In summary,this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.展开更多
This paper is a systematic review of the treatment of bipolar disorder: a systematic Google Scholar search aimed at treatment guidelines and clinical trials. The search for treatment guidelines returned 375 papers and...This paper is a systematic review of the treatment of bipolar disorder: a systematic Google Scholar search aimed at treatment guidelines and clinical trials. The search for treatment guidelines returned 375 papers and was last performed from June 1, 2022 to August 30, 2022. The literature suggests that lithium helps control and alleviate severe mood episodes, and olanzapine is effective for acute manic or mixed episodes of bipolar I disorder. Achieving effectiveness or remission is better with Cariprazine. Lurasidone improves cognitive performance. Quetiapine improves sleep quality and co-morbid anxiety. Lamotrigine helps delay depression, mania, and mild manic episodes. Antidepressants are best used in conjunction with mood stabilizers. For co-morbid treatment, carbamazepine and lithium in combination are more effective in the treatment of psychotic mania. Co-morbid anxiety treatment considers adjunctive olanzapine or lamotrigine. Co-morbid bulimia treatment considers a mood stabilizer. Co-morbid fatigue treatment considers a dawn simulator. For diet, pay attention to a healthy diet, patients can ingest probiotics and pay attention to the balance of fatty acids.展开更多
The olfactory circuit of the fruit fly Drosophila melanogaster has emerged in recent years as an excellent paradigm for studying the principles and mechanisms of information processing in neuronal circuits. We discuss...The olfactory circuit of the fruit fly Drosophila melanogaster has emerged in recent years as an excellent paradigm for studying the principles and mechanisms of information processing in neuronal circuits. We discuss here the organizational principles of the olfactory circuit that make it an attractive model for experimental manipulations, the lessons that have been learned, and future challenges.展开更多
Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In...Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.展开更多
Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence sugge...Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence suggesting that microglia-released galectin-3(gal3)plays a pivotal role by amplifying neuroinflammation in AD.However,the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.Methods Here,we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo(20-80 Hz)by performing electrophysiological recordings in the hippocampal CA3 area of wild-type(WT)mice and of the 5×FAD mouse model of AD.In addition,the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes,and amyloid-β(Aβ)plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout(KO).Results Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner,which was accompanied by impairment of cellular dynamics in fast-spiking interneurons(FSNs)and pyramidal cells.We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139,which also prevented Aβ42-induced degradation of gamma oscillations.Further-more,the 5×FAD mice lacking gal3(5×FAD-Gal3KO)exhibited WT-like gamma network dynamics and decreased Aβplaque load.Conclusions We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs,inducing a network performance collapse.Moreover,our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.展开更多
Anxiety disorders are currently a major psychiatric and social problem,the mechanisms of which have been only partially elucidated.The hippocampus serves as a major target of stress mediators and is closely related to...Anxiety disorders are currently a major psychiatric and social problem,the mechanisms of which have been only partially elucidated.The hippocampus serves as a major target of stress mediators and is closely related to anxiety modulation.Yet so far,its complex anatomy has been a challenge for research on the mechanisms of anxiety regulation.Recent advances in imaging,virus tracking,and optogenetics/chemogenetics have permitted elucidation of the activity,connectivity,and function of specific cell types within the hippocampus and its connected brain regions,providing mechanistic insights into the elaborate organization of the hippocampal circuitry underlying anxiety.Studies of hippocampal neurotransmitter systems,including glutamatergic,GABAergic,cholinergic,dopaminergic,and serotonergic systems,have contributed to the interpretation of the underlying neural mechanisms of anxiety.Neuropeptides and neuroinflammatory factors are also involved in anxiety modulation.This review comprehensively summarizes the hippocampal mechanisms associated with anxiety modulation,based on molecular,cellular,and circuit properties,to provide tailored targets for future anxiety treatment.展开更多
Background:Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay(NDD),but its genetic basis has not been fully characterized.This study attempted to analyze the genetic...Background:Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay(NDD),but its genetic basis has not been fully characterized.This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume(WBDV).Methods:We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years.We recruited only NDD patients without acquired etiologies or positive genetic results.Cranial magnetic resonance imaging(MRI)and clinical exome sequencing(2742 genes)data were acquired.A genetic burden test was performed,and the results were compared between patients with and without significant WBDV.Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development.Results:We recruited a total of 253 NDD patients.Among them,26 had significantly decreased WBDV(<-2 standard deviations[SDs]),and 14 had significantly increased WBDV(>+2 SDs).NDD patients with significant WBDV had higher rates of motor development delay(49.8%[106/213]vs.75.0%[30/40],P=0.003)than patients without significant WBDV.Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV.Analyses of the literature further demonstrated that these genes were not randomly identified:burden genes were more related to the brain development than background genes(P=1.656e^(-9)).In seven human brain regions related to motor development,we observed burden genes had higher expression before 37-week gestational age than postnatal stages.Functional analyses found that burden genes were enriched in embryonic brain development,with positive regulation of synaptic growth at the neuromuscular junction,positive regulation of deoxyribonucleic acid templated transcription,and response to hormone,and these genes were shown to be expressed in neural progenitors.Based on single 展开更多
The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson’s disease.However,the exact role of the mediodorsal thalamic nucleus in the function of the p...The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson’s disease.However,the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear.To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex,a model of Parkinson’s disease was established by injecting 8μg 6-hydroxydopamine into the substantia nigra compacta of rats.After 1 or 3 weeks,0.3μg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain.At 3 or 5 weeks after the initial injury,neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically.The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining.Results demonstrated that after injury,the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats.Compared with normal medial prefrontal cortical neurons,at 3 and 5 weeks after substantia nigra compacta injury,the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge,with an increased discharge interval.The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge,but the discharge interval was only higher at 3 weeks.At 3 weeks after the combined lesions,the discharge frequency,discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex.These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex.The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefron展开更多
The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nerv...The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases （DNMTs）, mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mi- totic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.展开更多
Traumatic brain injury can cause loss of neuronal tissue, remote symptomatic epilepsy, and cognitive deficits. However, the mechanisms underlying the effects of traumatic brain injury are not yet clear. Hippocampal ex...Traumatic brain injury can cause loss of neuronal tissue, remote symptomatic epilepsy, and cognitive deficits. However, the mechanisms underlying the effects of traumatic brain injury are not yet clear. Hippocampal excitability is strongly correlated with cognitive dysfunction and remote symptomatic epilepsy. In this study, we examined the relationship between traumatic brain injury-induced neuronal loss and subsequent hippocampal regional excitability. We used hydraulic percussion to generate a rat model of traumatic brain injury. At 7 days after injury, the mean modified neurological severity score was 9.5, suggesting that the neurological function of the rats was remarkably impaired. Electrophysiology and immunocytochemical staining revealed increases in the slope of excitatory postsynaptic potentials and long-term depression（indicating weakened long-term inhibition）, and the numbers of cholecystokinin and parvalbumin immunoreactive cells were clearly reduced in the rat hippocampal dentate gyrus. These results indicate that interneuronal loss and changes in excitability occurred in the hippocampal dentate gyrus. Thus, traumatic brain injury-induced loss of interneurons appears to be associated with reduced long-term depression in the hippocampal dentate gyrus.展开更多
The raphe nucleus is critical for feeding, rewarding and memory. However, how the heterogenous raphe neurons are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we gen...The raphe nucleus is critical for feeding, rewarding and memory. However, how the heterogenous raphe neurons are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing VGLUT3. VGLUT3 neurons control the efficacy of spatial memory retrieval by synapsing directly with parvalbumin-expressing GABA interneurons(PGIs) in the dentate gyrus. In a mouse model of Alzheimer's disease(AD mice),VGLUT3→PGIs synaptic transmission is impaired by ETV4 inhibition of VGLUT3 transcription. ETV4 binds to a promoter region of VGLUT3 and activates VGLUT3 transcription in VGLUT3 neurons. Strengthening VGLUT3→PGIs synaptic transmission by ETV4 activation of VGLUT3 transcription upscales the efficacy of spatial memory retrieval in AD mice. This study reports a novel circuit and molecular mechanism underlying the efficacy of spatial memory retrieval via ETV4 inhibition of VGLUT3 transcription and hence provides a promising target for therapeutic intervention of the disease progression.展开更多
CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP o...CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.展开更多
基金supported by the National Natural Science Foundation of China,No. 81870977 (to YW)the Natural Science Foundation of Heilongjiang Province of China,No. JQ2021H004 (to YW)+1 种基金PhD research foundation of Mudanjiang Medicine College,No. 2021-MYBSKY-039 (to WYL)Fundamental Research Funds for Heilongjiang Provincial Universities,No. 2021-KYYWF-0469 (to WYL)。
文摘Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2 a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2 a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2 a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2 a interneurons also play an important role in rhythmic patterning maintenance, leftright alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2 a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2 a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2 a interneurons transplanted in spinal cord injury foci.
基金supported by STI2030-Major Projects,No.2022ZD0207600 (to LZ)the National Natural Science Foundation of China,Nos.821 71446 (to JY),U22A20301 (to KFS),32070955 (to LZ)+1 种基金Guangdong Basic and Applied Basic Research Foundation,No.202381515040015 (to LZ)Science and Technology Program of Guangzhou of China,No.202007030012 (to KFS and LZ)
文摘Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited.Although regular exercise effectively improves learning and memory functions across multiple neurological diseases,its application in patients with epilepsy remains controversial.Here,we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy.Cognitive assays confirmed the improvement of object and spatial memory after endurance training,and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise.Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons,probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier.In summary,this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.
文摘This paper is a systematic review of the treatment of bipolar disorder: a systematic Google Scholar search aimed at treatment guidelines and clinical trials. The search for treatment guidelines returned 375 papers and was last performed from June 1, 2022 to August 30, 2022. The literature suggests that lithium helps control and alleviate severe mood episodes, and olanzapine is effective for acute manic or mixed episodes of bipolar I disorder. Achieving effectiveness or remission is better with Cariprazine. Lurasidone improves cognitive performance. Quetiapine improves sleep quality and co-morbid anxiety. Lamotrigine helps delay depression, mania, and mild manic episodes. Antidepressants are best used in conjunction with mood stabilizers. For co-morbid treatment, carbamazepine and lithium in combination are more effective in the treatment of psychotic mania. Co-morbid anxiety treatment considers adjunctive olanzapine or lamotrigine. Co-morbid bulimia treatment considers a mood stabilizer. Co-morbid fatigue treatment considers a dawn simulator. For diet, pay attention to a healthy diet, patients can ingest probiotics and pay attention to the balance of fatty acids.
基金L. Liang has been supported by a Stanford Graduate Fellow-ship and a Lubert Stryer Stanford Interdisciplinary Graduate Fellowship. L. Luo is an investigator at the Howard Hughes Medical InstituteOlfaction research in our lab has been supported by NIH grant R01-DC005982
文摘The olfactory circuit of the fruit fly Drosophila melanogaster has emerged in recent years as an excellent paradigm for studying the principles and mechanisms of information processing in neuronal circuits. We discuss here the organizational principles of the olfactory circuit that make it an attractive model for experimental manipulations, the lessons that have been learned, and future challenges.
基金supported by the Notional Natural Science Foundation of China,Nos.81371213 and 8107098 7the Natural Science Foundation of Shanghai,No.21ZR1468400 (all to QLY)。
文摘Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.
基金funding provided by Karolinska Institute.This work was supported by the Swedish Research Council,the Swedish Brain Foundation,the Swedish Alzheimer Foundation,theÅhlén Foundation(AF),the Berger Foundation(TD),the Olle Engkvist Foundation(TD),G&K Kock Foundation(TD),the Strategic Research Area MultiPark at Lund University(TD),the Foundation for Geriatric Diseases at Karolinska Institutet,theÅhlén Foundation(YAT),Consejo Nacional de Ciencia y Tecnología(CONACYT)postdoctoral fellowships and StratNeuro program at Karolinska Institutet(LEAG),Lindhés Advokabyra AB Grant and Stohnes Stiftelse(LEAG,YAT)the Spanish Ministerio de Ciencia e Innovación(MICIN/AEI/FEDER:PID2019-107677 GB-I00,ARM).
文摘Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence suggesting that microglia-released galectin-3(gal3)plays a pivotal role by amplifying neuroinflammation in AD.However,the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.Methods Here,we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo(20-80 Hz)by performing electrophysiological recordings in the hippocampal CA3 area of wild-type(WT)mice and of the 5×FAD mouse model of AD.In addition,the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes,and amyloid-β(Aβ)plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout(KO).Results Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner,which was accompanied by impairment of cellular dynamics in fast-spiking interneurons(FSNs)and pyramidal cells.We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139,which also prevented Aβ42-induced degradation of gamma oscillations.Further-more,the 5×FAD mice lacking gal3(5×FAD-Gal3KO)exhibited WT-like gamma network dynamics and decreased Aβplaque load.Conclusions We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs,inducing a network performance collapse.Moreover,our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.
基金supported by the National Natural Science Foundation of China(31970951)the Six Talent Peaks Project of Jiangsu Province(YY-005)+1 种基金the Shanghai Rising-Star Program(21QA1407900)“Zhong Ying Young Scholar”project of Cyrus Tang Foundation.
文摘Anxiety disorders are currently a major psychiatric and social problem,the mechanisms of which have been only partially elucidated.The hippocampus serves as a major target of stress mediators and is closely related to anxiety modulation.Yet so far,its complex anatomy has been a challenge for research on the mechanisms of anxiety regulation.Recent advances in imaging,virus tracking,and optogenetics/chemogenetics have permitted elucidation of the activity,connectivity,and function of specific cell types within the hippocampus and its connected brain regions,providing mechanistic insights into the elaborate organization of the hippocampal circuitry underlying anxiety.Studies of hippocampal neurotransmitter systems,including glutamatergic,GABAergic,cholinergic,dopaminergic,and serotonergic systems,have contributed to the interpretation of the underlying neural mechanisms of anxiety.Neuropeptides and neuroinflammatory factors are also involved in anxiety modulation.This review comprehensively summarizes the hippocampal mechanisms associated with anxiety modulation,based on molecular,cellular,and circuit properties,to provide tailored targets for future anxiety treatment.
基金grants from the Science and Technology Commission of Shanghai Municipal(No.19411964400)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)ZJLab.
文摘Background:Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay(NDD),but its genetic basis has not been fully characterized.This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume(WBDV).Methods:We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years.We recruited only NDD patients without acquired etiologies or positive genetic results.Cranial magnetic resonance imaging(MRI)and clinical exome sequencing(2742 genes)data were acquired.A genetic burden test was performed,and the results were compared between patients with and without significant WBDV.Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development.Results:We recruited a total of 253 NDD patients.Among them,26 had significantly decreased WBDV(<-2 standard deviations[SDs]),and 14 had significantly increased WBDV(>+2 SDs).NDD patients with significant WBDV had higher rates of motor development delay(49.8%[106/213]vs.75.0%[30/40],P=0.003)than patients without significant WBDV.Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV.Analyses of the literature further demonstrated that these genes were not randomly identified:burden genes were more related to the brain development than background genes(P=1.656e^(-9)).In seven human brain regions related to motor development,we observed burden genes had higher expression before 37-week gestational age than postnatal stages.Functional analyses found that burden genes were enriched in embryonic brain development,with positive regulation of synaptic growth at the neuromuscular junction,positive regulation of deoxyribonucleic acid templated transcription,and response to hormone,and these genes were shown to be expressed in neural progenitors.Based on single
基金supported by the Key Research Project of Science and Technology of Henan Province of China,No.14B180007(to LLF)the Development Project of Science and Technology of Luoyang Municipality of China,No.1401087A-5(to LLF)
文摘The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson’s disease.However,the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear.To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex,a model of Parkinson’s disease was established by injecting 8μg 6-hydroxydopamine into the substantia nigra compacta of rats.After 1 or 3 weeks,0.3μg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain.At 3 or 5 weeks after the initial injury,neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically.The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining.Results demonstrated that after injury,the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats.Compared with normal medial prefrontal cortical neurons,at 3 and 5 weeks after substantia nigra compacta injury,the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge,with an increased discharge interval.The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge,but the discharge interval was only higher at 3 weeks.At 3 weeks after the combined lesions,the discharge frequency,discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex.These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex.The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefron
文摘The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases （DNMTs）, mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mi- totic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.
基金supported by the National Natural Science Foundation of China,No.81330029,81501057the Natural Science Foundation of Tianjin of China,No.17JCQNJC12000the Tianjin Medical University General Hospital Funding in China,No.ZYYFY2016014
文摘Traumatic brain injury can cause loss of neuronal tissue, remote symptomatic epilepsy, and cognitive deficits. However, the mechanisms underlying the effects of traumatic brain injury are not yet clear. Hippocampal excitability is strongly correlated with cognitive dysfunction and remote symptomatic epilepsy. In this study, we examined the relationship between traumatic brain injury-induced neuronal loss and subsequent hippocampal regional excitability. We used hydraulic percussion to generate a rat model of traumatic brain injury. At 7 days after injury, the mean modified neurological severity score was 9.5, suggesting that the neurological function of the rats was remarkably impaired. Electrophysiology and immunocytochemical staining revealed increases in the slope of excitatory postsynaptic potentials and long-term depression（indicating weakened long-term inhibition）, and the numbers of cholecystokinin and parvalbumin immunoreactive cells were clearly reduced in the rat hippocampal dentate gyrus. These results indicate that interneuronal loss and changes in excitability occurred in the hippocampal dentate gyrus. Thus, traumatic brain injury-induced loss of interneurons appears to be associated with reduced long-term depression in the hippocampal dentate gyrus.
基金supported by the National Natural Science Foundation of China (31721002, 81920208014, 31930051, 81800133)China Postdoctoral Science Foundation Funded Project (2018M642853)。
文摘The raphe nucleus is critical for feeding, rewarding and memory. However, how the heterogenous raphe neurons are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing VGLUT3. VGLUT3 neurons control the efficacy of spatial memory retrieval by synapsing directly with parvalbumin-expressing GABA interneurons(PGIs) in the dentate gyrus. In a mouse model of Alzheimer's disease(AD mice),VGLUT3→PGIs synaptic transmission is impaired by ETV4 inhibition of VGLUT3 transcription. ETV4 binds to a promoter region of VGLUT3 and activates VGLUT3 transcription in VGLUT3 neurons. Strengthening VGLUT3→PGIs synaptic transmission by ETV4 activation of VGLUT3 transcription upscales the efficacy of spatial memory retrieval in AD mice. This study reports a novel circuit and molecular mechanism underlying the efficacy of spatial memory retrieval via ETV4 inhibition of VGLUT3 transcription and hence provides a promising target for therapeutic intervention of the disease progression.
基金This work was supported by Science and Technology Innovation 2030-Major Project(2021ZD0203501)the National Natural Science Foundation of China(81930030,31771109,and 31722023)+5 种基金the National Key R&D Program of China(2019YFA0508603)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)Project for Hangzhou Medical Disciplines of ExcellenceKey Project for Hangzhou Medical Disciplinesthe Fundamental Research Funds for the Central Universities of China(2018XZZX002-02,2019XZZX001-01-04,and 2019FZA7009)the National Postdoctoral Program for Innovative Talents(BX2021263).
文摘CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
