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Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

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Neural Regeneration Research 2024年第9期19卷 1973-1980页

作者： Yumei Yue Xiaodan Zhang Wen Lv Hsin-Yi Lai Ting Shen department of neurology of Sir Run Run Shaw hospital Zhejiang University School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina department of Emergency medicine The University of Hong KongHong Kong Special Administrative RegionChina department of neurology of the second affiliated hospital and school of brain science and brain medicine Interdisciplinary Institute of Neuroscience and TechnologyKey Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of MedicineHangzhouZhejiang ProvinceChina College of Biomedical Engineering and Instrument science Zhejiang UniversityHangzhouZhejiang ProvinceChina MOE Frontier science Center for brain science and brain-Machine Integration State Key Laboratory of Brain-machine IntelligenceSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic *** parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related *** glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial *** of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal ***,impairment of the glymphatic system could be considered as the final common pathway to *** evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions *** review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related *** focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and *** review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

关键词： atypical parkinsonism glymphatic system magnetic resonance imaging neurotoxic proteins Parkinson’s disease

Neural Circuitry Involving Substance P in Male Sexual Behavior

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Neuroscience Bulletin 2024年第4期40卷 544-546页

作者： Xinrong Wang Junqiang Zheng Han Xu department of neurobiology and department of neurology of the second affiliated hospital and school of brain science and brain medicine Zhejiang University School of MedicineHangzhou310058China Nanhu brain-Computer Interface Institute Hangzhou311100China Liangzhu Laboratory MOE Frontier Science Center for Brain Science and Brain-machine IntegrationState Key Laboratory of Brain-Machine IntelligenceZhejiang UniversityHangzhou311121China NHC and CAMS Key Laboratory of Medical neurobiology Zhejiang UniversityHangzhou310058China Lingang Laboratory Shanghai200031China

Male sexual behavior is an innate social behavior crucial for reproduction[1].Previous studies have identified several brain regions crucial for the control of both sexual and aggressive behaviors in ***,molecularly specified neural circuits that specifically control male sexual behavior remain *** with the inherently rewarding nature of sexual behavior,previous research has implicated the role of the dopamine system in regulating sexual desire[2].However,the interaction between reward and copulation at the circuit level remains largely ***,it is unclear if the associated neural pathways are specific in modulating sexual reward.

关键词： behavior neural specified

Chinese patients with adult onset leukodystrophy caused by CST3 variants

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Journal of Genetics and Genomics 2024年第7期51卷 778-780页

作者： Yi Zhang Zhi-Ying Wu department of Medical Genetics and Center for Rare Diseases Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical TranslationSecond Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Nanhu brain-computer Interface Institute HangzhouZhejiang 314050China department of neurology Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China MOE Frontier science Center for brain science and brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang 310012China

Leukodystrophies represent a group of cerebral white matter disorders that mainly affect axon-glia *** disorders are clinically diverse and display significant genetic *** is challenging to differentiate hereditary leukodystrophies,particularly those that present in adulthood,from acquired leukodystrophies and other genetic disorders,such as multiple sclerosis(MS)or hereditary spastic paraplegia(HSP)(Wei et al.,2021).Over the past few decades,a series of causative genes associated with leukodystrophies have been identified(Kohler et al.,2018).Nevertheless,a significant proportion of patients still lack a precise molecular diagnosis.

关键词： al. patients Kohler

Developmental Impairments of Synaptic Refinement in the Thalamus of a Mouse Model of Fragile X Syndrome

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Neuroscience Bulletin 2024年第4期40卷 439-450页

作者： Xiaotong Wu Yali Liu Xiaomeng Wang Lu Zheng Libiao Pan Hao Wang department of Neurosurgery of second affiliated hospital and school of brain science and brain medicine Key Laboratory for Biomedical Engineering of Education MinistryZhejiang University School of MedicineHangzhou310058China Nanhu brain-computer Interface Institute Hangzhou311100China NHC and CAMS Key Laboratory of Medical neurobiology MOE Frontier Science Center for Brain Research and Brain Machine IntegrationKey Laboratory of Precise Treatment and Clinical Translational Research of Neurological DiseasesSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhou310058China Lingang Laboratory Shanghai200031China

While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome(FXS),the thalamic mechanisms underlying this remain ***,we found that the developmental elimination of synapses formed between the principal nucleus of V(PrV)and the ventral posterior medial nucleus(VPm)of the somatosensory system was delayed in fragile X mental retardation 1 gene knockout(Fmr1 KO)mice,while the developmental strengthening of these synapses was *** showed excessive VGluT2 puncta in mutants at P12–13,but not at P7–8 or P15–16,confirming a delay in somatic pruning of PrV-VPm *** synaptic function was associated with a reduction in the frequency of quantal AMPA events,as well as developmental deficits in presynaptic vesicle size and *** results uncovered the developmental impairment of thalamic relay synapses in Fmr1 KO mice and suggest that a thalamic contribution to the somatosensory over-reactivity in FXS should be considered.

关键词： Fragile X syndrome Synaptic refinement VPm Sensory over-reactivity

Structures and ion transport mechanisms of plant high-affinity potassium transporters

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Molecular Plant 2024年第3期17卷 409-422页

作者： Jiangqin Wang Yanping Luo Fan Ye Zhong Jie Ding Shao Jian Zheng Shuai Qiao Yong Wang Jiangtao Guo Wei Yang Nannan Su international Institutes of medicine the Fourth Affiliated HospitalZhejang University School of MedicineYiwuZhejiang 322000China department of Biophysics and department of neurology of the Fourth affiliated hospital Zhejiang University School of MedicineHangzhouZhejang 310058China State Key Laboratory of Plant Environmental Resilience College of Life SciencesZhejang UniversityHangzhouZhejang 310058China College of Life sciences Zhejiang UniversityHangzhouZhejiang 310058China NHC and CAMS Key Laboratory of Medical neurobiology MOE Frontier Science Center for Brain Science and Brain-machine IntegrationSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang 310058China Nanhu brain-computer Interface Institute Hangzhou.Zheiang 311100.China

Plant high-affinity K^(+) transporters(HKTs)mediate Na^(+) and K^(+) uptake,maintain Na^(+)/K^(+) homeostasis,and therefore play crucial roles in plant salt *** this study,we present cryoelectron microscopy structures of HKTs from two classes,classI HKT1;1 from Arabidopsis thaliana(AtHKT1;1)and class II HKT2;1 from Triticum aestivum(TaHKT2;1),in both Na^(+) -and K^(+) -bound states at 2.6-to 3.0-A ***1;1and TaHKT2;1function *** HKT subunit consists of four tan-dem domain units(D1-D4)with a repeated K^(+) -channel-like M-P-M *** each subunit,D1-D4 assemble into an ion conduction pore with a pseudo-four-fold *** both TaHKT2;1and AtHKT1;1 have only one putative Na^(+) ion bound in the selectivity filter with a similar coordination pattern,the two HKTs display different K^(+) binding modes in the ***2;1 has three K^(+) ions bound in the selec-tivity filter,but AtHKT1;1 has only two K^(+) ions bound in the filter,which has a narrowed external entrance due to the presence of a Ser residue in the first filter *** structures,along with compu-tational,mutational,and electrophysiological analyses,enable us to pinpoint key residues that are critical for the ion selectivity of *** findings provide new insights into the ion selectivity and ion transport mechanisms of plant HKTs and improve our understanding about how HKTs mediate plant salt tolerance and enhance crop growth.

关键词： HKTs structure ion selectivity mechanism salt tolerance

Alzheimer’s disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling

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The Innovation 2024年第1期5卷 118-126页

作者： Qing-Qing Tao Xue Cai Yan-Yan Xue Weigang Ge Liang Yue Xiao-Yan Li Rong-Rong Lin Guo-Ping Peng Wenhao Jiang Sainan Li Kun-Mu Zheng Bin Jiang Jian-Ping Jia Tiannan Guo Zhi-Ying Wu department of neurology and Research Center of neurology in the second affiliated hospital and Key Laboratory of Medical neurobiology of Zhejiang Province Zhejiang University School of MedicineHangzhou 310009China Liangzhu Laboratory Zhejiang UniversityHangzhou 311100China Westlake Laboratory of Life sciences and Biomedicine Key Laboratory of Structural Biology of Zhejiang ProvinceSchool of Life SciencesWestlake UniversityHangzhou 310024China Institute of Basic Medical sciences Westlake Institute for Advanced StudyHangzho 310024China department of neurology First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China department of neurology First Affiliated HospitalSchool of MedicineXiamen UniversityXiamen 361009China Innovation Center for Neurological Disorders and department of neurology Xuanwu HospitalCapital Medical UniversityNational Clinical Research Center for Geriatric DiseasesBeijing 100053China MOE Frontier science Center for brain science and brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhou 310058China CAS Center for Excellence in brain science and Intelligence Technology Shanghai 200031China

Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic *** ADspecific early diagnostic and disease staging biomarkers are *** this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 *** biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 *** quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,*** the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,*** 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,*** 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative ***,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD *** findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.

关键词： cerebrospinal Alzheimer fluid

The neuroscience of pain,addiction,and anesthesia

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Zoological Research 2024年第3期45卷 709-710页

作者： Ji Hu Ping Zheng school of Life science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Medical neurobiology Institutes of Brain ScienceMOE Frontier Center for Brain ScienceDepartment of Neurology of Zhongshan HospitalFudan UniversityShanghai 200032China

Researchers and clinicians have long been interested in the mechanisms of pain,anesthesia,and *** International Association for the Study of Pain(IASP)defines pain as an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage(Raja et al.,2020).Drug addiction refers to a condition of reliance that develops from regular drug consumption,which may lead to withdrawal symptoms when use is *** involves the complete loss of consciousness induced by an inhaled or intravenous anesthetic(Tosello et al.,2022).In this special collection,Zoological Research presents research findings focused on pain,addiction,and anesthesia.

关键词： anesthesia damage

Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain

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science China(Life sciences) 2024年第1期67卷 67-82页

作者： Chun-Kui Zhang Pan Wang Yuan-Yuan Ji Jian-Shuai Zhao Jun-Xiang Gu Xian-Xia Yan Hong-Wei Fan Ming-Ming Zhang Yu Qiao Xiao-Die Liu Bao-Juan Li Ming-Hui Wang Hai-Long Dong Hao-Hong Li Peng-Cheng Huang Yun-Qing Li Wu-Gang Hou Jin-Lian Li Tao Chen department of Anatomy and K.K.Leung brain Research Centre Fourth Military Medical UniversityXi’an 710032China Beijing Institute of Basic Medical sciences Beijing 100850China Key Laboratory of Ministry of Public Health for Forensic science Xi’an Jiaotong UniversityXi’an 710061China department of Anesthesiology Xijing HospitalFourth Military Medical UniversityXi’an 710032China department of Neurosurgery the Second Affiliated Hospital of Xian Jiaotong UniversityXi’an 710004China school of Biomedical Engineering Fourth Military Medical UniversityXi’an 710032China affiliated Mental Health Centre and Hangzhou Seventh People’s hospital Zhejiang University School of MedicineHangzhou 310013China The MOE Frontier Research Center of brain&brain-machine Integration Zhejiang University School of Brain Science and Brain MedicineHangzhou 310058China department of neurology The First Affiliated Hospital of Nanchang UniversityNanchang 330006China department of Anatomy School of MedicineNorthwest UniversityXi’an 710069China

Chronic pain often develops severe mood changes such as ***,how chronic pain leads to depression remains elusive and the mechanisms determining individuals’responses to depression are largely *** we found that depression-like behaviors could only be observed in 67.9%of mice with chronic neuropathic pain,leaving 32.1%of mice with depression *** determined that the spike discharges of the ventral tegmental area(VTA)-projecting lateral habenula(LHb)glutamatergic(Glu)neurons were sequentially increased in sham,resilient and susceptible mice,which consequently inhibited VTA dopaminergic(DA)neurons through a LHbGlu-VTAGABA-VTADA ***,the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic *** of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic *** study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

关键词： chronic pain depression lateral habenula ventral tegmental area dopamine susceptibility

Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

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Neural Regeneration Research 2024年第2期19卷 360-368页

作者： Leyi Huang Wenjie Xiao Yan Wang Juan Li Jiaoe Gong Ewen Tu Lili Long Bo Xiao Xiaoxin Yan Lily Wan department of Anatomy and neurobiology Central South University Xiangya Medical SchoolChangshaHunan ProvinceChina department of neurology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina department of neurology Hunan Children’s HospitalChangshaHunan ProvinceChina department of neurology Brain Hospital of Hunan ProvinceChangshaHunan ProvinceChina

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug *** signaling through the excitatory neurotransmitter glutamate is intricately associated with *** glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic *** mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of *** this review,we first introduce the three groups of mGluRs and their associated signaling ***,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in *** addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also *** hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

关键词： antiepileptic drugs epileptogenesis metabotropic glutamate receptors(mGluRs) signal pathways therapeutic potentials