The clinical relevance of behavior testing in animal models of traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, with patients often suffering from consequences such as cognitive deficits, social abnormalities, anxiety, depression, pain, and motor dysfunction. Given that these impairments often have a significant impact on the patient's quality of life, a key aim of therapeutic intervention in TBI is to mitigate these effects. Translational strategies to develop such interventions have heavily featured animal models of TBI. To assess the efficacy of interventions in these models, a range of behavioral outcomes are utilized. However, in light of the past translational failures that have plagued the TBI field, the clinical relevance of these preclinical behavioral tests is now being scrutinized. This article will summarize the behavioral consequences of TBI in humans; describe common methods available for testing cognition, social function, motor ability, pain, as well as depression- and anxiety-like behaviors in animal models of TBI; provide an overview of the results from TBI animal model studies that have utilized these methods; and discuss these pre-clinical behavior methods and findings in terms of their relevance to the clinical TBI setting. We conclude that there is translational value in these methods and their related findings, but also suggest strategies and future research to improve the clinical relevance of behavior testing in animal models of TBI.Sandy R. Shultz, Stuart J. McDonald, Frances Corrigan, Bridgette D. Semple, Sabrina Salberg, Akram Zamani, Nigel C. Jones, and Richelle Mychasiu

Beyond the brain: peripheral interactions following traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability, and there are currently no pharmacological treatments known to improve patient outcomes. Unquestionably contributing towards a lack of effective treatments is the highly complex and heterogenous nature of TBI. In this invited review associated with the International Neurotrauma Symposium in Melbourne we highlight the recent surge of research that has demonstrated various central interactions with the periphery as a potential major contributor towards this heterogeneity and in particular the breadth of research from Australia. We describe the growing evidence of how extracranial factors such as polytrauma and infection can significantly alter TBI neuropathology. In addition, we highlight how dysregulation of the autonomic nervous system and the systemic inflammatory response induced by TBI can have profound pathophysiological effects on peripheral organs such as the heart, lung, gastrointestinal tract, liver, kidney, spleen and bone. Collectively, this review firmly establishes TBI as a systemic condition. Furthermore, the central and peripheral interactions that can occur following TBI must be further explored and accounted for in the ongoing search for effective treatments.Stuart J. McDonald, Jessica M. Sharkey, Mujun Sun ... Renee J. Turner, Anna V. Leonard ... Frances Corrigan ... et al

Angiogenic and Immunomodulatory Properties of Endothelial and Mesenchymal Stem Cells

It has been suggested that the effect of implanted cells on the local environment is important when selecting the appropriate cell type for tissue regeneration. Our aim was to compare the local tissue response to implanted human mesenchymal stem cells (MSC) and human umbilical vein endothelial cells (EC). MSC and EC were cultured in poly(l-lactide-co-1,5-dioxepan-2-one) scaffolds for 1 week in a bioreactor system, after which they were implanted subcutaneously in NOD/SCID mice. After 3 weeks, scaffolds were retrieved, and the mRNA expression of selected genes involved in hypoxia and inflammation was examined by real-time reverse tran- scription polymerase chain reaction and correlated with immunofluorescent staining for corresponding proteins. The Toll-like receptor signaling pathway was examined by superarray hybridization. The expression of 53 angiogenesis-related proteins was investigated by a proteome profiler angiogenesis antibody array kit. Vas- cularization was quantified using immunohistochemistry for CD31. The expression of hypoxia-inducible factors and biomarkers for angiogenesis was more strongly upregulated in response to implanted EC than to MSC, suggesting a higher sensitivity to low oxygen tension among EC. Hypoxic signaling was increased after implantation of EC compared with MSC, leading to a prolonged acute inflammatory phase that promoted ingrowth of vascular cells and establishment of the circulation. Inflammatory cytokines were also differently expressed at the gene and protein levels in the two experimental groups, resulting in altered recruitment of acute and chronic inflammatory cells. The end result of these differences was increased vessel formation within the constructs in the EC group

Pain in the developing brain: Early life factors alter nociception and neurobiological function in adolescent rats

Contains fulltext : 230742.pdf (Publisher’s version ) (Open Access)Although adverse early experiences prime individuals to be at increased risk for chronic pain, little research has examined the trauma-pain relationship in early life or the underlying mechanisms that drive pathology over time. Given that early experiences can potentiate the nociceptive response, this study aimed to examine the effects of a high-fat high-sugar (HFHS) diet and early life stress (maternal separation; [MS]) on pain outcomes in male and female adolescent rats. Half of the rats also underwent a plantar-incision surgery to investigate how the pain system responded to a mildly painful stimuli in adolescence. Compared to controls, animals on the HFHS diet, experienced MS, or had exposure to both, exhibited increased anxiety-like behavior and altered thermal and mechanical nociception at baseline and following the surgery. Advanced MRI demonstrated that the HFHS diet and MS altered maturation of the brain, leading to changes in brain volume and diffusivity within the anterior cingulate, amygdala, corpus callosum, nucleus accumbens, and thalamus, while also modifying integrity of the corticospinal tracts. The effects of MS and HFHS diet were often cumulative, producing exacerbated pain sensitivity and increased neurobiological change. As early experiences are modifiable, understanding their role in pain may provide targets for early intervention/prevention.15 p

The need to incorporate aged animals into the preclinical modeling of neurological conditions

Neurological conditions such as traumatic brain injury, stroke, Parkinson's disease, epilepsy, multiple sclerosis, and Alzheimer's disease are serious clinical problems that affect millions of people worldwide. The majority of clinical trials for these common conditions have failed, and there is a critical need to understand why treatments in preclinical animal models do not translate to patients. Many patients with these conditions are middle-aged or older, however, the majority of preclinical studies have used only young-adult animals. Considering that aging involves biological changes that are relevant to the pathobiology of neurological diseases, the lack of aged subjects in preclinical research could contribute to translational failures. This paper details how aging affects biological processes involved in neurological conditions, and reviews aging research in the context of traumatic brain injury, stroke, Parkinson's disease, epilepsy, multiple sclerosis, and Alzheimer's disease. We conclude that aging is an important, but often overlooked, factor that influences biology and outcomes in neurological conditions, and provide suggestions to improve our understanding and treatment of these diseases in aged patients.Mujun Sun, Stuart J. McDonald, Rhys D. Brady, Lyndsey Collins-Praino, Glenn R. Yamakawa, Mastura Monif, Terence J. O’Brien, Geoffrey C. Cloud Christopher G. Sobey, Richelle Mychasiuk, David J. Loane, Sandy R. Shult