L’anévrisme de l’aorte abdominale (AAA) est associé à des taux élevés de morbidité et de mortalité. A l’heure actuelle, le seul traitement curatif de l’AAA est chirurgical, aucune approche pharmacologique n’ayant démontré une efficacité suffisante. Une meilleure compréhension des mécanismes aboutissant au développement de l’AAA permettrait d’identifier de nouvelles cibles thérapeutiques. Bien qu’utiles dans cette démarche, les modèles animaux expérimentaux actuels ne reproduisent pas parfaitement la physiopathologie humaine. Les objectifs de ce travail étaient de : 1/ Créer et caractériser un nouveau modèle murin d’AAA associant application topique d’élastase et neutralisation du TGFβ. 2/ Etudier le rôle de l’IL1β dans ce modèle. La neutralisation du TGFβ chez des souris C57Bl6j aggravait la dilatation anévrismale induite par l’application d’élastase et favorisait la rupture aortique. Ceci était associé à une dégradation accrue de la matrice-extra-cellulaire, une infiltration de cellules inflammatoires au sein de la paroi aortique, la formation d’un thrombus intra-luminal ainsi qu’une augmentation de la néo-angiogénèse. L’utilisation de la technique d’imagerie par synchrotron a permis de montrer une destruction de la paroi aortique en l’absence de formation de dissection aboutissant à une rupture aortique transmurale fatale. L’expression génique de différentes cytokines, dont l’IL1β était augmentée dans la paroi aortique. Afin d’étudier le rôle de l’IL1β, 2 modèles d’invalidation ont été utilisé : l’induction d’AAA chez des souris déficientes en IL1β et l’injection systémique d’anticorps anti-IL1β. Les souris IL1β-/- étaient protégées du développement anévrismal et de la rupture après application d’élastase et neutralisation du TGFβ. En revanche, la neutralisation de l’IL1β par injection d’anticorps à un temps plus tardif ne limitait pas la progression de l’AAA et aboutissait à la rupture anévrismale. Cette étude a permis de créer un nouveau modèle murin d’AAA dont les caractéristiques sont proches de la physiopathologie humaine. L’invalidation génétique de l’IL1β, et non la neutralisation systémique à un temps tardif, limitait la croissance et prévenait la rupture anévrismale suggérant le rôle de cette cytokine au cours des stades précoces du développement de l’AAA. / Abdominal aortic aneurysm (AAA) is associated with extremely high morbidity and mortality rates. The only curative treatment relies on surgery as no drug has proven yet its efficacy to cure the disease. A better understanding of pathophysiological mechanisms involved in AAA development would help to identify new therapeutic targets. Even though current experimental animal models are useful to address this question, none of them perfectly mimics human disease. The aim of this study was: 1/ Create and characterize a new murine model of AAA based on topic application of elastase associated with systemic TGFβ neutralization. 2/ Study the effect of IL-1β in this model. We report that TGFβ neutralization in C57Bl6j male mice increased aneurysmal aortic dilatation induced by elastase and favored aortic rupture. This was associated with major vascular remodeling including the degradation of extracellular matrix, the infiltration of inflammatory cells in the aortic wall, the formation of an intraluminal thrombus and the increase of neoangiogenesis. Synchrotron-based ultrahigh ex-vivo resolution imaging revealed a wall disruption with no medial dissection culminating in fatal transmural aortic wall rupture. The gene expression of several cytokine including IL-1β was increased in the aortic wall. The effect of IL-1β was investigated using IL-1β-/- mice or using systemic injection of monoclonal anti-IL-1β antibody. IL-1β-/- mice were protected against aortic dilatation and aortic rupture after application of elastase associated with TGFβ neutralization. However, the injection of anti-IL-1β antibody did not limit the aortic dilatation and neither prevented the aortic rupture. In this study, we created a new murine model of AAA which reproduces the main pathophysiological human features. The genetic invalidation of IL-1β, but not its blockade after disease initiation prevented AAA dilatation and rupture, suggesting the role of this cytokine in the early stages of AAA development.

Colorectal cancer is the third most common cancer and the fourth most common cause of cancer-related death in the world. The global burden of colorectal cancer is also expected to increase by 60%, to over 2.2 million new cases and 1.1 million annual deaths, by the year 2030. Jackfruit is known for its packed nutrition including many antioxidants: vitamin C, carotenoids and flavanones. It has also been used in traditional medicine due to its potential protection against many chronic diseases. However, there is limited research studying the potential effect of jackfruit on colorectal cancer. Here, we used a well-established AOM/DSS mice model to investigate the impact of jackfruit-derived extracts on colitis-associated colorectal cancer. After 6-week treatment with diet containing 480 ppm jackfruit-derived extracts, the mice showed significantly alleviated colon tumorigenesis with a 46% decrease in tumor numbers of each mouse compared to vehicle group (2.1 ± 0.31 for 480 ppm jackfruit-derived fraction group vs 3.9 ± 0.67 for vehicle group, P < 0.05). The expression of the pro-inflammatory cytokines (Il-6 and Inf- γ) and pro-tumorigenic genes (Axin2, Vegf, Myc and Pcna) was also decreased in the group consuming 480 ppm jackfruit-derived extracts compared to the vehicle group. Together the results suggest that the consumption of jackfruit-derived extracts could protect against colitis-associated colorectal carcinogenesis in mice.

INTRODUCTION: SARS-CoV-2 is a novel virus from the coronavirus family that emerged in the Hubei province of China in December 2019 and rapidly spread throughout the world. On March 11, 2020, the World Health Organization declared a global pandemic. Infection with SARS-CoV-2 causes coronavirus disease 19 (COVID19) which can be fatal. There is an obvious and pressing need for research surrounding SARS-CoV-2 that will aid in eradication of this pandemic. OBJECTIVE: The goal of this study was to absolve the dire need for small animal models of human disease that demonstrate hallmark pathological features of infection. Due to ethical and financial obstacles, the use of animals that closely resemble human immunity, such as non-human primates, is often not a viable option. For this reason, there is a push to develop small animal models that can mimic human disease responses, particularly those in viral infections that have a narrow species tropism. To achieve this in the context of the novel coronavirus, SARS-CoV-2, we studied various mouse models and their capacity to become infected with and mount an immune response to SARS-CoV-2. Our goal was to identify a model that sufficiently mimics severe COVID19 seen in humans as well as provide molecular insight into pathways that prevent the development of severe disease. METHODS: NRG-L and HIS-NRGF-L mice were subcutaneously implanted with human fetal lung xenografts and infected with SARS-CoV-2. Tissues were stained with H&E for histopathological scoring. NRG-L and HIS-NRGF-L tissues were fluorescently labeled using 2 different multiplex immunohistochemistry panels. Slides were digitized by a Vectra Polaris™ fluorescent whole slide scanner and digital analysis was completed using HALO™. Statistical analysis was conducted using GraphPad Prism™ 9.0.1. RESULTS: Infected NRG-L mice present extensive histopathological manifestations when compared to uninfected controls. Cumulative histology scores at both 2 and 7DPI were increased when compared to uninoculated fLX. Neutrophil influx, intra-airspace necrosis, capillary fibrin thrombi, and presence of syncytial cells were the most significant independent observations that contributed to the increased cumulative score. Together these findings indicate that fLX inoculated with SARS-CoV-2 faithfully recapitulate several features of diffuse alveolar damage (DAD) described in severe COVID-19. HIS-NRGF-L mice displayed decreased influx of neutrophils, intra-airway necrosis, and syncytial cells when compared to NRG-L fLX. Hemorrhage was decreased at both 2 and 7 DPI for HIS-NRGF-L fLX compared to NRG-L fLX. Cumulative histology scores were decreased in HIS-NRGF-L fLX at 7 DPI when compared to NRG-L fLX. Taken together these findings support the hypothesis that human myeloid and lymphoid infiltrates suppress or prevent the disparate host response observed in NRGL-L fLX that manifested in pronounced diffuse alveolar damage. CONCLUSION: Using digital image analysis of multiplex immunohistochemistry paired with semi-quantitative histopathological scoring, this study characterized important hallmark lesions observed in severe COVID19 as seen in small animal models. NRG-L and HIS-NRGF-L mice that are subcutaneously implanted with human fetal lung xenografts are susceptible to infection with SARS-CoV-2 and can produce severe and moderate disease phenotypes respectively. Co-engraftment with human fetal lung tissue and human immune system components in HIS-NRGF-L mice suppresses the divergent host response that is observed in NRG-L mice. For this reason, NRG-L mice engrafted with fLX are an ideal small animal model of severe COVID19, whereas HIS-NRGF-L mice severe as a valuable and informative model for deciphering molecular mechanisms driving severe COVID-19 that will serve as targets for therapeutic development.

Le système vestibulaire est le seul sens ne possédant pas un cortex primaire mais plusieurs zones corticales rassemblées sous le terme « cortex vestibulaire ». Le rôle et le fonctionnement du cortex vestibulaire restent peu connus à l’état physiologique, et encore moins chez des personnes souffrant de pathologies vestibulaires ou de l’intégration multisensorielle. Parmi ces régions, l’hippocampe joue un rôle fondamental dans la cognition d’origine vestibulaire et en particulier dans l’orientation spatiale et la formation de carte cognitive. Le but de ce travail était d’étudier la répartition des influx vestibulaires au sein de l’hippocampe, chez le rat qui représente l’espèce où les connaissances sur l’hippocampe sont les plus développées. Pour cela nous avons mis au point une méthode de lésion labyrinthique chirurgicale et une méthode de stimulation électrique sélective de chaque senseur vestibulaire (3 ampoules canalaires, les macules utriculaires et sacculaires). Cette méthode a ensuite été appliquée pour étudier le reflex vestibulo-oculaire spécifique de chaque senseur du rat. Ce reflex vestibulo-oculaire a ensuite était utilisée comme témoin d’une stimulation efficace et sélective de chaque senseur vestibulaire. Nous avons enfin étudié la projection des influx vestibulaires au niveau de l’hippocampe par analyse immunohistochimique de la protéine cFOS, considéré comme un marqueur de l’activité neuronale. Les résultats retrouvent une prédominance de cFOS au niveau de l’hippocampe dorsal, dans la région CA2-CA3. Ces résultats sont cohérents avec l’implication de l’hippocampe dorsal dans la cognition et le rôle de CA3 dans l’encodage de nouvelles informations spatiales, dans la mémoire à court terme et dans la représentation spatiale géométrique de l’environnement. / The vestibular system is the only sense that lake a primary cortex but project to several cortical areas known as the "vestibular cortex". The roles and functioning of the vestibular cortex remain poorly known, neither in the physiological state, nor in pathologies involving the vestibular system. Among these cortices, the hippocampus plays a fundamental role in vestibular cognition and in particular in spatial orientation and cognitive map formation. The purpose of this work was to study the distribution of vestibular inputs within the rat’s hippocampus, which represents the species where hippocampus is best known. For this purpose we have developed a method of surgical labyrinthectomy and a method of selective electrical stimulation of each vestibular sensor (3 canals ampullae, utricular and saccular maculae). This method was then applied to study the vestibulo-ocular reflex specific of each sensor in the rat. This vestibulo-ocular reflex was further used during electrical stimulation of each sensor to control the effectiveness and selectiveness of the stimulation. Finally, we studied the vestibular imputs in the hippocampus by immunohistochemical analysis of the cFOS protein, which is considered as a marker of neuronal activity. The results show a predominance of cFOS labelling in the dorsal hippocampus, in the CA2-CA3 region. These results are consistent with the role of the dorsal hippocampus in cognition and the role of CA3 encoding of new spatial information within short-term memory and in processing the geometry of the environment.

Novel psychoactive substances (NPS) are a novel problem of the drug scene. NPS mimic effects of the "classic" illicit drugs, but since they have a different chemical structure, they are usually not covered by legislative control. The exact nature of the aforementioned effects depends merely on the description by users, with a proper scientific assessment still absent. Aim of this study is to evaluate effects and addictive potential of naphyrone (a derivative of cathinone) in Wistar rats. High concentration of naphyrone in the brain tissue discovered by pharmacokinetic analysis proved its high blood-brain barrier permeability. Brain level of naphyrone peaked at approximately 30 min after the treatment, nearly at the same time as in the serum. Since naphyrone administration significantly rises body temperature and increases overall locomotion, its stimulant effect is prominently apparent. Our study failed to prove any effect of naphyrone on sensorimotor gating. Tendency to produce conditioned place preference was observed but was not significant. My thesis reports on initial and novel findings about impact of naphyrone administration on physiological parameters of the animal model.

Purpose of this study was to show the efficacy and safety of the investigational product co.don chondrosphere® (ACT3D-S). ACT3D-S is a product for autologous chondrocyte transplantation that we used in an animal model, the merino land sheep. We compared the treatment of ACT3D-S (Group A: Investigational product) with an untreated control (Group B: Control Intervention) in a bilateral model, what means that by randomization one hind limb was chosen to be treated with ACT3D-S while the remaining hind limb was left without treatment.

Concussions are the injury and symptoms that can result from transmission of a biomechanical force to the brain. They represent a significant global health burden, and are the subject of a growing body of medical research. A concussion can only be definitively diagnosed by a medical professional based on symptoms, although advanced neuroimaging and biomarker-based approaches are promising future diagnostic tools. There is no treatment for concussion beyond following return-to-work or -play guidelines, which recommend avoiding strenuous physical and cognitive activities until they no longer exacerbate symptoms. Preclinical models of concussion have been used to examine pathophysiological processes underlying symptoms, which is an important step in developing tools for diagnosis and treatment. Historically the clinical translation of preclinical concussion research has been limited, and the use of anaesthesia, and preference for adult male rats may contribute to this. These means of reducing variability are justified, but preclinical research moving forward should address these limitations to translatability by including more clinically relevant subjects and avoiding anaesthesia. To this end, we developed a new preclinical model for pediatric concussion. Our awake closed head injury (ACHI) model is well-suited to this purpose because it produces a helmeted closed-head injury involving vertical and rotational displacement of the head, and does not require anaesthesia. Before the ACHI model can be used to investigate concussion mechanism, diagnosis, and treatment, it needs to be characterized to demonstrate that it produces clinically relevant neurobehavioral and pathological changes. We developed a modified neurologic assessment protocol to test neurologic function immediately after each injury. The Barnes maze, elevated plus maze, open field, and Rotarod were used to measure injury-related changes in cognition, anxiety, and motor function. The Barnes maze reversal task was used to detect more subtle cognitive impairments of executive function. Structural MRI was used to search for visible lesion, hemorrhage, or atrophy; and silver-stain histology was used to detect neurodegeneration. We determined repeated ACHI produced acute neurologic impairment with the NAP, and a mild spatial learning deficit potentially mediated impaired cognitive flexibility in the Barnes maze and reversal training. These were accompanied by neurodegeneration in the optic tract, hippocampus, and ipsilateral cortex during the first week of recovery. Thus, following the internationally recognised definition developed by the concussion in sport group, we demonstrated 1) an “impulsive” force transmitted to the head results in 2) the rapid onset of short-lived neurologic impairment that resolves spontaneously. This occurs 3) with normal structural neuroimaging, and 4) produces cognitive impairment, and LOC in a subset of cases. The ACHI model is the first in Canada to forego anaesthesia, and this is the first demonstration of neurocognitive impairment accompanied by diffuse neurodegeneration in the absence of structural MRI abnormalities after mild traumatic brain injury in juvenile male and female rats. / Graduate

The classic rodent model of Parkinson’s disease (PD) is produced by unilateral lesioning of pars compacta substantia nigra (SNpc) in adult rats, producing unilateral motor deficits which can be assessed by dopamine (DA) D2 receptor (D2-R) agonist induction of measurable unilateral rotations. Bilateral SNpc lesions in adult rats produce life-threatening aphagia, adipsia, and severe motor disability resembling paralysis-a PD model that is so compromised that it is seldom used. Described in this paper is a PD rodent model in which there is bilateral 99% loss of striatal dopaminergic innervation, produced by bilateral intracerebroventricular or intracisternal 6-hydroxydopamine (6-OHDA) administration to perinatal rats. This procedure produces no lethality and does not shorten the life span, while rat pups continue to suckle through the pre-weaning period; and eat without impairment post-weaning. There is no obvious motor deficit during or after weaning, except with special testing, so that parkinsonian rats are indistin-guishable from control and thus allow for behavioral assessments to be conducted in a blinded manner. L-DOPA (L-3,4-dihydroxyphenylalanine) treatment increases DA content in striatal tissue, also evokes a rise in extraneuronal (i.e.,in vivo microdialysate) DA, and is able to evoke dyskinesias. D2-R agonists produce effects similar to those of L-DOPA. In addition, effects of both D1-and D2-R agonist effects on overt or latent receptor supersensitization are amenable to study. Elevated basal levels of reactive oxygen species (ROS), namely hydroxyl radical, occurring in dopaminergic denervated striatum are suppressed by L-DOPA treatment. Striatal serotoninergic hyperinnervation ensuing after perinatal dopaminergic denervation does not appear to interfere with assessments of the dopaminergic system by L-DOPA or D1-or D2-R agonist challenge. Partial lesioning of serotonin fibers with a selective neurotoxin either at birth or in adulthood is able to eliminate sero-toninergic hyperinnervation and restore the normal level of serotoninergic innervation. Of all the animal models of PD, that produced by perinatal 6-OHDA lesioning provides the most pronounced destruction of nigrostriatal neurons, thus representing a model of severe PD, as the neurochemical outcome resembles the status of severe PD in humans but without obvious motor deficits.

Extinguished alcohol-maintained responding has been shown to relapse in aresurgence preparation when food-reinforced responding is subsequently extinguished within the same context. However, drug and nondrug reinforcers are often specific to different contexts. Accordingly, the present experiments sought to determine whether loss of an alternative source of nondrug reinforcement in one context could produce relapse to drug seeking in a separate context. In one experiment, rats made topographically different responses for food or alcohol in alternating components of a multiple schedule. Both reinforcers were delivered during baseline, alcohol was withheld during the second phase of the experiment, and finally both reinforcers were withheld during the final phase. Extinguished alcohol-maintained responding increased upon discontinuation of food deliveries, but may have increased due to similarity between the final experimental phase and an initial training phase. In a second experiment, the training phase that complicated interpretation of the elevated responding observed in Experiment 1 was eliminated altogether. Alcohol seeking again relapsed upon discontinuation of food, suggesting that the training conditions were not the cause of the observed relapse in Experiment 1. Thus, loss of a nondrug reinforcer in one context can produce relapse to drug seeking in another. This procedure may provide a novel model of drug relapse in which loss of context-specific, alternative nondrug reinforcers precipitates relapse to drug seeking in a separate context.

Patients with Alzheimer disease often report presence of neuropsychiatric symptoms even before the presence of cognitive decline itself. The most reported ones are anxiety, depression, emotional dysregulation, apathy and agitation. The aim of this work was to investigate the presence of anxiety- and depression-like behaviour, and eventually dysregulation of social behaviour and emotional memory impairment via behavioural approach on the TgF344-AD (tg) rat model. Results show that tg rats display anxiety-like behaviour in several different tests and parameters. Tg rats of the age of 10 months spent more time around the wall and less in the middle of the arena. Surprisingly, this anxiety-like phenotype has not been demonstrated in the older (14 months) rats. Tg rats spent also less time peeking out from closed arms and looking down from open arms. Moreover, tg rats displayed anxiety-like behaviour in all observed parameters in the Social interaction test. Social deficit expressed as a smaller investment of time into the anogenital and non- anogenital exploration and following of counterparts. In the Forced swim test, tg rats did not spend more time immobile, thus depression-like phenotype has not been demonstrated in these animals. Moreover, 10 months old tg rats spent surprisingly less time...