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Control of defensive behavior by the nucleus of Darkschewitsch GABAergic neurons

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National Science Review 2024年第4期11卷 70-83页

作者： Huiying Zhao Jinrong Liu Yujin Shao Xiang feng Binhan Zhao Li Sun Yijun Liu Linghui Zeng Xiao-ming Li Hongbin Yang Shumin Duan Yan-qin Yu department of neurology of Second Affiliated Hospital and School of brain Science and brain Medicine Zhejiang University School of Medicine Nanhu brain-Computer Interface institute Liangzhu Laboratory MOE Frontier Science Center for Brain Science and Brain-Machine Integration State Key Laboratory of Brain-Machine Intelligence Zhejiang University NHC and CAMS Key Laboratory of Medical Neurobiology Zhejiang University Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University

The nucleus of Darkschewitsch(ND), mainly composed of GABAergic neurons, is widely recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons(NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot shock.Optogenetic and chemogenetic manipulations revealed that NDGABA neurons mediate freezing behavior.Moreover, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal gray(l PAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part(Gi V). Together,these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from the l PAG to Gi V, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain.

关键词： nucleus of Darkschewitsch GABAergic population defensive behavior freezing neural circuitry

A Spleen Tyrosine Kinase’s Sky in Neuronal Degeneration

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Neuroscience Bulletin 2024年第2期40卷 273-276页

作者： Wan-Yun Zhang Sen Lin department of neurology Xinqiao HospitalThe Second Afliated HospitalArmy Medical UniversityChongqing 400042China Chongqing institute for brain and Intelligence Guangyang Bay LaboratoryChongqing 400064China

With the growing elderly population,neurodegenerative disorders like Alzheimer's disease(AD)are emerging as a significant public health concern.It is widely acknowledged in the scientific community that the accumulation of neurotoxic aggregates,such as amyloid beta(Aβ),within the central nervous system is a major factor in the development of these disorders.furthermore,human genome-wide association studies have identified mutations in microglial receptors that may be linked to a number of neurodegenerative diseases[1].

关键词： Aβ Spleen Alzheimer

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 protein.Atypical 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 disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment 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 damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous 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 remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The 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 gliosis.This 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

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 biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSf)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We 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,respectively.In the validation cohort,58 and 21 CSf proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 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,respectively.The 19-protein CSf biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSf and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.

关键词： cerebrospinal Alzheimer fluid

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 males.Yet,molecularly specified neural circuits that specifically control male sexual behavior remain elusive.Consistent 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 unexplored.Besides,it is unclear if the associated neural pathways are specific in modulating sexual reward.

关键词： behavior neural specified

Vitamin D-binding protein in plasma microglia-derived extracellular vesicles as a potential biomarker for major depressive disorder

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Genes & Diseases 2024年第2期11卷 1009-1021页

作者： Gaojia Zhang Ling Li Yan Kong Dandan Xu Yu Bao Zhiting Zhang Zhixiang Liao Jiao Jiao Dandan fan Xiaojing Long Ji Dai Chunming Xie Zhiqiang Meng Zhijun Zhang department of neurology Affiliated Zhongda HospitalResearch Institution of NeuropsychiatrySchool of MedicineSoutheast UniversityNanjingJiangsu 210009China department of Biochemistry and Molecular Biology School of MedicineSoutheast UniversityNanjingJiangsu 210009China Shenzhen Key Laboratory of Drug Addiction Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of Sciences (CAS)ShenzhenGuangdong 518000China CAS Key Laboratory of brain Connectome and Manipulation The Brain Cognition and Brain Disease Institute (BCBDI)Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong 518055China Lauterbur Research Center for Biomedical Imaging Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong 518055China Shenzhen-Hong Kong institute of brain Sciences-Shenzhen fundamental Research Institutions ShenzhenGuangdong 518000China brain Cognition and brain Disease institute Department of Mental Health and Public HealthFaculty of Life and Health SciencesShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong 518055China

No well-established biomarkers are available for the clinical diagnosis of major depressive disorder(MDD).Vitamin D-binding protein(VDBP)is altered in plasma and postmortem dorsolateral prefrontal cortex(DLPfC)tissues of MDD patients.Thereby,the role of VDBP as a potential biomarker of MDD diagnosis was further assessed.Total extracellular vesicles(EVs)and brain cell-derived EVs(BCDEVs)were isolated from the plasma of first-episode drug-naïve or drug-free MDD patients and well-matched healthy controls(HCs)in discovery(20 MDD patients and 20 HCs)and validation cohorts(88 MDD patients and 38 HCs).VDBP level in the cerebrospinal fluid(CSf)from chronic glucocorticoid-induced depressed rhesus macaques or prelimbic cortex from lipopolysaccharide(LPS)-induced depressed mice and wild control groups was measured to evaluate its relationship with VDBP in plasma microglia-derived extracellular vesicles(MDEVs).VDBP was significantly decreased in MDD plasma MDEVs compared to HCs,and negatively correlated with HAMD-24 score with the highest diagnostic accuracy among BCDEVs.VDBP in plasma MDEVs was decreased both in depressed rhesus macaques and mice.A positive correlation of VDBP in MDEVs with that in CSf was detected in depressed rhesus macaques.VDBP levels in prelimbic cortex microglia were negatively correlated with those in plasma MDEVs in depressed mice.The main results suggested that VDBP in plasma MDEVs might serve as a prospective candidate biomarker for MDD diagnosis.

关键词： Biomarker Cerebrospinal fluid Major depressive disorder Microglia derived extracellular vesicles Vitamin-D binding protein

Potential role of hippocampal neurogenesis in spinal cord injury induced post-trauma depression

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Neural Regeneration Research 2024年第10期19卷 2144-2156页

作者： Ying Ma Yue Qiao Xiang Gao Spinal Cord and brain Injury Research Group Stark Neuroscience Research InstituteIndianapolisINUSA department of Neurological Surgery Indiana University School of MedicineIndianapolisINUSA department of neurology Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The largescale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.

关键词： antidepressants chronic pain depression exercise hippocampal neurogenesis inflammation inhibition neuroinflammation physical activity deficits social isolation spinal cord injury

Status of biomarker development for frontotemporal dementia and amyotrophic lateral sclerosis

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Neural Regeneration Research 2024年第10期19卷 2117-2118页

作者： Yue Yang Qi Cheng Jianqun Gao Woojin Scott Kim brain and Mind Centre&School of Medical Sciences The University of SydneySydneyNSWAustralia department of neurology and Neurophysiology Liverpool HospitalSydneyNSWAustralia Stroke and neurology Research Group Ingham Institute for Applied Medical ResearchSydneyNSWAustralia Shanghai Key Laboratory of Anesthesiology and brain functional Modulation ShanghaiChina Clinical Research Center for Anesthesiology and Perioperative Medicine ShanghaiChina Translational Research institute of brain and brain-Like Intelligence Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghaiChina

frontotemporal dementia(fTD) and amyotrophic lateral sclerosis(ALS) are neurodegenerative diseases that belong to the same disease spectrum,with overlapping of genetic and pathological features.Genetic mutations in TA... 详细信息

关键词： amyotrophic sclerosis diseases

In patients who had a stroke or TIA, enlarged perivascular spaces in basal ganglia may cause future haemorrhagic strokes

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Stroke & Vascular neurology 2024年第1期9卷 8-17,I0001-I0033页

作者： Yu Tian Mengxing Wang Yuesong Pan Xia Meng Xingquan Zhao Liping Liu Yongjun Wang Yilong Wang department of neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Chinese institute for brain Research BeijingChina National Center for Neurological Diseases BeijingChina Advanced Innovation Center for Human brain Protection Capital Medical UniversityBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina

Introduction It remains unclear whether enlarged perivascular spaces(EPVS)predict poor clinical outcomes in patients with acute ischaemic stroke(AIS)or transient ischaemic attack(TIA).Method Data were obtained from the Third China National Stroke Registry study.We estimated EPVS in basal ganglia(BG)and centrum semiovale(CSO)using a semiquantified scale(Grade from 0 to 4).Using Cox and logistic regression analyses,the associations of EPVS with 3-month and 1-year adverse outcomes(including recurrent stroke,ischaemic stroke,haemorrhagic stroke,combined vascular event,disability and mortality)were explored.Sensitivity analyses of any association of cerebral small vessel disease at baseline and development of a small arterial occlusion(SAO)were conducted.Result Among 12603 patients with AIS/TIA,median age was 61.7±11.6 years,and 68.2%were men.After adjusting for all potential confounders,frequent-to-severe BG-EPVS was associated with a decreased risk of recurrent ischaemic stroke(HR 0.71,95%CI 0.55 to 0.92,p=0.01)but an increased risk of haemorrhagic stroke(HR 1.99,95%CI 1.11 to 3.58,p=0.02)at 1 year after AIS/TIA,compared with none-to-mild BG-EPVS.Patients with frequent-to-severe CSO-EPVS had a decreased risk of disability(OR 0.76,95%CI 0.62 to 0.92,p=0.004)and all-cause death(HR 0.55,95%CI 0.31 to 0.98,p=0.04)within 3-month but not 1-year follow-ups,compared with those with none-to-mild BG-EPVS.Sensitivity analyses showed that both BG-EPVS(HR 0.43,95%CI 0.21 to 0.87,p=0.02)and CSO-EPVS(HR 0.58,95%CI 0.35 to 0.95,p=0.03)were associated with a decreased risk of subsequent ischaemic stroke in patients with SAO during 1-year follow-up.Conclusion BG-EPVS increased the risk of haemorrhagic stroke in patients already with AIS/TIA within 1 year.Therefore,caution is recommended when selecting antithrombotic agents for secondary stroke prevention in patients with AIS/TIA and more severe BG-EPVS.

关键词： patients haemorrhagic prevention