Use of non-mammalian alternative models for neurotoxicological study

The field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals, and resource limitations and ethical concerns associated with testing using traditional mammalian species. National and international government agencies have defined a need to reduce, refine or replace mammalian species in toxicological testing with alternative testing methods and non-mammalian models. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expense and using fewer mammals. Recent advances in genetic technologies and the strong conservation between human and non-mammalian genomes allow for the dissection of the molecular pathways involved in neurotoxicological responses and neurological diseases using genetically tractable organisms. In this review, applications of four non-mammalian species, zebrafish, cockroach, Drosophila, and Caenorhabditis elegans, in the investigation of neurotoxicology and neurological diseases are presented.     

基于CiteSpace的创伤性脑损伤研究文献计量学分析

目的通过对创伤性脑损伤（TBI）研究文献进行计量学分析,探索TBI领域的研究热点和研究趋势。 方法基于Web of Science核心数据库检索2016~2020年TBI研究的相关文献,通过CiteSpace.5.8.R3对发表文章年度分布、作者、机构、国家、期刊、被引情况和关键词等进行分析,并根据关键词的词频、中心性和聚类情况探讨TBI领域的研究热点和趋势。 结果（1）筛选后共纳入14 991篇文献,美国是发文量最多的国家,哈佛大学医学院是发文量最多的机构。（2）氧化应激、死亡率、儿童TBI、创伤后应激障碍、康复治疗是近5年TBI领域研究热点。（3）TBI的模型及损伤效应-生物学机制-诊断及治疗指南-个体治疗是TBI研究领域的研究趋势。 结论青少年人群TBI的损伤效应、分子机制、治疗方法的可靠性及有效性是TBI领域现在和未来研究的重点和方向。     

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Still it remains unclear what aspect of TBI pathology is targeted by DA therapies and what time-course of treatment is most beneficial for patient outcomes. Fortunately, ongoing research in animal models has begun to elucidate the pathophysiology of DA alterations after TBI. The purpose of this review is to discuss clinical and experimental research examining DAergic therapies after TBI, which will in turn elucidate the importance of DA for cognitive function/dysfunction after TBI as well as highlight the areas that require further study.     

Animal models of head trauma

Animal models of traumatic brain injury (TBI) are used to elucidate primary and secondary sequelae underlying human head injury in an effort to identify potential neuroprotective therapies for developing and adult brains. The choice of experimental model depends upon both the research goal and underlying objectives. The intrinsic ability to study injury-induced changes in behavior, physiology, metabolism, the blood/tissue interface, the blood brain barrier, and/or inflammatory- and immune-mediated responses, makes in vivo TBI models essential for neurotrauma research. Whereas human TBI is a highly complex multifactorial disorder, animal trauma models tend to replicate only single factors involved in the pathobiology of head injury using genetically well-defined inbred animals of a single sex. Although such an experimental approach is helpful to delineate key injury mechanisms, the simplicity and hence inability of animal models to reflect the complexity of clinical head injury may underlie the discrepancy between preclinical and clinical trials of neuroprotective therapeutics. Thus, a search continues for new animal models, which would more closely mimic the highly heterogeneous nature of human TBI, and address key factors in treatment optimization.     

The neurophysiology of brain injury.

OBJECTIVE: This article reviews the mechanisms and pathophysiology of traumatic brain injury (TBI). METHODS: Research on the pathophysiology of diffuse and focal TBI is reviewed with an emphasis on damage that occurs at the cellular level. The mechanisms of injury are discussed in detail including the factors and time course associated with mild to severe diffuse injury as well as the pathophysiology of focal injuries. Examples of electrophysiologic procedures consistent with recent theory and research evidence are presented. RESULTS: Acceleration/deceleration (A/D) forces rarely cause shearing of nervous tissue, but instead, initiate a pathophysiologic process with a well defined temporal progression. The injury foci are considered to be diffuse trauma to white matter with damage occurring at the superficial layers of the brain, and extending inward as A/D forces increase. Focal injuries result in primary injuries to neurons and the surrounding cerebrovasculature, with secondary damage occurring due to ischemia and a cytotoxic cascade. A subset of electrophysiologic procedures consistent with current TBI research is briefly reviewed. CONCLUSIONS: The pathophysiology of TBI occurs over time, in a pattern consistent with the physics of injury. The development of electrophysiologic procedures designed to detect specific patterns of change related to TBI may be of most use to the neurophysiologist. SIGNIFICANCE: This article provides an up-to-date review of the mechanisms and pathophysiology of TBI and attempts to address misconceptions in the existing literature.     

The potential for animal models to provide insight into mild traumatic brain injury: Translational challenges and strategies

Mild traumatic brain injury (mTBI) is a common health problem. There is tremendous variability and heterogeneity in human mTBI, including mechanisms of injury, biomechanical forces, injury severity, spatial and temporal pathophysiology, genetic factors, pre-injury vulnerability and resilience factors, and clinical outcomes. Animal models greatly reduce this variability and heterogeneity, and provide a means to study mTBI in a rigorous, controlled, and efficient manner. Rodent models, in particular, are time- and cost-efficient, and they allow researchers to measure morphological, cellular, molecular, and behavioral variables in a single study. However, inter-species differences in anatomy, morphology, metabolism, neurobiology, and lifespan create translational challenges. Although the term “mild” TBI is used often in the pre-clinical literature, clearly defined criteria for mild, moderate, and severe TBI in animal models have not been agreed upon. In this review, we introduce current issues facing the mTBI field, summarize the available research methodologies and previous studies in mTBI animal models, and discuss how a translational research approach may be useful in advancing our understanding and management of mTBI.     

Nanometer ultrastructural brain damage following low intensity primary blast wave exposure

Blast-induced mild traumatic brain injury(m TBI) is of particular concern among military personnel due to exposure to blast energy during military training and combat.The impact of primary low-intensity blast mediated pathophysiology upon later neurobehavioral disorders has been controversial.Developing a military preclinical blast model to simulate the pathophysiology of human blast injury is an important first step.This article provides an overview of primary blast effects and perspectives of our recent studies demonstrating ultrastructural changes in the brain and behavioral disorders resulting from open-field blast exposures up to 46.6 k Pa using a murine model.The model is scalable and permits exposure to varying magnitudes of primary blast injuries by placing animals at different distances from the blast center or by changing the amount of C4 charge.We here review the implications and future applications and directions of using this animal model to uncover the underlying mechanisms related to primary blast injury.Overall,these studies offer the prospect of enhanced understanding of the pathogenesis of primary low-intensity blast-induced TBI and insights for prevention,diagnosis and treatment of blast induced TBI,particularly m TBI/concussion related to current combat exposures.     

From cell death to neuronal regeneration: building a new brain after traumatic brain injury

During the past decade, there has been accumulating evidence of the involvement of passive and active cell death mechanisms in both the clinical setting and in experimental models of traumatic brain injury (TBI). Traditionally, research for a treatment of TBI consists of strategies to prevent cell death using acute pharmacological therapy. However, to date, encouraging experimental work has not been translated into successful clinical trials. The development of cell replacement therapies may offer an alternative or a complementary strategy for the treatment of TBI. Recent experimental studies have identified a variety of candidate cell lines for transplantation into the injured CNS. Additionally, the characterization of the neurogenic potential of specific regions of the adult mammalian brain and the elucidation of the molecular controls underlying regeneration may allow for the development of neuronal replacement therapies that do not require transplantation of exogenous cells. These novel strategies may represent a new opportunity of great interest for delayed intervention in patients with TBI.     

Results of the NIH consensus conference on "rehabilitation of persons with traumatic brain injury"

In 1998, the National Institute for Health (NIH) organized a consensus conference about the rehabilitation of persons with traumatic brain injury (TBI). The conference results are based on an extensive bibliography from the scientific literature and presentations at the conference. The focus of this conference was the evaluation of rehabilitative measures for the cognitive and behavioral consequences of TBI, and the extent to which specific interventions are supported by existing evidence. Specifically, the conference considered the following aspects and their implications for rehabilitation: the epidemiology of TBI in the United States, the consequences in terms of pathophysiology, impairments, functional limitations, disabilities, societal limitations, and economic impact, the mechanisms underlying functional recovery following TBI, the common therapeutic interventions for the cognitive and behavioral sequelae of TBI, and the models for comprehensive coordinated multi-disciplinary rehabilitation. Based on the answers to these questions, the conference tried to give recommendations regarding rehabilitation practices for people with TBI, and identified areas where further research is needed.     

Transient Receptor Potential Melastatin 2 Expression is Increased Following Experimental Traumatic Brain Injury in Rats

Traumatic brain injury (TBI) elicits a sequence of complex biochemical changes including oxidative stress, oedema, inflammation and excitotoxicity. These factors contribute to the high morbidity and mortality following TBI, although their underlying molecular mechanisms remain poorly understood. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel, highly expressed in the brain and immune cells. Recent studies have implicated TRPM2 channels in processes involving oxidative stress, inflammation and cell death. However, no studies have investigated the role of TRPM2 in TBI pathophysiology. In the present study, we have characterised TRPM2 mRNA and protein expression following experimental TBI. Adult male Sprague Dawley rats were injured using the impact-acceleration model of diffuse TBI with survival times between 5 and 5 days. Real-time RT-PCR (including reference gene validation studies) and semi-quantitative immunohistochemistry were used to quantify TRPM2 mRNA and protein levels, respectively, following TBI. Significant increases in TRPM2 mRNA and protein expression were observed in the cerebral cortex and hippocampus of injured animals, suggesting that TRPM2 may contribute to TBI injury processes such as oxidative stress, inflammation and neuronal death. Further characterisation of how TRPM2 may contribute to TBI pathophysiology is warranted.     

Late evolutionary appearance of ‘peripheral-type’ binding sites for benzodiazepines

Four classes of non-mammalian vertebrates were examined for the presence of both 'brain-specific' and 'peripheral-type' binding sites for benzodiazepines in the central nervous system. 'Brain-specific' binding sites for benzodiazepines were found in the central nervous systems of all non-mammalian vertebrates studied. However, in contrast to mammals, either very low or undetectable levels of 'peripheral-type' binding sites for benzodiazepines were observed in the central nervous systems of these non-mammalian vertebrates. Furthermore, the density of 'peripheral-type' binding sites for benzodiazepines in non-mammalian vertebrate heart was less than or equal to 2% of that found in mammalian cardiac tissue. These findings suggest a very late evolutionary appearance of 'peripheral-type' binding sites for benzodiazepines, implying that these sites may have (a) highly specialized function(s) in both peripheral tissues and the central nervous system.     

Postinjury administration of L-deprenyl improves cognitive function and enhances neuroplasticity after traumatic brain injury

The rat model of combined central fluid percussion traumatic brain injury (TBI) and bilateral entorhinal cortical lesion (BEC) produces profound, persistent cognitive deficits, sequelae associated with human TBI. In contrast to percussive TBI alone, this combined injury induces maladaptive hippocampal plasticity. Recent reports suggest a potential role for dopamine in CNS plasticity after trauma. We have examined the effect of the dopamine enhancer l-deprenyl on cognitive function and neuroplasticity following TBI. Rats received fluid percussion TBI, BEC alone, or combined TBI + BEC lesion and were treated once daily for 7 days with l-deprenyl, beginning 24 h after TBI alone and 15 min after BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl treatment. Cognitive performance was assessed on days 11-15 postinjury and brains from the same cases examined for dopamine beta-hydroxylase immunoreactivity (DBH-IR) and acetylcholinesterase (AChE) histochemistry. Significant cognitive improvement relative to untreated injured cases was observed in both TBI groups following l-deprenyl treatment; however, no drug effects were seen with BEC alone. l-Deprenyl attenuated injury-induced loss in DBH-IR over CA1 and CA3 after TBI alone. However, after combined TBI + BEC, l-deprenyl was only effective in protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with l-deprenyl in both injury models. After TBI + BEC, l-deprenyl also increased AChE in the dentate molecular layer relative to untreated injured cases. These results suggest that dopaminergic/noradrenergic enhancement facilitates cognitive recovery after brain injury and that noradrenergic fiber integrity is correlated with enhanced synaptic plasticity in the injured hippocampus.     

Models of Traumatic Cerebellar Injury

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Studies of human TBI demonstrate that the cerebellum is sometimes affected even when the initial mechanical insult is directed to the cerebral cortex. Some of the components of TBI, including ataxia, postural instability, tremor, impairments in balance and fine motor skills, and even cognitive deficits, may be attributed in part to cerebellar damage. Animal models of TBI have begun to explore the vulnerability of the cerebellum. In this paper, we review the clinical presentation, pathogenesis, and putative mechanisms underlying cerebellar damage with an emphasis on experimental models that have been used to further elucidate this poorly understood but important aspect of TBI. Animal models of indirect (supratentorial) trauma to the cerebellum, including fluid percussion, controlled cortical impact, weight drop impact acceleration, and rotational acceleration injuries, are considered. In addition, we describe models that produce direct trauma to the cerebellum as well as those that reproduce specific components of TBI including axotomy, stab injury, in vitro stretch injury, and excitotoxicity. Overall, these models reveal robust characteristics of cerebellar damage including regionally specific Purkinje cell injury or loss, activation of glia in a distinct spatial pattern, and traumatic axonal injury. Further research is needed to better understand the mechanisms underlying the pathogenesis of cerebellar trauma, and the experimental models discussed here offer an important first step toward achieving that objective.     

Cardiovascular regeneration in non-mammalian model systems: what are the differences between newts and man?

The mammalian heart cannot regenerate substantial cardiac injuries, while certain non-mammalian vertebrates such as certain fish (Danio rerio) and amphibiae (Notophthalmus viridescens) are able to repair the heart without functional impairment. In mammalians, the prevailing repair process is accompanied by fibrosis and scarring, while zebrafish and newts can replace lost contractile tissue by newly formed cardiac muscle with only little or no scar formation. A better understanding of cardiac regeneration in non-mammalian vertebrates might provide new insights for the manipulation of regenerative pathways in the human heart. Here, we summarize the current knowledge in cardiac regeneration of newts and the principal differences to repair processes in mammalian hearts.     

Traumatic subarachnoid hemorrhage: our current understanding and its evolution over the past half century

Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the US, especially among the young. Primary injury in TBI is preventable, whereas secondary injury is treatable. As a result, considerable research efforts have been focused on elucidating the pathophysiology of secondary injury and determining various prognosticators in the hopes of improving final outcome by minimizing secondary injury. One such variable, traumatic subarachnoid hemorrhage (tSAH), has been the focus of many discussions over the past half century as numerous clinical studies have shown tSAH to be associated with adverse outcome. Whether the relationship of tSAH with poorer outcome in TBI is merely an epiphenomenon or a result of direct cause and effect is unclear. Some investigators believe that tSAH is merely a marker of severer TBI, while others argue that it directly causes deleterious effects such as vasospasm and ischemia. At the present time, no proven treatment regimen aimed specifically at decreasing the detrimental effects of tSAH exists, although calcium channel blockers traditionally thought to target vasospasm have shown some promises. Given that tSAH may primarily be an early indicator of associated and evolving brain injury, vigilant diagnostic surveillance including serial head CT and prevention of secondary brain damage owing to hypotension, hypoxia and intracranial hypertension may be more cost-effective than attempting to treat potential adverse sequelae associated with tSAH.     

Signaling pathways that regulate axon regeneration

Neurons in the mammalian central nervous system (CNS) cannot regenerate axons after injury. in contrast, neurons in the mammalian peripheral nervous system and in some non-mammalian models, such as C. elegans and Drosophila, are able to regrow axons. Understanding the molecular mechanisms by which these neurons support axon regeneration will help us find ways to enhance mammalian CNS axon regeneration. Here, recent studies in which signaling pathways regulating naturally-occurring axon regeneration that have been identified are reviewed, focusing on how these pathways control gene expression and growth-cone function during axon regeneration.     

Animal models of trauma-induced coagulopathy

Resurgent study of trauma-induced coagulopathy (TIC) has delivered considerable improvements in survival after injury. Robust, valid and clinically relevant experimental models of TIC are essential to support the evolution of our knowledge and management of this condition. The aims of this study were to identify and analyze contemporary animal models of TIC with regard to their ability to accurately characterize known mechanisms of coagulopathy and/or to test the efficacy of therapeutic agents. A literature review was performed.Structured search of the indexed online database MEDLINE/PubMed in July 2010 identified 43 relevant articles containing 23 distinct animal models of TIC. The main aim of 26 studies was to test a therapeutic and the other 17 were conducted to investigate pathophysiology. A preponderance of porcine models was identified. Three new models demonstrating an endogenous acute traumatic coagulopathy (ATC) have offered new insights into the pathophysiology of TIC.Independent or combined effects of induced hypothermia and metabolic acidosis have been extensively evaluated. Recently, a pig model of TIC has been developed that features all major etiologies of TIC, although not in correct chronological order.This review identifies a general lack of experimental research to keep pace with clinical developments. Tissue injury and hemorrhagic shock are fundamental initiating events that prime the hemostatic system for subsequent iatrogenic insults. New animal models utilizing a variety of species that accurately simulate the natural clinical trajectory of trauma are urgently needed.     

Neuroinflammation and blood–brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets

Traumatic Brain Injury (TBI) is the most frequent cause of death and disability in young adults and children in the developed world, occurring in over 1.7 million persons and resulting in 50,000 deaths in the United States alone. The Centers for Disease Control and Prevention estimate that between 3.2 and 5.3 million persons in the United States live with a TBI-related disability, including several neurocognitive disorders and functional limitations. Following the primary mechanical injury in TBI, literature suggests the presence of a delayed secondary injury involving a variety of neuroinflammatory changes. In the hours to days following a TBI, several signaling molecules and metabolic derangements result in disruption of the blood–brain barrier, leading to an extravasation of immune cells and cerebral edema. The primary, sudden injury in TBI occurs as a direct result of impact and therefore cannot be treated, but the timeline and pathophysiology of the delayed, secondary injury allows for a window of possible therapeutic options. The goal of this review is to discuss the pathophysiology of the primary and delayed injury in TBI as well as present several preclinical studies that identify molecular targets in the potential treatment of TBI. Additionally, certain recent clinical trials are briefly discussed to demonstrate the current state of TBI investigation.     

Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury

Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI is alteration in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase, i.e., encoding, maintenance, or retrieval, is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally, we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury.     

Personal narrative approaches in rehabilitation following traumatic brain injury: A synthesis of qualitative research

Although narrative storytelling has been found to assist identity construction, there is little direct research regarding its application in rehabilitation following traumatic brain injury (TBI). The aim of this review was to identify published evidence on the use of personal narrative approaches in rehabilitation following TBI and to synthesise the findings across this literature. A systematic search of four databases was conducted in December 2016. No limit was set on the start date of the search. Personal narrative approaches were defined as direct client participation in sharing personal stories using written, spoken or visual methods. The search retrieved 12 qualitative research articles on the use of personal narrative approaches in TBI rehabilitation. Thematic synthesis of the narrative data and authors’ reported findings of the 12 articles yielded an overall theme of building a strengths-based identity and four sub-themes: 1) expressing and communicating to others; 2) feeling validated by the act of someone listening; 3) reflecting and learning about oneself; and 4) being productive. The findings of this review support the use of personal narrative approaches in addressing loss of identity following TBI. Healthcare professionals and the community are encouraged to seek opportunities for survivors of TBI to share their stories.