Valid Animal Model Research Articles

Modélisation expérimentale de l’agrégation et de la propagation de l’α-synucléine dans les synucléinopathies

During the past two decades, a myriad of studies have suggested a central pathogenic role for a-synuclein in Parkinson's disease. Recent studies have unravelled self-aggregation and prion-like spreading properties for a-synuclein. Of particular importance was the seminal observation of Lewy body-like structures in grafted fetal dopaminergic neurons of patients with Parkinson's disease. This conceptual breakthrough generated the " host-to-the-graft " hypothesis orprion-like hypothesis. Nowadays, mechanisms underlying these new properties appear as putative disease-modifying targets. As the lack of valid animal models for Parkinson's disease is considered as a roadblock toward therapeutic intervention, the use of the newly developed models based on the prion-like properties of a-synuclein should allow future target validation.

Minimal invasive surgical procedure of inducing myocardial infarction in mice.

Myocardial infarction still remains the main cause of death in western countries, despite considerable progress in the stent development area in the last decades. For clarification of the underlying mechanisms and the development of new therapeutic strategies, the availability of valid animal models are mandatory. Since we need new insights into pathomechanisms of cardiovascular diseases under in vivo conditions to combat myocardial infarction, the validity of the animal model is a crucial aspect. However, protection of animals are highly relevant in this context. Therefore, we establish a minimally invasive and simple model of myocardial infarction in mice, which assures a high reproducibility and survival rate of animals. Thus, this models fulfils the requirements of the 3R principle (Replacement, Refinement and Reduction) for animal experiments and assure the scientific information needed for further developing of therapeutical strategies for cardiovascular diseases.

Minimal Invasive Surgical Procedure of Inducing Myocardial Infarction in Mice

Myocardial infarction still remains the main cause of death in western countries, despite considerable progress in the stent development area in the last decades. For clarification of the underlying mechanisms and the development of new therapeutic strategies, the availability of valid animal models are mandatory. Since we need new insights into pathomechanisms of cardiovascular diseases under in vivo conditions to combat myocardial infarction, the validity of the animal model is a crucial aspect. However, protection of animals are highly relevant in this context. Therefore, we establish a minimally invasive and simple model of myocardial infarction in mice, which assures a high reproducibility and survival rate of animals. Thus, this models fulfils the requirements of the 3R principle (Replacement, Refinement and Reduction) for animal experiments and assure the scientific information needed for further developing of therapeutical strategies for cardiovascular diseases.

Characterization of long-term motor deficits in the 6-OHDA model of Parkinson's disease in the common marmoset

Research aimed at developing new therapies for Parkinson's disease (PD) critically depend on valid animal models of the disease that allows for repeated testing of motor disabilities over extended time periods. We here present an extensive characterization of a wide range of motor symptoms in the 6-OHDA marmoset model of PD when tested over several months. The severity of motor deficits was quantified in two ways: (i) through manual scoring protocols appropriately adapted to include species specific motor behavior and (ii) using automated quantitative motion tracking based on image processing of the digital video recordings. We show that the automated methods allow for rapid and reliable characterization of motor dysfunctions, thus complementing the manual scoring procedures, and that robust motor symptoms lasting for several months could be induced when using a two-stage neurotoxic lesioning procedure involving one hemisphere at a time. This non-human primate model of PD should therefore be well suited for long-term evaluation of novel therapies for treatment of PD.

Acute caffeine administration affects zebrafish response to a robotic stimulus

Zebrafish has been recently proposed as a valid animal model to investigate the fundamental mechanisms regulating emotional behavior and evaluate the modulatory effects exerted by psychoactive compounds. In this study, we propose a novel methodological framework based on robotics and information theory to investigate the behavioral response of zebrafish exposed to acute caffeine treatment. In a binary preference test, we studied the response of caffeine-treated zebrafish to a replica of a shoal of conspecifics moving in the tank. A purely data-driven information theoretic approach was used to infer the influence of the replica on zebrafish behavior as a function of caffeine concentration. Our results demonstrate that acute caffeine administration modulates both the average speed and the interaction with the replica. Specifically, zebrafish exposed to elevated doses of caffeine show reduced locomotion and increased sensitivity to the motion of the replica. The methodology developed in this study may complement traditional experimental paradigms developed in the field of behavioral pharmacology.

The role of CD8 T lymphocytes in rickettsial infections.

Arthropod-borne obligately intracellular bacteria pose a difficult challenge to the immune system. The genera Rickettsia, Orientia, Ehrlichia, and Anaplasma evolved mechanisms of immune evasion, and each interacts differently with the immune system. The roles of CD8 T cells include protective immunity and immunopathology. In Rickettsia infections, CD8 T cells are protective mediated in part by cytotoxicity toward infected cells. In contrast, TNF-α overproduction by CD8 T cells is pathogenic in lethal ehrlichiosis by induction of apoptosis/necrosis in hepatocytes. Yet, CD8 T cells, along with CD4 T cells and antibodies, also contribute to protective immunity in ehrlichial infections. In granulocytic anaplasmosis, CD8 T cells impact pathogen control modestly but could contribute to immunopathology by virtue of their dysfunction. While preliminary evidence indicates that CD8 T cells are important in protection against Orientia tsutsugamushi, mechanistic studies have been neglected. Valid animal models will enable experiments to elucidate protective and pathologic immune mechanisms. The public health need for vaccines against these agents of human disease, most clearly O. tsutsugamushi, and the veterinary diseases, canine monocytotropic ehrlichiosis (Ehrlichia canis), heartwater (Ehrlichia ruminantium), and bovine anaplasmosis (A. marginale), requires detailed immunity and immunopathology investigations, including the roles of CD8 T lymphocytes.

Examining the Consequences of Pre‐natal Exposure to Stress in the Behavior of Adult Offspring

Stress has been associated to the development of cognitive and other behavioral deficits. Moreover, it is well established that stress, during, and after a pregnancy, has multiple quantifiable effects in the overall development of the offspring. Our lab is interested in studying the predisposition to psychosis on the offspring upon maternal induction of stress together with N-methyl-D-aspartate (NMDA) receptor hypofunction during pregnancy. Thus, our first step is determining psychotic-like phenotypes in a group subjected solely to stress during pregnancy. Towards this end, mice were randomly divided into 2 groups: control and stressed. Males and females were paired to induce pregnancy. Five days after confirmation of a vaginal plug; a stress induction procedure was randomly administered on the experimental group. This procedure was continued until birth, after which the pups were allowed to be nurtured for 21 days. Pups were subsequently tested for behavioral abnormalities related to cognition, anxiety, sensorimotor gating, etc. Our results indicate a significant increase in anxiety-related behaviors in both the pups and mothers of the experimental group. Incidence of depression was also significantly increased in the experimental group compared with the control. Taken together, our findings so far suggest that prenatal stress exposure significantly changes several facets of adult mice behavior. Interestingly, the behaviors that are altered have been used to validate animal models of schizophrenia, suggesting that this experimental protocol will be useful to compare with additional groups showing additional dysfunction of the NMDA receptor.

Histological Bulbar Manifestations in the ALS Rat

Background: Almost all patients with amyotrophic lateral sclerosis (ALS) develop bulbar symptoms; therefore, it is important to have valid animal models that accurately reflect these features. While the SOD1-G93A rat is extensively used as an ALS model, bulbar symptoms in this model are not well characterized. Objective: In the present study, we aimed to better characterize bulbar dysfunction in terms of histology to determine whether the SOD1-G93A rat is a useful model for bulbar-onset ALS. Methods: Sixty-day-old SOD1-G93A rats on a Sprague-Dawley background and age-matched wild-type controls were assessed weekly for global motor function, facial nerve function, and vagal nerve function. The study endpoint was determined when an SOD1-G93A rat could not right itself within 30 s of being placed on its side. At that point, neuronal counts were assessed in different brainstem cranial nerve nuclei. In addition, the masseter muscle, posterior belly of the digastric muscle, and tongue muscle were evaluated for intact neuromuscular junctions. Results: Our data demonstrate decreases in the number of motor neurons in the trigeminal, facial, and hypoglossal nuclei, as well as compromised neuromuscular junction integrity in the muscles they innervate. Conclusion: These findings suggest that, from a histological standpoint, the SOD1-G93A rat is a valid model of ALS bulbar symptoms.

Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: A potential model for study of defective copper regulation in metabolic liver disease

Ob/ob mice provide an animal model for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) in patients with obesity and type-2 diabetes. Low liver copper has been linked to hepatic lipid build-up (steatosis) in animals with systemic copper deficiency caused by low-copper diets. However, hepatic copper status in patients with NAFLD or NASH is uncertain, and a validated animal model useful for the study of hepatic copper regulation in common forms of metabolic liver disease is lacking. Here, we report parallel measurements of essential metal levels in whole-liver tissue and defatted-dried liver tissue from ob/ob and non-obese control mice. Measurements in whole-liver tissue from ob/ob mice at an age when they have developed NAFLD/NASH, provide compelling evidence for factitious lowering of copper and all other essential metals by steatosis, and so cannot be used to study hepatic metal regulation in this model. By marked contrast, metal measurements in defatted-dried liver samples reveal that most essential metals were actually normal and indicate specific lowering of copper in ob/ob mice, consistent with hepatic copper deficiency. Thus ob/ob mice can provide a model useful for the study of copper regulation in NAFLD and NASH, provided levels are measured in defatted-dried liver tissue.

Default mode network, motor network, dorsal and ventral basal ganglia networks in the rat brain: comparison to human networks using resting state-fMRI.

Rodent models are developed to enhance understanding of the underlying biology of different brain disorders. However, before interpreting findings from animal models in a translational aspect to understand human disease, a fundamental step is to first have knowledge of similarities and differences of the biological systems studied. In this study, we analyzed and verified four known networks termed: default mode network, motor network, dorsal basal ganglia network, and ventral basal ganglia network using resting state functional MRI (rsfMRI) in humans and rats. Our work supports the notion that humans and rats have common robust resting state brain networks and that rsfMRI can be used as a translational tool when validating animal models of brain disorders. In the future, rsfMRI may be used, in addition to short-term interventions, to characterize longitudinal effects on functional brain networks after long-term intervention in humans and rats.

Alterations of reward mechanisms in bulbectomised rats

The positive association between alcoholism and depression is a common clinical observation. We investigated the relationship between depression and reward mechanisms using a validated animal model for depressive-like behaviour, the olfactory bulbectomy in rats.The effects of bilateral olfactory bulbectomy on reward mechanisms were studied in two different experimental paradigms – the voluntary self-administration of ethanol and the conditioned place preference to alcohol injection and compared to the effects of ethanol on locomotor activity and body core temperature. The voluntary ethanol intake was increased significantly in bulbectomised rats in a drinking experiment and also after a period of abstinence. Conditioned place preference (CPP) was induced in all animals. However, bulbectomised rats needed a higher dose of alcohol to produce CPP. The sedative effect of ethanol on locomotor activity was reduced in bulbectomised animals. Measurement of body temperature revealed a dose-dependent hypothermic effect of ethanol in both groups.These results suggest that the reward mechanisms may be altered in this animal model as a common phenomenon associated with depression. Furthermore, they support the hypothesis that the addictive and/or rewarding properties of some drugs of abuse may be modified in depression.

Role of Laterodorsal Thalamic Nucleus during Absence Seizure Attacks

Introduction: A typical absence epilepsy is a type of nonconvulsive and generalized epilepsy. The main feature of these attacks is a sudden brief impairment of consciousness. The disturbances in thalamocortical loop play an important role in pathogenesis of absence seizures. However, it is not clear that which part of this network triggers the seizure. This study was aimed to investigate the role of latrodorsal (LD) thalamic neurons during spike and wave discharges (SWDs) in WAG/Rij rats, as the most valid animal model of absence epilepsy. Materials and Methods: Single unit activities in the LD thalamic nucleus and electrocorticogram of somatosensory cortex were simultaneously recorded in six-month-old WAG/Rij rats. Results: During SWDs, unit activity in the LD thalamic nucleus showed burstlike discharges, which were started before the peak component of SWDs. In SWD-free periods, burst like activity in the LD was reduced. Conclusion: Our findings suggest that the burst firing of LD may stimulate the neocortex to exhibit SWDs. It can be concluded that inhibition of

Treatment of PD-1(-/-) mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients.

The mechanism of idiosyncratic drug-induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune-mediated and adaptation represents immune tolerance. In this study we found that AQ treatment of Cbl-b(-/-) and PD-1(-/-) mice, which have impaired immune tolerance, resulted in a slightly greater injury. Cotreatment of C57BL/6 with AQ and anti-CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in T regulatory (Treg) cells and T helper cells expressing PD-1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the alanine aminotransferase (ALT) activity in these mice returned to normal despite continued treatment. Cotreatment of PD-1(-/-) mice with anti-CTLA4 antibody and AQ resulted in the greatest increase in ALT (200-300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis. The lymphocyte infiltration included T and B cells, and the CD8(+) T cells produced perforin and granzyme. In addition, the ALT activity in PD-1(-/-) mice cotreated with anti-CTLA4 antibody and AQ did not return to normal, as it had in other mice. We report here the first animal model of IDILI that is similar to the IDILI that occurs in humans, and it was accomplished by inhibiting immune tolerance.

Review of Human Pathogenic Fungi: Molecular Biology and Pathogenic Mechanisms

Review of Human Pathogenic Fungi: Molecular Biology and Pathogenic Mechanisms

Evaluation of Partial Transection versus Synovial Debridement of the ACL as Novel Canine Models for Management of ACL Injuries

A major hurdle in investigating important clinical questions in knee ligament treatment is a lack of valid translational animal models. This study characterizes the effects of partial transection versus synovial debridement of the anterior (cranial) cruciate ligament (ACL) in dogs. A total of 27 adult purpose-bred research hounds underwent surgery and were assessed over the following 8 weeks. Dogs were randomized into the following three ACL status groups: sham control (n = 9), intact ACL with synovial debridement (exposed ACL) (n = 9), and partial transection of the ACL (partial tear ACL) (n = 9). Dogs in the exposed ACL group and partial tear ACL group had significantly (p < 0.05) more severe lameness, pain, effusion, reduced function, and reduced comfortable range of motion compared with controls, with the partial tear ACL group being most severely affected. More severe ACL and whole-joint pathology, and radiographic scores for osteoarthritis were present in the partial tear ACL group compared with exposed and/or sham control group. On the basis of these findings, biologic components of ACL injury (exposed ACL) played a role in whole-joint inflammation, but the clinical and pathological effects were more severe when both biologic and biomechanical components were present (i.e., partial tear ACL). These novel canine models were successfully developed to evaluate partial transection versus synovial debridement of the ACL and these models will be used to evaluate treatment options for acute management of ACL injuries.

Electrical Stimulation of the Nucleus Accumbens Shell Reduces Voluntary Ethanol Consumption in Bulbectomized Rats

Background: Alcoholism is often accompanied by depression. It has been shown that deep electrical stimulation of the nucleus accumbens is effective in the treatment of alcoholism. Objective: Despite the promising results of clinical trials, the mechanisms underlying its effects are still unclear. To elucidate these mechanisms, valid animal models are needed. Methods: We investigated the effects of electrical stimulation of the nucleus accumbens shell (NAS) and nucleus accumbens core (NAC) on alcohol intake in bulbectomized rats. Bilateral removal of the olfactory bulbs (OBX) is considered a valid animal model of depression. Results: It was shown that electrical stimulation of the NAS with the described stimulus parameters significantly reduced voluntary ethanol intake in OBX rats. After the cessation of stimulation, this effect became insignificant. In contrast, stimulation of the NAC did not modify voluntary ethanol intake. In sham-bulbectomized animals, voluntary ethanol intake was negligible and ethanol consumption did not alter as a result of electrical stimulation of the NAC or NAS Conclusions: Our study underlines the relevance of the OBX model in the study of depression comorbid alcohol intake. Moreover, it might be useful in the study of the mechanisms underlying the clinical effectiveness of electrical stimulation of the NAS in the treatment of alcoholism.

Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review.

Cognitive dysfunction and negative symptoms of schizophrenia remain an unmet clinical need. Therefore, it is essential that new treatments and approaches are developed to recover the cognitive and social impairments that are seen in patients with schizophrenia. These may only be discovered through the use of carefully validated, aetiologically relevant and translational animal models. With recent renewed interest in the neurodevelopmental hypothesis of schizophrenia, postnatal administration of N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) has been proposed as a model that can mimic aspects of schizophrenia pathophysiology. The purpose of the current review is to examine the validity of this model and compare it with the adult subchronic PCP model. We review the ability of postnatal PCP administration to produce behaviours (specifically cognitive deficits) and neuropathology of relevance to schizophrenia and their subsequent reversal by pharmacological treatments. We review studies investigating effects of postnatal PCP on cognitive domains in schizophrenia in rats. Morris water maze and delayed spontaneous alternation tasks have been used for working memory, attentional set-shifting for executive function, social novelty discrimination for selective attention and prepulse inhibition of acoustic startle for sensorimotor gating. In addition, we review studies on locomotor activity and neuropathology. We also include two studies using dual hit models incorporating postnatal PCP and two studies on social behaviour deficits following postnatal PCP. Overall, the evidence we provide supports the use of postnatal PCP to model cognitive and neuropathological disturbances of relevance to schizophrenia. To date, there is a lack of evidence to support a significant advantage of postnatal PCP over the adult subchronic PCP model and full advantage has not been taken of its neurodevelopmental component. When thoroughly characterised, it is likely that it will provide a useful neurodevelopmental model to complement other models such as maternal immune activation, particularly when combined with other manipulations to produce dual or triple hit models. However, the developmental trajectory of behavioural and neuropathological changes induced by postnatal PCP and their relevance to schizophrenia must be carefully mapped out. Overall, we support further development of dual (or triple) hit models incorporating genetic, neurodevelopmental and appropriate environmental elements in the search for more aetiologically valid animal models of schizophrenia and neurodevelopmental disorders (NDDs).

Translational Models of Gambling-Related Decision-Making.

Gambling is a harmless, recreational pastime that is ubiquitous across cultures. However, for some, gambling becomes a maladaptive and compulsive, and this syndrome is conceptualized as a behavioural addiction. Laboratory models that capture the key cognitive processes involved in gambling behaviour, and that can be translated across species, have the potential to make an important contribution to both decision neuroscience and the study of addictive disorders. The Iowa gambling task has been widely used to assess human decision-making under uncertainty, and this paradigm can be successfully modelled in rodents. Similar neurobiological processes underpin choice behaviour in humans and rats, and thus, a preference for the disadvantageous "high-risk, high-reward" options may reflect meaningful vulnerability for mental health problems. However, the choice behaviour operationalized by these tasks does not necessarily approximate the vulnerability to gambling disorder (GD) per se. We consider a number of psychological challenges that apply to modelling gambling in a translational way, and evaluate the success of the existing models. Heterogeneity in the structure of gambling games, as well as in the motivations of individuals with GD, is highlighted. The potential issues with extrapolating too directly from established animal models of drug dependency are discussed, as are the inherent difficulties in validating animal models of GD in the absence of any approved treatments for GD. Further advances in modelling the cognitive biases endemic in human decision-making, which appear to be exacerbated in GD, may be a promising line of research.

S1P signaling: new therapies and opportunities.

Development of sphingosine-1-phosphate receptor 1 (S1P1) modulators to dampen inflammation and its sequelae is becoming increasingly promising for treating medical conditions characterized by significant immunopathology. As shown by the non-selective S1P receptor modulator FTY720 (fingolimod [Gilenya®]) in the treatment of relapsing-remitting multiple sclerosis (MS), the ability to use S1P1 modulation to precisely block immune cell traffic—immunomodulation—while maintaining immunosurveillance, has opened therapeutic opportunities in various other immune-derived chronic pathologies, including inflammatory bowel disease (IBD), lupus, psoriasis, as well as, potentially, in early acute viral respiratory infection. Proof-of-concept studies across validated animal models with S1P receptor modulators highly selective for S1P1, such as BAF-312 (Siponimod), KRP-203, ONO-4641 (Ceralifimod), ponesimod and RPC-1063, and emerging clinical trials for safety and efficacy in humans, particularly in MS, ulcerative colitis (UC) and psoriasis, have set the stage for us to consider additional testing in various other autoimmune diseases.

A review of hyperacusis and future directions: part II. Measurement, mechanisms, and treatment.

Hyperacusis can be extremely debilitating, and at present, there is no cure. In this detailed review of the field, we consolidate present knowledge in the hope of facilitating future research. We review and reference the literature on hyperacusis and related areas. This is the 2nd of a 2-part review. Hyperacusis encompasses a wide range of reactions to sounds, which can be grouped into the categories of excessive loudness, annoyance, fear, and pain. Reasonable approaches to assessing the different forms of hyperacusis are emerging, including brain-imaging studies. Researchers are only beginning to understand the many mechanisms at play, and valid animal models are still evolving. There are many counseling and sound-therapy approaches that some patients find helpful, but well-controlled studies are needed to measure their long-term efficacy and to test new approaches. Hyperacusis can make life difficult in this increasingly noisy world, forcing sufferers to dramatically alter their work and social habits. We believe this is an opportune time to explore approaches to better understand and treat hyperacusis.