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This chapter highlights the pivotal role of animal models in unraveling the intricate biological mechanisms and complex neural networks associated with emotional processing and psychiatric disorders, including anxiety, depression, and addiction. These models contribute significantly to understanding distinct brain circuits governing specific emotional behaviors and uncovering potential alterations in pathological conditions. Exploring inter-individual variability and sex differences in emotional behaviors using these models is crucial for advancing our knowledge of emotional processing and dysregulation. This chapter emphasizes the importance of extending the time window analyzed, as well as the importance of using computational tools such as machine learning. Integrating cutting-edge computational tools will enable a finer understanding of the neurobiology of emotions, fostering improved interpretability of both preclinical and clinical results. Ultimately, preclinical models play a vital role in comprehending the neurobiology underlying emotional dysregulation, contributing essential insights for the development of effective treatment strategies for mental disorders.
Preclinical and clinical research have devoted limited attention to women’s health. Animal models centred on female-specific factors will improve our understanding of mental health disorders. Exploring the heterogeneity of mental health disorders, in concert with attention to female-specific factors, will accelerate the discovery of efficacious treatments for mental health disorders.
Helicobacter pylori (H. pylori) is closely associated with gastric cancer and peptic ulcers. The effectiveness of antibiotic treatment against H. pylori is diminished by the emergence of drug-resistant strains, side effects, high cost and reinfections. Given the circumstances, it is imperative to develop a potent vaccination targeting H. pylori. Understanding H. pylori’s pathogenicity and the host’s immune response is essential to developing a vaccine. Furthermore, vaccine evaluation necessitates the careful selection of design formulation. This review article aims to provide a concise overview of the considerations involved in selecting the optimal antigen, adjuvant, vaccine delivery system and laboratory animal model for vaccine formulation. Furthermore, we will discuss some significant obstacles in the realm of developing a potent vaccination against H. pylori.
The crucial role of animal models in biomedical research calls for philosophical investigation of how and whether knowledge about human diseases can be gained by studying other species. This Element delves into the selection and construction of animal models to serve as preclinical substitutes for human patients. It explores the multifaceted roles animal models fulfil in translational research and how the boundaries between humans and animals are negotiated in this process. The book also covers persistent translational challenges that have sparked debates across scientific, philosophical, and public arenas regarding the limitations and future of animal models. Among the are persistent tensions between standardization and variation in medicine, as well as between strategies aiming to reduce and recapitulate biological complexity. Finally, the book examines the prospects of replacing animal models with animal-free methods. The Element demonstrates why animal modeling should be of interest to philosophers, social scientists, and scientists alike.
Sulfur mustard (SM) is a threat to both civilian and military populations. Human skin is highly sensitive to SM, causing delayed erythema, edema, and inflammatory cell infiltration, followed by the appearance of large fluid-filled blisters. Skin wound repair is prolonged following blistering, which can result in impaired barrier function. Key to understanding the action of SM in the skin is the development of animal models that have a pathophysiology comparable to humans such that quantitative assessments of therapeutic drugs efficacy can be assessed. Two animal models, hairless guinea pigs and swine, are preferred to evaluate dermal products because their skin is morphologically similar to human skin. In these animal models, SM induces degradation of epidermal and dermal tissues but does not induce overt blistering, only microblistering. Mechanisms of wound healing are distinct in these animal models. Whereas a guinea pig heals by contraction, swine skin, like humans, heals by re-epithelialization. Mice, rats, and rabbits are also used for SM mechanistic studies. However, healing is also mediated by contraction; moreover, only microblistering is observed. Improvements in animal models are essential for the development of therapeutics to mitigate toxicity resulting from dermal exposure to SM.
We examine some of the genetic features of neuroticism (N) taking as an animal model the Maudsley Reactive (MR) and Maudsley Nonreactive (MNR) rat strains which were selectively bred, respectively, for high and low open-field defecation (OFD) starting in the late 1950s. To draw analogies with human genetic studies, we explore the genetic correlation of N with irritable bowel syndrome (IBS). We review progress with the rat model and developments in the field of human complex trait genetics, including genetic association studies that relate to current understanding of the genetics of N. The widespread differences in the tone of the peripheral sympathetic nervous system that have been found between the Maudsley strains, particularly those observed in the colon, may underly the differences in OFD (MNR, higher sympathetic tone and zero defecation). In humans, a large genome-wide association study (GWAS) reported six genes contributing to IBS, four of which were implicated in mood and anxiety disorders or were expressed in the brain, with three of the four also expressed in the nerve fibers and ganglia of the gut. Heritability of N is estimated at around 50% in twin and family studies, and GWASs identified hundreds of loci, enabling estimation of genome-wide correlations (rg) with other traits. Significantly, the estimate for rg between risk of IBS, anxiety, N, and depression was >0.5 and suggested genetic pleiotropy without evidence for causal mechanisms. Findings on the adrenergic pharmacology of the colon, coupled with new understanding of the role of the locus ceruleus in modifying afferent information from this organ, generate hypotheses that challenge traditional cause/effect notions about the relationship of the central nervous system to peripheral events in response to stress, suggest specific targets for gene action in the Maudsley model and emphasize the value of reciprocal evaluation of genetic architecture underlying N in rodents and humans.
While it has the potential to deliver important human benefits, animal-based pain research raises ethical questions, because it involves inducing pain in sentient beings. Ethical decision-making, connected with this variety of research, requires informed harm-benefit analysis, and the aim of this paper is to provide information for such an analysis. We present an overview of the different models and their consequences for animal welfare, showing that, of the many animal models available, most have a considerable welfare impact on the animal. While the usual approach to pain control through administration of analgesic substances is usually unsuitable in pain research, refinement remains an option, both within the experimental protocol and in general husbandry and handling. Drawing on the overview, we develop a discussion of the ethical acceptability of animal-based pain research against the background of the kinds of harm done to the animals involved, the potential for refinement, and the expected benefits of the research.
Animal models have long been used to investigate human mental disorders, including depression, anxiety, and schizophrenia. This practice is usually justified in terms of the benefits (to humans) outweighing the costs (to the animals). The author argues on utility maximization grounds that we should phase out animal models in neuropsychiatric research. The leading theories of how human minds and behavior evolved invoke sociocultural factors whose relation to nonhuman minds, societies, and behavior has not been homologized. Thus, it is not at all clear that we are gaining the epistemic or clinical benefits we want from this animal-based research.
The blood brain barrier (BBB) is a highly selective permeable barrier that separates the blood and the central nervous system. Anesthesia is an integral part of surgery, and there is little known about the impact of anesthetics on the BBB. Therefore, it is imperative to explore reversible or modifiable variables such as anesthetic agents that influence BBB integrity. We aimed to synthesize the literature pertaining to the various effects of anesthetics on the BBB.
Methods:
MEDLINE, Embase, and Cochrane were searched from inception up to September 2022.
Results:
A total of 14 articles met inclusion into the review. The articles included nine randomized control studies (64.3%) and five quasi-experimental studies (35.7%). Twelve studies used volatile anesthetics, one study used fentanyl intravenously, and one study used pentobarbital or ketamine intraperitoneally. BBB structural deficits following the administration of an anesthetic agent included ultrastructural deficits, decreases in tight junctions, and decreases in BBB components. BBB functional deficits included permeability increases following exposure to volatile anesthetics. However, two studies found decreased permeability after fentanyl, pentobarbital, or ketamine exposure. Moreover, the impact of anesthetics on the BBB seems to be related to the duration of exposure. Notably, study findings also suggest that changes following anesthetic exposure demonstrate some reversibility over the short-term.
Conclusion:
Overall, our systematic review highlights interesting findings pertaining to the impact of anesthetic agents on BBB integrity in previously healthy models. These findings and mechanisms should inspire future work to aid practitioners and healthcare teams potentially better care for patients.
Overexposure to Se is detrimental to glucose metabolism, mainly because of its pro-oxidant effects and the overexpression of selenoproteins. This systematic review evaluated the effects of Se supplementation on glycaemic control in healthy rodents. The methodology followed the PRISMA. We searched the databases for articles published up to May 2022. The risk of bias and the methodological quality were assessed using the SYRCLE and CAMARADES. The results are presented as meta-analytic estimates of the overall standardised mean difference (SMD) and 95 % CI. Of the 2359 records retrieved, thirteen studies were included, of which eleven used sodium selenite and two used zero-valent Se nanoparticles as supplement. Nine studies were included in the meta-analysis. Generally, the risk of bias was high, and 23·1 % of the studies were of high quality. Supplementation with sodium selenite significantly increased fasting blood glucose (SMD = 2·57 (95 % CI (1·07, 4·07)), I2 = 93·5 % (P = 0·001). Subgroup analyses showed effect size was larger for interventions lasting between 21 and 28 d (SMD = 25·74 (95 % CI (2·29, 9·18)), I2 = 96·1 % (P = 0·001)) and for a dose of 864·7 μg/kg/d of sodium selenite (SMD = 10·26 (95 % CI (2·42, 18·11), I2 = 97·1 % (P = 0·010)). However, it did not affect glutathione peroxidase activity (SMD = 0·60 (95 % CI (-0·71, 1·91)), I2 = 83·2 % (P = 0·37)). The current analysis demonstrated the adverse effects of sodium selenite supplementation on glycaemic control in healthy rodents.
Hallucinations occur in the absence of sensory stimulation and result in vivid perceptual experiences of nonexistent events that manifest across a range of sensory modalities. Approaches from the field of experimental and cognitive psychology have leveraged the idea that associative learning experiences can evoke conditioning-induced hallucinations in both animals and humans. In this review, we describe classical and contemporary findings and highlight the variables eliciting these experiences. We also provide an overview of the neurobiological mechanisms, along with the associative and computational factors that may explain hallucinations that are generated by representation-mediated conditioning phenomena. Through the integration of animal and human research, significant advances into the psychobiology of hallucinations are possible, which may ultimately translate to more effective clinical applications.
Animal model systems play a fundamental role in the development and evaluation of novel treatments for Alzheimer’s disease (AD). The examination of safety and tolerability in animal models is a necessary first step prior to any human clinical trials. Equally important, preclinical testing of novel therapeutics in disease relevant models is required for the determination if a potential therapeutic should advance. There are a number of important considerations in the preclinical workflow that range from selection of the most appropriate animal model related to drug mechanism of action, as well as what AD-relevant measures are to be evaluated to determine if a candidate therapy should advance. In this chapter we highlight the process of preclinical animal model testing for novel therapeutics in AD, as well as detail several of the models utilized and the measures relevant to AD. We also include the emerging approaches to provide better AD animal models (MODEL-AD) as well as emerging approaches to refine the process of identifying new treatments (TREAT-AD).
There are many challenges of proper drug dosing with nanodelivery systems. The first part of this discussion concerns how experts think about drug dosing with conventional drugs. In the second part, we need to consider the differences between nanodevices and traditional drug delivery, and pharmacokinetics using nanodrug delivery. Drug dosing uses scale-up methods from animal model data before testing on humans. New organ-on-a-chip and human-on-a-chip technologies may someday replace animal data.
The incorporation of target engagement, efficacy, and imaging abnormalities biomarkers on preclinical (animal) drug development brings the promise of accelerating drug development. In this chapter, we will highlight innovative methodological considerations that will bring greater predictive power relative to the traditional approaches in the preclinical stage of drug discovery. First, we discuss various animal models used in Alzheimer’s disease research and important aspects to consider when choosing the appropriate model to test a novel therapeutic intervention. Second, compared to the traditional histological methods, utilizing in vivo biomarkers in preclinical assessment allows quantifying disease pathophysiology with complex longitudinal designs. We discuss the feasibility and implications of longitudinal study designs and how the same in vivo biomarkers used in human clinical trials can be implemented to evaluate the preclinical development stages. Lastly, we discuss why the incorporation of methods from human clinical trials can advance the preclinical phases of drug discovery.
Infection by malaria parasites (Plasmodium spp.) remains one of the leading causes of morbidity and mortality, especially in tropical regions of the world. Despite the availability of malaria control tools such as integrated vector management and effective therapeutics, these measures have been continuously undermined by the emergence of vector resistance to insecticides or parasite resistance to frontline antimalarial drugs. Whilst the recent pilot implementation of the RTS,S malaria vaccine is indeed a remarkable feat, highly effective vaccines against malaria remain elusive. The barriers to effective vaccines result from the complexity of both the malaria parasite lifecycle and the parasite as an organism itself with consequent major gaps in our understanding of their biology. Historically and due to the practical and ethical difficulties of working with human malaria infections, research into malaria parasite biology has been extensively facilitated by animal models. Animals have been used to study disease pathogenesis, host immune responses and their (dys)regulation and further disease processes such as transmission. Moreover, animal models remain at the forefront of pre-clinical evaluations of antimalarial drugs (drug efficacy, mode of action, mode of resistance) and vaccines. In this review, we discuss commonly used animal models of malaria, the parasite species used and their advantages and limitations which hinder their extrapolation to actual human disease. We also place into this context the most recent developments such as organoid technologies and humanized mice.
There is no doubt that intracytoplasmic sperm injection (ICSI) has been a major breakthrough in treating male infertility, accounting for 70–80% of all the cycles performed worldwide. Surprisingly, there were very few animal studies conducted before the first babies were born, in part because of technical challenges that were experienced in most animal systems. Technological advancements were required to develop appropriate animal models for assessing the safety of ICSI. These studies identified many cytoskeletal changes that occurred in the oocyte cytoplasm after ICSI versus natural conception or even IVF, raising concerns about the long-term health of ICSI offspring. This chapter summarizes the animal models that have contributed to our understanding of the cellular and molecular aspects of ICSI, as well as providing models to investigate both the developmental origins of adult disease and transgenerational implications as they relate to ICSI.
Epidemiologically, metabolic disorders have garnered much attention, perhaps due to the predominance of obesity. The early postnatal life represents a critical period for programming multifactorial metabolic disorders of adult life. Though altricial rodents are prime subjects for investigating neonatal programming, there is still no sufficiently generalised literature on their usage and methodology. This review focuses on establishing five approach-based models of neonatal rodents adopted for studying metabolic phenotypes. Here, some modelled interventions that currently exist to avoid or prevent metabolic disorders are also highlighted. We also bring forth recommendations, guidelines and considerations to aid research on neonatal programming. It is hoped that this provides a background to researchers focused on the aetiology, mechanisms, prevention and treatment of metabolic disorders.
The present work evaluated animal models comprising direct and maternal effects to estimate (co)variance components and genetic parameters of growth rates and Kleiber ratio in Harnali sheep. The information on pedigree and targeted traits of 1862 lambs born to 144 sires and 591 dams was collected for the period from 1998 to 2018. The traits studied were average daily gain from birth to 3 months of age (ADG1), 3 months to 6 months of age (ADG2), and 6 months to 12 months of age (ADG3) and their corresponding Kleiber ratios as KR1, KR2 and KR3, respectively. The statistical methods included the general linear model for analyzing the effects of fixed factors and animal models for deriving variance components for targeted traits. According to best model evaluated on the basis of likelihood ratio test, the estimated direct heritability was low in magnitude and ranged from 0.04 to 0.14. Direct heritability estimates for ADG1, ADG2, ADG3, KR1, KR2 and KR3 were 0.06, 0.14, 0.05, 0.04, 0.11 and 0.05, respectively. The maternal genetic effects contributed (4–7%) significantly for ADG1, KR1 and KR2 traits. The genetic correlations ranged from −0.35 ± 0.11 (ADG1-KR2) to 0.98 ± 0.01 (ADG2-KR2 and ADG3-KR3) and phenotypic correlations ranged from −0.36 ± 0.02 to 0.98 ± 0.01 for ADG1-KR2 and ADG2-KR2, respectively. The significant maternal effects along with low levels of direct effects for average daily gain and Kleiber ratio at different age group should be considered while setting selection and managerial strategies to achieve anticipated growth rates in Harnali sheep.
Menno Reindert Kruk was born in 1944 in the Netherlands. He did his PhD on the ‘Origins of Hypothalamic Aggression’ and became President of the International Society for the Study of Aggression. He coordinated Hungarian-Dutch cooperation on ‘Stress and Aggression Interactions’ and an interdisciplinary multicenter research program on the ‘Neuroanatomy and Temporal Structure of Hypothalamic Responses’. His main research focus was the interaction between brain function, hormones, and behavior, with the aim of understanding brain mechanisms during violent behavior. He specifically explored how aggression could be studied using methods from the natural sciences and animal models, first to clarify which hypothalamic neurons mediate attack during electrical stimulation and then to register their activity during social interactions in order to understand ‘pathological’ processes in aggression. The research methods he used included ethological, pharmacological, endocrine, physiological, and mathematical approaches. He developed animal models of functional and pathological aggression and the mathematical tools to describe and analyze the effects of drugs and hormones on behavioral structure and on social interactions between animals. He studied the crucial role of corticosteroid feedback to the brain for the control of aggressive behavior and studied the interactions between the processing of conflict-related stimuli and stress hormones in humans.
Objective and rationale: Animal models are critical for the study of mental disorders and their treatments but are repeatedly criticized for problems with validity and reproducibility. One approach to enhance validity and reproducibility of models is to use test batteries rather than single tests. Yet, a question regarding batteries is whether one can expect a consistent individual behavioural phenotype in mice across tests that can be presumed to be part of the same construct. This study was designed to explore the relationship between the behaviours of mice across tests in some variations of test batteries for depression- and anxiety-like behaviours. Methods: Female and male healthy, intact, and untreated mice from the ICR and black Swiss strains were used in four separate experiments. With some variations, mice were exposed to a battery of behavioural tests representing affective- and anxiety-like behaviours. Data were analysed for differences between sexes and for correlations between behaviours within and across the tests in the battery. Results: No differences were found between the sexes. With very few exceptions, we found correlations within tests (when one test has more than one measure or is repeated) but not across different tests within the battery. Conclusions: The results cast some doubt on the utility of behavioural test batteries to represent different facets of emotional behaviour in healthy intact outbred mice, without any interventions or treatments. Additional studies are designed to explore whether stronger relationship between the tests will appear after manipulations or drug treatments.