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Blood-brain barrier pathology in cerebral small vessel disease

Neural Regeneration Research 2024年第6期19卷 1233-1240页

作者： Ruxue Jia Gemma Solé-Guardia Amanda J.Kiliaan Department of Medical Imaging Anatomy Radboud University Medical Center Donders Institute for Brain Cognition & Behavior Center for Medical Neuroscience Preclinical Imaging Center PRIME Radboud Alzheimer Center

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

关键词： blood-brain barrier dysfunction cerebral blood flow cerebral hypoperfusion endothelial dysfunction hypertension inflammation magnetic resonance imaging neurovascular unit oxidative stress small vessel disease tight junctions transcytosis

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Versatile strategies for adult neurogenesis:avenues to repair the injured brain

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Neural Regeneration Research 2024年第4期19卷 774-780页

作者： Junyi Zhao Siyu Liu Xianyuan Xiang Xinzhou Zhu The brain Cognition and brain Disease institute(BCBDI) Shenzhen Institute of Advanced TechnologyChinese Academy of Sciences Faculty of Life and Health Sciences Shenzhen Institutes of Advanced TechnologyChinese Academy of Sciences Shenzhen-Hong Kong institute of brain Science-Shenzhen Fundamental Research Institutions

brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neurogenesis actually happens in the adult human brain,there is now substantial evidence to support its occurrence.Although neurogenesis is usually significantly stimulated by injury,the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient.Alternatively,exogenous stem cell transplantation has shown promising results in animal models,but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use.Recently,a high focus was placed on glia-to-neuron conversion under single-factor regulation.Despite some inspiring results,the validity of this strategy is still controversial.In this review,we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury.We also discuss their advantages and drawbacks,as to provide a comprehensive account of their potentials for further studies.

关键词： adult neurogenesis glia-to-neuron conversion ischemic stroke neurogenic niche neuroinflammation stem cell transplantation traumatic brain injury

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Rapid Unconscious Acquisition of Conditioned Fear with Low-Spatial-Frequency but Emotionally Neutral Stimuli

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Research 2024年第1期2023卷 753-762页

作者： Yujie Chen Si Chen Zhongju Sun Xilei Zhang Xiangyong Yuan Liang Wang Yi Jiang State Key Laboratory of brain and Cognitive Sciences CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of PsychologyChinese Academy of SciencesBeijing 100101China Department of Psychology University of Chinese Academy of SciencesBeijing 100049China Chinese institute for brain Research Beijing 102206China CAS Key Laboratory of Mental Health Institute of PsychologyChinese Academy of SciencesBeijing 100101China

It has long been proposed that emotionally“prepared”(i.e.,fear-related)stimuli are privileged in the unconscious acquisition of conditioned fear.However,as fear processing is suggested to highly depend on the coarse,low-spatial-frequency(LSF)components of the fear-related stimuli,it is plausible that LSF may play a unique role in the unconscious fear conditioning even with emotionally neutral stimuli.Here,we provided empirical evidence that,following classical fear conditioning,an invisible,emotionally neutral conditioned stimulus(CS+)with LSF,but not with high spatial frequency(HSF),can rapidly elicit stronger skin conductance responses(SCRs)and larger pupil diameters than its CS−counterpart.In comparison,consciously perceived emotionally neutral CS+with LSF and HSF elicited comparable SCRs.Taken together,these results support that the unconscious fear conditioning does not necessarily entail emotionally prepared stimuli but prioritizes LSF information processing and highlight the crucial distinctions between the unconscious and the conscious fear learning.These findings not only coincide with the postulation that a rapid,spatial-frequency-dependent subcortical route is engaged in unconscious fear processing but also suggest the existence of multiple routes for conscious fear processing.

关键词： neutral necessarily diameters

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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

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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

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Next-generation regenerative therapy for ischemic stroke using peripheral blood mononuclear cells

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Neural Regeneration Research 2024年第11期19卷 2341-2342页

作者： Masato Kanazawa Itaru Ninomiya Yutaka Otsu Masahiro Hatakeyama Department of Neurology Brain Research InstituteNiigata UniversityNiigataJapan

Stroke is the second leading cause of death and the third leading cause of disability worldwide after heart disease.Researchers predict that stroke deaths and permanent disabilities will increase worldwide by the year 2050.Single-target therapies may be insufficient,because ischemic cerebral injury involves several mechanisms.Cell-mediated therapies are ideal,because they target multiple cell types to enhance protection and recovery.

关键词： ischemic death cerebral

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Multi-region calcium imaging in freely behaving mice with ultra-compact head-mounted fluorescence microscopes

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National Science Review 2024年第1期11卷 161-173页

作者： Feng Xue Fei Li Ke-ming Zhang Lufeng Ding Yang Wang Xingtao Zhao Fang Xu Danke Zhang Mingzhai Sun Pak-Ming Lau Qingyuan Zhu Pengcheng Zhou Guo-Qiang Bi institute of Artiflcial Intelligence Hefei Comprehensive National Science Center Department of Precision Machinery and Precision Instruments University of Science and Technology of China Hefei National Laboratory for Physical Sciences at the Microscale University of Science and Technology of China Interdisciplinary Center for brain Information the Brain Cognition and Brain Disease Institute Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Faculty of Life and Health Sciences Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences School of Life Sciences University of Science and Technology of China institute of Semiconductors Chinese Academy of Sciences Department of Modern Life Sciences and Biotecnology Xiongan Institute of Innovation Xiongan New Area Shenzhen-Hong Kong institute of brain Science-Shenzhen Fundamental Research Institutions Suzhou institute for Advanced Research University of Science and Technology of China

To investigate the circuit-level neural mechanisms of behavior, simultaneous imaging of neuronal activity in multiple cortical and subcortical regions is highly desired. Miniature head-mounted microscopes offer the capability of calcium imaging in freely behaving animals. However, implanting multiple microscopes on a mouse brain remains challenging due to space constraints and the cumbersome weight of the equipment.Here, we present TINIscope, a Tightly Integrated Neuronal Imaging microscope optimized for electronic and opto-mechanical design. With its compact and lightweight design of 0.43 g, TINIscope enables unprecedented simultaneous imaging of behavior-relevant activity in up to four brain regions in mice.Proof-of-concept experiments with TINIscope recorded over 1000 neurons in four hippocampal subregions and revealed concurrent activity patterns spanning across these regions. Moreover, we explored potential multi-modal experimental designs by integrating additional modules for optogenetics, electrical stimulation or local field potential recordings. Overall, TINIscope represents a timely and indispensable tool for studying the brain-wide interregional coordination that underlies unrestrained behaviors.

关键词： miniature microscope multiple sites calcium imaging multimodal integration hippocampus

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A Novel Retrograde AAV Variant for Functional Manipulation of Cortical Projection Neurons in Mice and Monkeys

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Neuroscience Bulletin 2024年第1期40卷 90-102页

作者： Yefei Chen Jingyi Wang Jing Liu Jianbang Lin Yunping Lin Jinyao Nie Qi Yue Chunshan Deng Xiaofei Qi Yuantao Li Ji Dai Zhonghua Lu Department of Anesthesiology Shenzhen Maternity and Child Healthcare HospitalThe First School of Clinical MedicineSouthern Medical UniversityShenzhen 518027China Shenzhen Technological Research Center for Primate Translational Medicine Shenzhen Key Laboratory for Molecular Biology of Neural DevelopmentShenzhen-Hong Kong Institute of Brain ScienceShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China University of Chinese Academy of Sciences Beijing 100049China CAS Key Laboratory of brain Connectome and Manipulation the Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Guangdong Provincial Key Laboratory of brain Connectome and Behavior the Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Biomedical Research institute Hubei University of MedicineShiyan 442000China Faculty of Life and Health Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Retrograde adeno-associated viruses(AAVs)are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks.However,few retro-grade AAV capsids have been shown to offer access to cor-tical projection neurons across different species and enable the manipulation of neural function in non-human primates(NHPs).Here,we report the development of a novel retro-grade AAV capsid,AAV-DJ8R,which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques.In addition,intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations.Moreover,AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen.These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.

关键词： Retrograde AAV Capsid variant Cortical projection neuron Optogenetics Monkey

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Promotion of structural plasticity in area V2 of visual cortex prevents against object recognition memory deficits in aging and Alzheimer's disease rodents

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Neural Regeneration Research 2024年第8期19卷 1835-1841页

作者： Irene Navarro-Lobato Mariam Masmudi-Martín Manuel F.López-Aranda Juan F.López-Téllez Gloria Delgado Pablo Granados-Durán Celia Gaona-Romero Marta Carretero-Rey Sinforiano Posadas María E.Quiros-Ortega Zafar U.Khan Laboratory of Neurobiology Centro de Investigaciones Médico Sanitarias(CIMES)University of MalagaMalagaSpain Department of Medicine Faculty of MedicineUniversity of MalagaMalagaSpain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas(CIBERNED) Institute of Health Carlos IIIMadridSpain the donders institute for brain Cognition and Behaviour Radboud UniversityNijmegenThe Netherlands the brain Metastasis Group National Cancer Research Centre(CNIO)MadridSpain the Department of Neurobiology University of California-Los AngelesLos AngelesCAUSA

Memory deficit,which is often associated with aging and many psychiatric,neurological,and neurodegenerative diseases,has been a challenging issue for treatment.Up till now,all potential drug candidates have failed to produce satisfa ctory effects.Therefore,in the search for a solution,we found that a treatment with the gene corresponding to the RGS14414protein in visual area V2,a brain area connected with brain circuits of the ventral stream and the medial temporal lobe,which is crucial for object recognition memory(ORM),can induce enhancement of ORM.In this study,we demonstrated that the same treatment with RGS14414in visual area V2,which is relatively unaffected in neurodegenerative diseases such as Alzheimer s disease,produced longlasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer’s disease.Furthermore,we found that the prevention of memory deficits was mediated through the upregulation of neuronal arbo rization and spine density,as well as an increase in brain-derived neurotrophic factor(BDNF).A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer s disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits.These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer’s disease.Therefore,our findings of RGS14414gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.

关键词： behavioral performance brain-derived neurotrophic factor cognitive dysfunction episodic memory memory circuit activation memory deficits memory enhancement object recognition memory prevention of memory loss regulator of G protein signaling

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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 unclear.Here,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 disrupted.Immunohistochemistry 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 synapses.Impaired synaptic function was associated with a reduction in the frequency of quantal AMPA events,as well as developmental deficits in presynaptic vesicle size and density.Our 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

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