Critical mass: The rise of a touchscreen technology community for rodent cognitive testing

The rise in the number of users and institutions utilizing the rodent touchscreen technology for cognitive testing over the past decade has prompted the need for knowledge mobilization and community building. To address the needs of the growing touchscreen community, the first international touchscreen symposium was hosted at Western University. Attendees from around the world attended talks from expert neuroscientists using touchscreens to examine a vast array of questions regarding cognition and the nervous system. In addition to the symposium, a subset of attendees was invited to partake in a hands-on training course where they received touchscreen training covering both hardware and software components. Beyond the two touchscreen events, virtual platforms have been developed to further support touchscreen users: (a) Mousebytes.ca , which includes a data repository of rodent touchscreen tasks, and (b) Touchscreencognition.org , an online community with numerous training and community resources, perhaps most notably a forum where members can ask and answer questions. The advantages of the rodent touchscreen technology for cognitive neuroscience research has allowed neuroscientists from diverse backgrounds to test specific cognitive processes using well-validated and standardized apparatus, contributing to its rise in popularity and its relevance to modern neuroscience research. The commitment of the touchscreen community to data, task development and information sharing not only ensures an expansive future of the use of rodent touchscreen technology but additionally, quality research that will increase translation from preclinical studies to clinical successes.     

Translational cognitive neuroscience of dementia with touchscreen operant chambers

Translational cognitive neuroscience of dementia involves mainly two areas: the validation of newly developed dementia animal models and the preclinical assessment of novel drug candidates in such model animals. To validate new animal models, a multidomain panel (battery) approach is essential in that dementia is, by definition, not merely a memory disorder but rather a multidomain cognitive/behavior disorder: animal modeling with a certain type of dementia would develop cognitive impairments in multiple (two at minimum) domains in a specific order according to unique spreading patterns of its neuropathology. In new drug development, the availability of highly sensitive tools assessing animal cognition is crucial to the detection of cognitive decline at the earliest stage of the disease, which may be an optimal time point to test a drug candidate. Using interspecies translatable (analogous) cognitive tasks would also be necessary to successfully predict the efficacy of drug candidates in subsequent clinical trials. Currently, this translational prediction is seriously limited given discrepancies in behavioral assessment methods between animals and humans in the preclinical and clinical trials, respectively. Since neurodegenerative diseases are often accompanied by not only cognitive but also affective and movement disorders, simultaneous assessment of task-relevant locomotor behavior and motivation is also important to rule out the effects of potential confounders. The touchscreen operant platform may satisfy these needs by offering several advantages over conventional methodology. In this review, we discuss the touchscreen operant chamber system and highlight some of its qualities as a promising and desirable tool for translational research of dementia.     

遥感在生物多样性研究中的应用进展

随着人口的持续增长, 人类经济活动对自然资源的利用强度不断升级以及全球气候变暖, 全球物种正以前所未有的速度丧失, 生物多样性成为了全球关注的热点问题。传统生物多样性研究以地面调查方法为主, 重点关注物种或样地水平, 但无法满足景观尺度、区域尺度以及全球尺度的生物多样性保护和评估需求。遥感作为获取生物多样性信息的另一种手段, 近年来在生物多样性领域发展迅速, 其覆盖广、序列性以及可重复性等特点使之在大尺度生物多样性监测和制图以及评估方面具有极大优势。本文主要通过文献收集整理, 从观测手段、研究尺度、观测对象和生物多样性关注点等方面综述了遥感在生物多样性研究中的应用现状, 重点分析不同遥感平台的技术优势和局限性, 并探讨了未来遥感在生物多样性研究的应用趋势。遥感平台按观测高度可分为近地面遥感、航空遥感和卫星遥感, 能够获取样地-景观-区域-洲际-全球尺度的生物多样性信息。星载平台在生物多样性研究中应用最多, 航空遥感的应用研究偏少主要受飞行成本限制。近地面遥感作为一个新兴平台, 能够直接观测到物种的个体, 获取生物多样性关注的物种和种群信息, 是未来遥感在生物多样性应用中的发展方向。虽然遥感技术在生物多样性研究中的应用存在一定的局限性, 未来随着传感器发展和多源数据融合技术的完善, 遥感能更好地从多个尺度、全方位地服务于生物多样性保护和评估。     

Proteomics in aging research: A roadmap to clinical,translational research

The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational “omics” since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)‐based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O‐Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age‐associated across studies. Enrichment analysis of the 232 age‐associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin‐like growth factor (IGF) signaling, mitogen‐activated protein kinases (MAPK), hypoxia‐inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age‐relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy.     

Preclinical research in Rett syndrome: setting the foundation for translational success

In September of 2011, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and the Rett Syndrome Research Trust (RSRT) convened a workshop involving a broad cross-section of basic scientists, clinicians and representatives from the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the pharmaceutical industry and private foundations to assess the state of the art in animal studies of Rett syndrome (RTT). The aim of the workshop was to identify crucial knowledge gaps and to suggest scientific priorities and best practices for the use of animal models in preclinical evaluation of potential new RTT therapeutics. This review summarizes outcomes from the workshop and extensive follow-up discussions among participants, and includes: (1) a comprehensive summary of the physiological and behavioral phenotypes of RTT mouse models to date, and areas in which further phenotypic analyses are required to enhance the utility of these models for translational studies; (2) discussion of the impact of genetic differences among mouse models, and methodological differences among laboratories, on the expression and analysis, respectively, of phenotypic traits; and (3) definitions of the standards that the community of RTT researchers can implement for rigorous preclinical study design and transparent reporting to ensure that decisions to initiate costly clinical trials are grounded in reliable preclinical data.     

Modeling neurodevelopmental cognitive deficits in tasks with cross‐species translational validity

Numerous psychiatric disorders whose cognitive dysfunction links to functional outcome have neurodevelopmental origins including schizophrenia, autism and bipolar disorder. Treatments are needed for these cognitive deficits, which require development using animal models. Models of neurodevelopmental disorders are as varied and diverse as the disorders themselves, recreating some but not all aspects of the disorder. This variety may in part underlie why purported procognitive treatments translated from these models have failed to restore functioning in the targeted patient populations. Further complications arise from environmental factors used in these models that can contribute to numerous disorders, perhaps only impacting specific domains, while diagnostic boundaries define individual disorders, limiting translational efficacy. The Research Domain Criteria project seeks to ‘develop new ways to classify mental disorders based on behavioral dimensions and neurobiological measures’ in hopes of facilitating translational research by remaining agnostic toward diagnostic borders derived from clinical presentation in humans. Models could therefore recreate biosignatures of cognitive dysfunction irrespective of disease state. This review highlights work within the field of neurodevelopmental models of psychiatric disorders tested in cross‐species translational cognitive paradigms that directly inform this newly developing research strategy. By expounding on this approach, the hopes are that a fuller understanding of each model may be attainable in terms of the cognitive profile elicited by each manipulation. Hence, conclusions may begin to be drawn on the nature of cognitive neuropathology on neurodevelopmental and other disorders, increasing the chances of procognitive treatment development for individuals affected in specific cognitive domains.     

FDG-PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer's disease

The lack of reliable translational procedures applicable to both patients and experimental models are a major obstacle for the advancement of basic research as well as for the development of therapeutics. This is particularly relevant to neurodegenerative disorders such as AD (Alzheimer's disease), where the predictive validity of animal models and procedures applied preclinically have met with little success. Two approaches available for human diagnostics are currently experiencing major advancements in preclinical research: in vivo imaging using MRI (magnetic resonance imaging) or PET (positron-emission tomography) and recordings of brain electrical activity via surface EEG (electroencephalogram). The present paper reviews the results obtained so far in rodent AD models, and summarizes advantages and disadvantages of such procedures.     

Touchscreen learning deficits in Ube3a,Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Mutant mouse models of neurodevelopmental disorders with intellectual disabilities provide useful translational research tools, especially in cases where robust cognitive deficits are reproducibly detected. However, motor, sensory and/or health issues consequent to the mutation may introduce artifacts that preclude testing in some standard cognitive assays. Touchscreen learning and memory tasks in small operant chambers have the potential to circumvent these confounds. Here we use touchscreen visual discrimination learning to evaluate performance in the maternally derived Ube3a mouse model of Angelman syndrome, the Ts65Dn trisomy mouse model of Down syndrome, and the Mecp2^Bird mouse model of Rett syndrome. Significant deficits in acquisition of a 2‐choice visual discrimination task were detected in both Ube3a and Ts65Dn mice. Procedural control measures showed no genotype differences during pretraining phases or during acquisition. Mecp2 males did not survive long enough for touchscreen training, consistent with previous reports. Most Mecp2 females failed on pretraining criteria. Significant impairments on Morris water maze spatial learning were detected in both Ube3a and Ts65Dn, replicating previous findings. Abnormalities on rotarod in Ube3a, and on open field in Ts65Dn, replicating previous findings, may have contributed to the observed acquisition deficits and swim speed abnormalities during water maze performance. In contrast, these motor phenotypes do not appear to have affected touchscreen procedural abilities during pretraining or visual discrimination training. Our findings of slower touchscreen learning in 2 mouse models of neurodevelopmental disorders with intellectual disabilities indicate that operant tasks offer promising outcome measures for the preclinical discovery of effective pharmacological therapeutics.     

Ethical hurdles for translational research

The notion of translational research has gained considerable currency over the past few years. While such an approach promises great scientific and clinical advances, the penumbra of translational research tends to incorporate prioritizing scientific projects based upon their potential for translation; tight financial connections between sponsors, scientists and clinical investigators; and sometimes research involving biological approaches for which there is little experience determining safety. It is these aspects of translational research that raise some serious ethical challenges. In this report, we examine three specific areas that raise ethical questions: (1) the potential implications of prioritizing research objectives based on the potential for translation; (2) cautions related to moving from bench to bedside (and back again); and (3) unique questions for translational research initiatives in academic medical centers. Based on this examination, it is clear that the financial and ethical costs as well as benefits of taking a translational approach need to be considered. In the meantime, exquisite attention needs to be paid whenever translational research is likely to affect the traditional fiduciary responsibilities of scientists, clinicians and institutions to research subjects, patients and students. Successful mechanisms that might be developed to address any untoward effects should be shared and evaluated.     

The FaceBase Consortium: a comprehensive program to facilitate craniofacial research

The FaceBase Consortium consists of ten interlinked research and technology projects whose goal is to generate craniofacial research data and technology for use by the research community through a central data management and integrated bioinformatics hub. Funded by the National Institute of Dental and Craniofacial Research (NIDCR) and currently focused on studying the development of the middle region of the face, the Consortium will produce comprehensive datasets of global gene expression patterns, regulatory elements and sequencing; will generate anatomical and molecular atlases; will provide human normative facial data and other phenotypes; conduct follow up studies of a completed genome-wide association study; generate independent data on the genetics of craniofacial development, build repositories of animal models and of human samples and data for community access and analysis; and will develop software tools and animal models for analyzing and functionally testing and integrating these data. The FaceBase website (http://www.facebase.org) will serve as a web home for these efforts, providing interactive tools for exploring these datasets, together with discussion forums and other services to support and foster collaboration within the craniofacial research community.     

Curiosity and cure: translational research strategies for neural repair-mediated rehabilitation

Clinicians who seek interventions for neural repair in patients with paralysis and other impairments may extrapolate the results of cell culture and rodent experiments into the framework of a preclinical study. These experiments, however, must be interpreted within the context of the model and the highly constrained hypothesis and manipulation being tested. Rodent models of repair for stroke and spinal cord injury offer examples of potential pitfalls in the interpretation of results from developmental gene activation, transgenic mice, endogeneous neurogenesis, cellular transplantation, axon regeneration and remyelination, dendritic proliferation, activity-dependent adaptations, skills learning, and behavioral testing. Preclinical experiments that inform the design of human trials ideally include a lesion of etiology, volume and location that reflects the human disease; examine changes induced by injury and by repair procedures both near and remote from the lesion; distinguish between reactive molecular and histologic changes versus changes critical to repair cascades; employ explicit training paradigms for the reacquisition of testable skills; correlate morphologic and physiologic measures of repair with behavioral measures of task reacquisition; reproduce key results in more than one laboratory, in different strains or species of rodent, and in a larger mammal; and generalize the results across several disease models, such as axonal regeneration in a stroke and spinal cord injury platform. Collaborations between basic and clinical scientists in the development of translational animal models of injury and repair can propel experiments for ethical bench-to-bedside therapies to augment the rehabilitation of disabled patients.     

Myocardial infarction and intramyocardial injection models in swine

Sustainable and reproducible large animal models that closely replicate the clinical sequelae of myocardial infarction (MI) are important for the translation of basic science research into bedside medicine. Swine are well accepted by the scientific community for cardiovascular research, and they represent an established animal model for preclinical trials for US Food and Drug Administration (FDA) approval of novel therapies. Here we present a protocol for using porcine models of MI created with a closed-chest coronary artery occlusion-reperfusion technique. This creates a model of MI encompassing the anteroapical, lateral and septal walls of the left ventricle. This model infarction can be easily adapted to suit individual study design and enables the investigation of a variety of possible interventions. This model is therefore a useful tool for translational research into the pathophysiology of ventricular remodeling and is an ideal testing platform for novel biological approaches targeting regenerative medicine. This model can be created in approximately 8-10 h.     

Comparison between touchscreen operant chambers and water maze to detect early prefrontal dysfunction in mice

The relative lack of sensitive and clinically valid tests of rodent behavior might be one of the reasons for the limited success of the clinical translation of preclinical Alzheimer's disease (AD) research findings. There is a general interest in innovative behavioral methodology, and protocols have been proposed for touchscreen operant chambers that might be superior to existing cognitive assessment methods. We assessed and analyzed touchscreen performance in several novel ways to examine the possible occurrence of early signs of prefrontal (PFC) functional decline in the APP/PS1 mouse model of AD. Touchscreen learning performance was compared between APP/PS1-21 mice and wildtype littermates on a C57BL/6J background at 3, 6 and 12 months of age in parallel to the assessment of spatial learning, memory and cognitive flexibility in the Morris water maze (MWM). We found that older mice generally needed more training sessions to complete the touchscreen protocol than younger ones. Older mice also displayed defects in MWM working memory performance, but touchscreen protocols detected functional changes beginning at 3 months of age. Histological changes in PFC of APP/PS1 mice indeed occurred as early as 3 months. Our results suggest that touchscreen operant protocols are more sensitive to PFC dysfunction, which is of relevance to the use of these tasks and devices in preclinical AD research and experimental pharmacology.     

Humanized mice in translational biomedical research

The culmination of decades of research on humanized mice is leading to advances in our understanding of human haematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer biology and regenerative medicine. In this Review, we discuss the development of these new generations of humanized mice, how they will facilitate translational research in several biomedical disciplines and approaches to overcome the remaining limitations of these models.     

The BTBR Mouse Model of Autism Spectrum Disorders Has Learning and Attentional Impairments and Alterations in Acetylcholine and Kynurenic Acid in Prefrontal Cortex

Autism is a complex spectrum of disorders characterized by core behavioral deficits in social interaction, communication, repetitive stereotyped behaviors and restricted interests. Autism frequently presents with additional cognitive symptoms, including attentional deficits and intellectual disability. Preclinical models are important tools for studying the behavioral domains and biological underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J (BTBR) mouse strain has been used as an animal model of core behavioral deficits in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and communication, but other aspects of their cognitive phenotype, including attentional performance, are not well characterized. We examined the attentional abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the human continuous performance task of attention, and so both the task and apparatus have translational relevance to human touchscreen cognitive testing. We also measured basal extracellular levels of a panel of neurotransmitters within the medial prefrontal cortex, a brain region critically important for performing the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an inability to withhold responding, and decreased motivation, as compared to C57Bl/6J mice. Both of these features characterize attentional deficit disorders in humans. BTBR mice also display decreased accuracy in detecting short stimuli, lower basal levels of extracellular acetylcholine and higher levels of kynurenic acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal cortex is required for accurate performance of the 5-CSRTT, consequently this cholinergic deficit may underlie less accurate performance in BTBR mice. Based on our findings that BTBR mice have attentional impairments and alterations in a key neural substrate of attention, we propose that they may be valuable for studying mechanisms for treatment of cognitive dysfunction in individuals with attention deficits and autism.     

CRISPR/Cas9-mediated genome editing: From basic research to translational medicine

The recent development of the CRISPR/Cas9 system as an efficient and accessible programmable genome-editing tool has revolutionized basic science research. CRISPR/Cas9 system-based technologies have armed researchers with new powerful tools to unveil the impact of genetics on disease development by enabling the creation of precise cellular and animal models of human diseases. The therapeutic potential of these technologies is tremendous, particularly in gene therapy, in which a patient-specific mutation is genetically corrected in order to treat human diseases that are untreatable with conventional therapies. However, the translation of CRISPR/Cas9 into the clinics will be challenging, since we still need to improve the efficiency, specificity and delivery of this technology. In this review, we focus on several in vitro, in vivo and ex vivo applications of the CRISPR/Cas9 system in human disease-focused research, explore the potential of this technology in translational medicine and discuss some of the major challenges for its future use in patients.     

SysFinder:A customized platform for search,comparison and assisted design of appropriate animal models based on systematic similarity

Animal models are increasingly gaining values by cross-comparisons of response or resistance to clinical agents used for patients.However,many disease mechanisms and drug effects generated from animal models are not transferable to human.To address these issues,we developed SysFinder(http://lifecenter.sgst.cn/SysFinder),a platform for scientists to find appropriate animal models for translational research.SysFinder offers a "topic-centered" approach for systematic comparisons of human genes,whose functions are involved in a specific scientific topic,to the corresponding homologous genes of animal models.Scientific topic can be a certain disease,drug,gene function or biological pathway.SysFinder calculates multi-level similarity indexes to evaluate the similarities between human and animal models in specified scientific topics.Meanwhile,SysFinder offers species-specific information to investigate the differences in molecular mechanisms between humans and animal models.Furthermore,SysFinder provides a userfriendly platform for determination of short guide RNAs(sgRNAs) and homology arms to design a new animal model.Case studies illustrate the ability of SysFinder in helping experimental scientists.SysFinder is a useful platform for experimental scientists to carry out their research in the human molecular mechanisms.     

Ethical issues in translational research

The translation of biomedical research knowledge to effective clinical treatment is essential to the public good and is a main focus of current health policy. However, recent health policy initiatives intended to foster the translation of basic science into clinical and public health advances must also consider the unique bioethical issues raised by the increased focus on translational research. Safety of study participants and balancing of risk due to treatment with the potential benefits of the research is tantamount. This article synthesizes theory from clinical ethics, operational design, and philosophy to provide a bioethical framework for the health policy of translational research.     

Proteomics in Parkinson’s disease: current trends,translational snags and future possibilities

Proteomic technologies are widely used to understand the molecular mechanism of Parkinson’s disease (PD) and to develop biomarkers for its early diagnosis. The differential expression patterns of brain, cerebrospinal fluid and blood proteins of patients or chemically induced animal models are used to identify protein fingerprints for developing diagnostic and therapeutic strategies for PD. A number of differentially expressed proteins associated with energy metabolism, oxidative stress, signal transduction, electron transport and detoxification pathways are identified using proteomic strategies. Proteomics immensely contributed to the detection of qualitative and quantitative changes of expressed proteins and their post-translational modifications. An update on proteomics-driven research for developing early biomarkers and understanding the molecular aspects of PD, along with their translational snags, challenges and future possibilities, are discussed in this review.     

转化医学研究中生命伦理学辩护的现况分析与前瞻思考

转化医学作为一门新兴学科,运用多学科交叉策略来推动医学发展,从临床实践中发现问题,将其凝练成科学问题进行基础医学研究,再将研究成果应用到疾病诊断、治疗和预防过程中,使其真正发挥作用,是一个从基础医学到临床应用的双向进程。转化医学已逐步融入各个学科,并在干细胞研究、生物标志物、细胞信号转导、药物及器具研发及个体化医学等各个领域发挥重要作用。随着转化医学研究深入,一些临床试验势必对人体存在一定伤害和潜在危险,存在各种伦理问题。虽说科学研究与伦理道德是一对相互冲击的矛盾,但两者在总体上又是一致的,共同决定着社会前进步伐。科研的重大进步必然会对伦理道德提出更高要求,而伦理道德的高标准又规范、引导、促进科学研究朝着正确方向迈进,两者相辅相成。鉴于伦理辩护对于转化医学研究强有力的支撑,建议在转化医学研究中能进一步完善伦理监管体系,发挥机构伦理委员会的功效,持续加大伦理培训的力度,强化研究人员的伦理道德修养,从而为转化医学的发展夯实人文基础。