单细胞转录组测序在药物成瘾研究中的应用

药物成瘾是复杂的中枢神经系统疾病，相关基础与临床研究均证实药物成瘾的神经机制及神经环路在成瘾行为形成的不同阶段逐渐发生改变。利用全基因组关联研究、全基因组测序、全外显子测序或高通量转录组测序等技术的组学研究对包括药物成瘾在内的精神疾病遗传的脆弱性进行了深入研究。上述单核苷酸多态性检测技术或测序技术主要预测疾病的遗传风险位点。然而，许多中枢神经系统疾病的发生与环境因素密切相关，而且在疾病发展的不同阶段，相关基因的表达存在脑区特异性的细胞异质性信息。因此，传统研究对发病机制的解释存在一定的局限性。单细胞转录组测序技术是针对单个细胞进行转录水平的测定，规避了传统测序对细胞群体平均转录水平检测的缺点，可以定量描述细胞异质性。近年来，单细胞转录测序技术在神经精神科学研究中的应用逐渐受到关注，本文总结了该技术在神经科学研究中的重要应用，并以药物成瘾为例，重点阐述说明其在中枢神经系统疾病中的应用价值。     

Comparative psychology and the grand challenge of drug discovery in psychiatry and neurodegeneration

Drug discovery for brain disorders is undergoing a period of upheaval. Faced with an empty drug pipeline and numerous failures of potential new drugs in clinical trials, many large pharmaceutical companies have been shrinking or even closing down their research divisions that focus on central nervous system (CNS) disorders. In this paper, we argue that many of the difficulties facing CNS drug discovery stem from a lack of robustness in pre-clinical (i.e., non-human animal) testing. There are two main sources for this lack of robustness. First, there is the lack of replicability of many results from the pre-clinical stage, which we argue is driven by a combination of publication bias and inappropriate selection of statistical and experimental designs. Second, there is the frequent failure to translate results in non-human animals to parallel results in humans in the clinic. This limitation can only be overcome by developing new behavioral tests for non-human animals that have predictive, construct, and etiological validity. Here, we present these translational difficulties as a “grand challenge” to researchers from comparative cognition, who are well positioned to provide new methods for testing behavior and cognition in non-human animals. These new experimental protocols will need to be both statistically robust and target behavioral and cognitive processes that allow for better connection with human CNS disorders. Our hope is that this downturn in industrial research may represent an opportunity to develop new protocols that will re-kindle the search for more effective and safer drugs for CNS disorders.     

斑马鱼行为学实验在神经科学中的应用

斑马鱼作为新型模式动物的优势正在逐渐被人们所认识,其应用的领域也越来越宽广．斑马鱼在神经生物学中的应用,除了在发育方面比其他模式动物更具优势外,在行为学方面的应用也更加丰富．由于斑马鱼幼体在受精后前两天通体透明,眼睛大小占到大脑体积的二分之一以上,成鱼昼夜节律明显,对光反应强烈,因此斑马鱼在视觉领域应用的优势十分明显．斑马鱼的嗅觉、听觉器官都在体表可见,可以很容易地用行为学实验手段对嗅觉和听觉功能进行检测．斑马鱼习性好动,利用斑马鱼进行运动方面的行为学观察也非常便利．斑马鱼具有群聚习性,在社会生物学研究方面正得到越来越多的关注．斑马鱼行为学是一种比较简单而又有效地分析神经整合功能的方法,并形成了许多相关的实验模型．     

社会认知神经科学的取向与研究进展

社会认知神经科学是社会心理学和认知神经科学相结合的新兴多学科研究领域,其强调在社会、认知与脑神经等三个层面的交互作用上去理解心理现象。前几年主要是对刻板印象、态度与态度改变、他人知觉、自我认知以及情绪与认知交互作用等方面进行了深入研究,其主要范式是应用认知神经科学的方法来验证社会心理学在这些范围内上的各种不同的理论观点,当前的研究主要集中在知觉和再认的社会标记、社会判断和归因、评价调节知觉和经验以及社会交互作用等传统的社会心理学方面,并取得了突破性进展。展望未来的研究,其将在系统准则研究发展的基础上,把当今的社会认知研究与认知神经科学在理论和方法论上整合起来,为揭示人类高级社会心理现象的神经基础,开辟一条崭新的研究道路。     

Nogo在中枢神经损伤再生中的作用机制

Nogo是中枢神经系统（CNS）少突胶质细胞分泌的一种髓磷脂蛋白,它的主要功能是抑制损伤后轴突的再生,它含有两个完全独立的具有抑制活性的结构域：位于细胞内的amino—Nogo和位于细胞表面的Nogo-66。Nogo-66是通过与受体复合体NgR／p75／Lingo—1结合,触发Rho信号通路来发挥作用。Nogo及其信号转导机制日益成为CNS损伤再生的研究热点,就Nogo在CNS损伤再生中的作用机制作一综述。     

Interactive Social Neuroscience to Study Autism Spectrum Disorder

Individuals with autism spectrum disorder (ASD) demonstrate difficulty with social interactions and relationships, but the neural mechanisms underlying these difficulties remain largely unknown. While social difficulties in ASD are most apparent in the context of interactions with other people, most neuroscience research investigating ASD have provided limited insight into the complex dynamics of these interactions. The development of novel, innovative “interactive social neuroscience” methods to study the brain in contexts with two interacting humans is a necessary advance for ASD research. Studies applying an interactive neuroscience approach to study two brains engaging with one another have revealed significant differences in neural processes during interaction compared to observation in brain regions that are implicated in the neuropathology of ASD. Interactive social neuroscience methods are crucial in clarifying the mechanisms underlying the social and communication deficits that characterize ASD.     

Immunosuppressant FK506: Focusing on neuroprotective effects following brain and spinal cord injury

The secondary damage that follows central nervous system (CNS) injury is a target for neuroprotective agents aimed at tissue and function sparing. FK506, a clinically used immunosuppressant, acts neuroprotectively in rat models of brain and spinal cord injury and ischemia. Evidence of in vivo experimental studies highlights the neuroprotective role of FK506 by its direct impact on various cell populations within the CNS. The participation of FK506 in modulation of post-traumatic inflammatory processes is a further potential aspect involved in CNS neuroprotection. In this review we provide an overview of the current laboratory research focusing on the multiple effects of FK506 on neuroprotection following CNS injury.     

Gravity sensing in the central nervous system

For human based space research it is of high importance to understand the influence of gravity on the properties of the central nervous system (CNS). Untill now it is not much known about how neuronal tissue can sense gravity. The aim of this study was to find out weather and how the CNS, as a complex system, can percept and react to changes in gravity. Neuronal tissue and especially the CNS fulfils all the requirements for excitable media. Consequently, self-organisation, pattern formation and propagating excitation waves as typical events of excitable media have been observed in such tissue. The Spreading Depression (SD), an excitation depression wave is the most obvious and best described of these phenomena in the CNS. In our experiments we showed that the properties of the SD and therefore the CNS in its properties as an excitable medium reacts very sensitive to changes in gravity.     

宏基因组测序在中枢神经系统感染性疾病诊断中的应用及研究进展

中枢神经系统(central nervous system,CNS)感染是指由病毒、细菌或真菌等侵染中枢神经系统引起的急性或慢性炎症性(或非炎症性)疾病,致死率高,易引发严重后遗症。由于检测通量及灵敏度的限制,一半以上的中枢神经系统感染患者无法通过常规检测方法确定病原体。宏基因组测序是一种新兴的病原检测技术,能够极大地提升病原检出率。当前部分临床医生及相关从业人员对宏基因组测序的认识存在不足,限制了其在临床诊疗中的快速推广和应用。本文系统介绍了宏基因组测序整体流程,综述了该技术在中枢神经系统感染性疾病诊疗中的发展历程和最新研究进展,希望为中枢神经系统感染性疾病的诊断和治疗提供参考。     

空间转录物组学技术进展及其在神经科学领域中的应用

空间转录物组学是在单细胞RNA测序技术基础上实现细胞空间位置信息测定的组学技术。该技术克服了单细胞转录物组学在单细胞分离建库过程中丢失细胞在组织中空间信息的问题,可同时提供研究对象的转录物组数据信息和在组织中的空间位置信息。空间转录物组学技术对研究细胞谱系的发生过程、细胞间的调控机制和相互作用等具有重要作用,是组学技术研究的重要发展方向和热点。近年来,空间转录物组学技术发展迅速,新的检测方法不断产生,检测灵敏度、分辨率和检测通量等技术指标不断提升。本文根据获取空间信息的原理不同,将较为常用的空间转录物组学技术进行了分类,总结了各类方法的检测原理、代表性技术手段及其相应的技术指标。随后,从脑细胞类型区分与细胞层图谱构建、神经系统相关疾病特征分析与标志物研究两个方面举例论述了空间转录物组学技术在神经科学中的应用。最后,对空间转录物组学技术目前存在的问题进行了总结,并对其未来的发展方向进行了展望。     

中枢神经再生抑制因子及免疫治疗研究

成体哺乳动物中枢神经损伤后早期轴突再生失败的一个主要原因是由于髓磷脂抑制分子的存在。Nogo、髓磷脂相关糖蛋白以及少突胶质细胞髓磷脂糖蛋白等神经再生抑制因子的发现,大大促进了中枢神经再生分子机制的研究。它们均能独立通过Nogo-66受体产生对轴突再生的抑制效应,髓磷脂抑制分子及其信号转导机制的研究日益成为中枢神经再生的研究热点,髓磷脂及其信号转导分子特别是Nogo-66受体、p75神经营养素受体成为损伤后促进轴突再生、抑制生长锥塌陷的主要治疗靶点。抑制上述抑制因子及相关受体NgR或p75NTR可能有助于中枢神经损伤的修复,围绕这些抑制因子及其相关受体介导的信号转导途径,人们提出了多种治疗中枢神经损伤的新思路,其中免疫学方法尤其受到关注。     

Intranasal administration: a potential solution for cross-BBB delivering neurotrophic factors

Neurotrophic factors (NTFs) are endogenous polypeptides that regulate the growth, survival, differentiation, and functioning of neurons. The neuroprotective effects of NTFs in experimental animals give strong rationale for developing therapies for neurological disorders. However, when NTFs are applied in clinical trials, great expectation leads to equal disappointment. NTFs are large molecular-weighted and hydrophilic proteins, which limits their access to the central nervous system (CNS) after systemic administration, principally due to poor blood-brain barrier (BBB) permeability and unfavorable pharmacokinetic profiles. Although intracerebral infusion may transport NTFs into the CNS, the invasiveness limits its clinical application. Intranasal administration has been under research for decades and presents promising outcomes in preclinical studies for brain delivering of NTFs. After intranasal delivery, NTFs gain direct and quick access into the CNS at concentrations high enough to elicit their biological effects, bypassing the BBB and minimizing systemic exposure. Due to its invasiveness and convenience, intranasal delivery is feasible for NTFs administration. Although direct evidence of nose-to-brain pathway in human is lacking due to ethical problems, the existence of the nose-to-cerebral spinal fluid pathway has been verified in men. Furthermore, there is abundant indirect evidence for the nose-to-brain pathway as determined by the efficacy of intranasally administered neuroproteins, such as insulin, oxytocin, and vasopressin in clinical trials. Based on the solid preclinical research supporting the efficacy of intranasal NTFs, and the successful clinical application of neuroproteins (not NTFs), it is time to evaluate clinical application of NTFs in treating both acute and chronic CNS diseases.     

Neural stem cells and neurospheres--re-evaluating the relationship

For most of the past century, the prospect of replacing lost or damaged cells in the central nervous system (CNS) was hampered by the opinion that the adult mammalian CNS was incapable of generating new nerve cells. This belief, like most dogmas, was essentially founded on a lack of experimental evidence to the contrary. The overturning of this 'no new neuron' hypothesis began midway through the twentieth century with a series of reports documenting neurogenesis in the postnatal and adult brain, continued with the isolation and in vitro culture of neurogenic cells from the adult mammalian brain, and culminated in the discovery of a population of multipotent, self-renewing cells in the adult CNS (that is, bona fide neural stem cells). Although a variety of techniques were initially used, the neurosphere assay (NSA) rapidly emerged as the assay of choice and has since become a valuable tool for isolating, and understanding the biology of, embryonic and adult CNS stem cells. Like all technologies, it is not without its limitations. In this article we will highlight several shortcomings of the assay related to its application and interpretation that we believe have led to a significant body of research whose conclusions may well be misleading.     

The Role of PML in the Nervous System

The promyeloctic leukemia protein PML is a tumor suppressor that was originally identified due to its involvement in the (15;17) translocation of acute promyelocytic leukemia. While the majority of early research has focused upon the role of PML in the pathogenesis of leukemia, more recent evidence has identified important roles for PML in tissues outside the hemopoietic system, including the central nervous system (CNS). Here, we review recent literature on the role of PML in the CNS, with particular focus on the processes of neurodevelopment and neurodegeneration, and propose new lines of investigation.     

AutoMate: Enabling Autonomic Applications on the Grid

The increasing complexity, heterogeneity, and dynamism of emerging pervasive Grid environments and applications has necessitated the development of autonomic self-managing solutions, that are inspired by biological systems and deal with similar challenges of complexity, heterogeneity, and uncertainty. This paper introduces Project AutoMate and describes its key components. The overall goal of Project Automate is to investigate conceptual models and implementation architectures that can enable the development and execution of such self-managing Grid applications. Illustrative autonomic scientific and engineering Grid applications enabled by AutoMate are presented. The research presented in this paper is supported in part by the National Science Foundation via grants numbers ACI 9984357, EIA 0103674, EIA 0120934, ANI 0335244, CNS 0305495, CNS 0426354 and IIS 0430826. The authors would like to acknowledge the contributions of M. Agarwal, V. Bhat and N. Jiang to this research.     

Identification of distinct and age‐dependent p16High microglia subtypes

Cells expressing high levels of the cyclin‐dependent kinase (CDK)4/6 inhibitor p16 (p16^High) accumulate in aging tissues and promote multiple age‐related pathologies, including neurodegeneration. Here, we show that the number of p16^High cells is significantly increased in the central nervous system (CNS) of 2‐year‐old mice. Bulk RNAseq indicated that genes expressed by p16^High cells were associated with inflammation and phagocytosis. Single‐cell RNAseq of brain cells indicated p16^High cells were primarily microglia, and their accumulation was confirmed in brains of aged humans. Interestingly, we identified two distinct subpopulations of p16^High microglia in the mouse brain, with one being age‐associated and one present in young animals. Both p16^High clusters significantly differed from previously described disease‐associated microglia and expressed only a partial senescence signature. Taken together, our study provides evidence for the existence of two p16‐expressing microglia populations, one accumulating with age and another already present in youth that could positively and negatively contribute to brain homeostasis, function, and disease.     

The Impact of Neuroscience on Music Education Advocacy and Philosophy

This content analysis examines how philosophy and advocacy articles published between 2005 and 2010 were influenced by current neuroscience research. The contents of twelve journals were explored, resulting in the inclusion of forty-five articles in this analysis. Recently, there has been a growing interest in neuroscientific research on music. Articles were coded for latent content and emerging themes to determine if this interest has begun to be expressed in philosophy and advocacy writings. The educational implications and issues of using neuroscientific findings are addressed, and recommendations are offered for using future research for advocacy purposes.     

情绪的脑机制研究在社会认知神经科学中的进展

社会认知神经科学是近几年国外新兴起的交叉学科,旨在阐述社会性、情绪性的体验与行为的心理和神经基础。它综合了认知神经科学与社会心理学研究的长处,对刻板印象、态度与态度改变、他人知觉、自我认知以及情绪与认知交互作用等方面进行了深入研究。主要范式是应用认知神经科学的方法来验证社会心理学在这些范畴上的各种不同理论观点,并在某些方面取得了突破性进展,但仍存在着广泛的发展空间。随着当前各种脑成像技术的革新,人们对情绪状态下大脑的神经活动的了解在原来认知的层面上有了进一步提升。本文主要阐述社会认知神经科学在情绪的脑机制研究上所取得的进展。     

SPECT neuroimaging in translational research of CNS disorders

High resolution SPECT imaging is an emerging field and there are only limited studies as yet available in this direction. Still there is continuous effort to achieve better spatial and temporal resolution in order to obtain detailed structural and functional information of different brain regions in small experimental animals. Recently, SPECT imaging system has been used to perform in vivo imaging using specific radioligands to further elucidate the role of dopaminergic, serotonergic, and cholinergic neurotransmission in relation to regional cerebral blood flow in various human CNS disorders and in gene-manipulated mouse models of neurodegeneration. Although in vivo and non-invasive translational research can be performed by high-resolution microPET imaging system, its limited spatial resolution restricts detailed anatomical and functional information of different brain regions involved in disease process. Recently developed NanoSPECT/CT imaging system has a better spatial resolution hence can be used to correlate and confirm microPET imaging data and determine the precise structural and functional anatomy of CNS disorders and their remission. Moreover SPECT imaging system reduces the cost and number of animals and provides detailed information of CNS disorders at the cellular, molecular and genetic level. Furthermore, SPECT system is economical, provides less radiation burden, and can be used to study bio-distribution of newly synthesized radioligands with increased target to non-target ratios, quality control, and clinical applications. It is envisaged that high-resolution SPECT imaging system will further improve in vivo non-invasive translational research on CNS disorders of unknown etiopathogenesis and their treatment in future.     

Mutations in NPHS1 in a Chinese child with congenital nephrotic syndrome

Since the identification of the NPHS1 gene, which encodes nephrin, various investigators have demonstrated that the NPHS1 mutation is a frequent cause of congenital nephrotic syndrome (CNS); it is found in 98% of Finnish children with this syndrome and in 39-80% of non-Finnish cases. In China, compound heterozygous mutations in the NPHS1 gene have been identified in two Chinese families with CNS. To our knowledge, however, whether or not NPHS1 is the causative gene in sporadic Chinese CNS cases has not been established. We identified a homozygous mutation of NPHS1, 3250insG (V1084fsX1095), in a Chinese child with sporadic CNS. This finding leads us to suggest that NPHS1 mutations are also present in sporadic Chinese CNS cases. This gives additional support for the necessity for genetic examination of mutations in the NPHS1 gene in Chinese children with sporadic CNS.