Animal Models for Neurological Disorders

Alzheimer’s disease (AD) is a type of dementia characterized pathologically by inappropriate neuronal loss in the specific brain regions, mainly in the hippocampus and cerebral cortex, where an accumulation of insoluble plaques of amyloid-beta (Aβ) and tau tangles formation occurs, resulting in progressive memory loss, impaired thinking, deterioration and changes in personality and mood. Alzheimer’s disease now possesses a significant health burden and is considered the main source of inability among aged individuals. Recently, Alzheimer's Disease International (ADI) evaluations of 2019 featured that there would be more than 50 million individuals living with dementia around the world, a figure set to increment to 152 million by 2050. Somebody creates dementia-like clockwork, and the current year expense of dementia is assessed at US $1trillion, a figure set to twofold by 2030. AD is the leading cause of dementia and accounts for 60-80% of cases. In spite of the fact that Aβ conglomeration and neurofibrillary tangles (NFTs) development are notable major causative components engaged with AD pathogenesis, the researchers failed to cure or prevent progression of disease effectively by focusing on these pathogenic variables. Thus, tackling AD is a complex job, as we have erudite lately by continuous phase III clinical trial programs failures. Due to the lack of a clear etiology and increased morbidity associated with Alzheimer's disease, there is an immediate need to investigate the underlying causes of the disease and design and develop novel therapeutic agents to slow or reverse disease progression. Animal models mimicking different types of ADlike pathological conditions, which is an essential component in discovering potential therapeutic targets and studying mechanism of action behind that therapeutic agent, as we know, are primary tools in the field of biomedical research including AD. This chapter discusses emerging pathophysiological mechanisms and drug targets, as well as a summary of in-vivo/ex-vivo, in-vitro, QSAR, and in-silico models commonly used in Alzheimer's disease research. Moreover, we will also describe how to select suitable and valid models and the specifications and relevance of a couple of behavioral assessment methods.

Animal models help understand the possible pathways involved in a disease's pathophysiology, and they offer a significant test to screen the potential of a therapeutic compound. Depression is a chronic mental illness that affects the world's population widely. There are different behavioral and non-behavioral models of depression used in experimental animals to explore and understand the primary mechanism of depression. These models produce different types of depressive symptoms that can correlate with human depressive symptoms. This study highlights the stress and non-stress models by distinguishing the merits and demerits of models used for depression.

Animal models provide an opportunity to decipher the relationships between the nervous system and animal behaviour as they serve as obligatory tools for screening for new drugs. As psychosis is a chronic and complex mental disorder, therefore, different theories are available. However, the pathophysiology of psychosis is still not fully clear, making it challenging to develop a coherent framework appropriate for animal modeling. Though, limited animal models are available to explore several relevant theories and to evaluate specific mechanistic hypotheses. These animal models have been based on neurotransmitter systems supposed to be involved in psychosis. Now, the emphasis has been shifted to targeting related brain areas to explore possible pathophysiological hypotheses. In the present chapter, the authors have described various behavioural and non-behavioural animal models to test for antipsychotics. Emphasis has been given to the procedure because these models help to shape the direction of future research.

Parkinson's is the 2nd most common neurodegenerative disease in which symptoms range from several motor (rigidity, tremors, and bradykinesia) and nonmotor symptoms (cognitive impairment). These symptoms mainly arise due to alterations in dopaminergic pathways that disturb dopamine release, transmission, and storage. Animal models are employed to study human diseases to understand the disease's genetic and pathophysiological aspects. Several pathological conditions, such as the deposition of Lewy bodies, endoplasmic reticulum stress-induced unfolded proteins, and neuroinflammation, result in the degeneration of dopaminergic neurons. These reasons make the screening and evaluation of antiparkinsonian drugs more tedious and difficult. Animal model of Parkinson's includes neurotoxin model (MPTP, 6-OHDA, Paraquat, rotenone] and newer genetic model [α–synuclein, LRKK2, PINK). In this chapter, we have focused on the mode of action, advantages, and disadvantages of animal models of Parkinson's disease.

Vascular cognitive impairment (VCI) encompasses vascular dementia (VaD) and is the second leading form of dementia after Alzheimer’s disease (AD) plaguing the elderly population. VaD is a progressive disease that affects cognitive abilities, especially executive functioning. At present VaD lacks suitable animal models, which constrain the progress of identification of molecular and cellular mechanisms of the disease and developing suitable interventions. In this chapter, we will present and discuss the experimental animal models that have been used for VaD studies. The limitations and strengths of these models, along with important research findings, are also addressed.

Multiple sclerosis (MS) is a chronic inflammatory, autoimmune disease characterized by neuronal demyelination of the Central Nervous System (CNS). It affects more than 2 million people worldwide. Animal models are of great importance in elucidating immune-pathological mechanisms of MS. The three most commonly studied categories of MS animal models are (1) the Experimental Autoimmune Encephalomyelitis (EAE); (2) chronic demyelinating disease models through virus inoculation known as Theiler's Murine Encephalomyelitis Virus (TMEV) infection and (3) toxin-induced models of demyelination, comprising the focal toxin-induced demyelination by lysolecithin (lysophosphatidylcholine), ethidium bromide, antigalactocerebroside (GaIC) antibody) and systemic toxin-induced demyelination by cuprizone. EAE is a widely accepted animal model that reflects the pathological mechanisms of MS, making it highly useful to analyze new therapeutic approaches. However, TMEV infection and toxin-induced models are most suitable for studying the role of de and remyelination processes and axonal injury or repair in MS. Furthermore, Zebrafish models have also emerged in recent years as novel animal models for MS because of their swift development and controllable genetic manipulations. In a nutshell, despite their limitations, animal models remain the most useful research tools to answer specific research questions related to pathological mechanisms and to validate potential experimental therapies for MS.

Schizophrenia, a chronic debilitating brain disorder, affects about 1% of the world’s population and is one of the most complex diseases in psychiatry. Despite intensive research, the molecular etiology and pathophysiology of the disease remain ambiguous and limited. Modeling aspects of schizophrenia in animals is critical for understanding the pathophysiology of the disease and may play a pivotal role in the development of novel treatments. This chapter aims to review various animal and invitro models relevant to schizophrenia and discuss various aspects to comprehend the pathophysiology, mimic the symptoms and utility in novel target identification and development. The clinical symptoms of schizophrenia are broadly classified as positive, negative, and cognitive, with the current treatments focusing mainly on positive symptoms and a limited focus on negative and cognitive symptoms. We further focus on the models to evaluate various cognitive deficits associated with schizophrenia which tend to be long-lasting, like working memory, visual memory, attention, and social cognition.

Abstract: Autism Spectrum Disorder (ASD) involves social interaction deficit, impaired communication skills, and pervasive and stereotypic behavior. It also involves co-morbidities such as anxiety, aggressive nature, and epilepsy. Apart from the above, this disorder also affects physiological co-morbidities that co-exist with behavioral symptoms, such as immune system and mitochondrial dysfunction, and gastrointestinal complications, leading to oxidative stress neuroinflammation, further worsening the behavioral complications. It has been reported that 23%-70% of patients who have ASD account for gastrointestinal complications, which correlate with behaviors relevant to autistic endophenotype. A strong gut-brain dysbiosis occurs in ASD patients due to the enormous production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut-flora, worsening the behavioral neurochemical and mitochondrial dysfunction. This further leads to the generation of free radical species responsible for synthesizing pro-inflammatory cytokines, which cause microglia activation. There are various animal models of autism, such as the induced animal model and transgenic animal model, which could give valuable hints toward understanding the molecular, cellular, and pathomorphological processes involved in this neurodevelopmental disorder heterogeneous and has a multifactorial origin. However, though all animal models focus on establishing the face validity of ASD, very few focus on construct validity and predictive validity about gut-brain dysbiosis in ASD patients because of the abnormal gut-flora leaky-gut phenomenon. Thus, in this chapter, our focus would be to understand the phenomenon of gut-brain cross-talk in ASD, the role of short-chain fatty acids, and to bring forth the neuropsychopathology of propanoic acid (PPA)-induced rat model of ASD, which can help in establishing construct as well as predictive validity with the gut-brain cross-talk and the neuroimmune as well as behavioral complications occurring as a result of short-chain fatty acids and abnormal gut flora.

Huntington's disease (HD) is a neurological disorder caused due to mutation in the dominant IT15 gene. It is a “trinucleotide repeat” disorder caused by an increase in the number of CAG repeats in the HD gene. Progressive cell death in the cortex and striatum accompanied by a decline in cognitive, motor, and psychiatric functions are the disease's characteristics. Various animal models for HD have been developed to provide insight into disease pathology and study therapeutic strategies outcomes. Previous HD studies are primarily based on toxin-induced models to learn mitochondrial dysfunction and cell death induced by excitotoxicity seen in the HD brain. The discovery of the huntingtin mutation in 1993 resulted in creating new models that introduce a similar genetic defect in animals and then studied the disease's pathophysiology. Various Genetic models are developed to date. Invertebrate models of HD: Caenorhabditis elegans and Drosophila melanogaster models; rodent models, and some transgenic large animal models are discussed here. Each model has its advantages and limitations. The researcher must decide which model to use depending on the study's type and requirements.

Streptozotocin (STZ) through the intraperitoneal route is used as a diabetic model, while intracerebroventricular (ICV) STZ administration in rodents is a model for sporadic Alzheimer's disease (AD). It majorly induces insulin resistance along with oxidative stress, mitochondrial dysfunction, and neuroinflammation in prime brain regions of the cortex and hippocampus. The significant pathological hallmarks in AD are phosphorylated tau protein generated neurofibrillary tangles and amyloid plaques which are also observed in this model. The ICV-STZ model can be validated through various behavioral, biochemical, mitochondrial, molecular, and histopathological analyses. The potential target molecules in the insulin signaling pathway could include IR, IRS-1, PI3K, AKT, GSK-3β, etc. In a nutshell, we can say that the ICV-STZ model is quite robust for insulin-resistant sporadic AD; however, there are a few limitations like mortality and the requirement of sophisticated procedure.

Despite intensive research, brain tumor remains one of the deadliest forms of cancer with rapid progression and poor prognosis. A brain tumor is physically, emotionally, socially, and financially challenging not only for the patient but also for the caregiver. Morbid conditions like seizures, paralysis, cognitive impairment, and permanent neurological damage are the potential impacts of either the disease or therapy. Poor long-term survival with the 5-year and 10-year survival rates of almost 36% and 31%, respectively, adds to the burden. Animal models have undergone constant development with time and remain an indispensable tool for exploring the underlying pathophysiological mechanism and evaluating potential therapeutic strategies. Initial brain tumor models used chemical carcinogens to induce brain tumors, with nitrosourea derivatives being the favorable choice. These tumors could be maintained easily under in vitro conditions as cell lines and grafted in suitable syngeneic or xenogeneic hosts to study the cellular and physiological features of different types of brain tumors. The advent of transgenic technology has revolutionized animal modeling by allowing the manipulation of the host genome. Transgenic animals with gain/loss of function (knock-in/knockout) can be produced to investigate the role of any specific protein/gene involved in the cell cycle, metabolism, and signal transduction. Since the first oncomice in the 1980s, the transgenic technique and the subsequent expression of the transgene have been carefully worked out in mice. The role of different mutations, tumor suppressors, and oncogenes has also been studied. 2D and 3D in vitro techniques for faster evaluation and pre-screening of drugs have been established to mimic the brain microenvironment by manipulation of the culture conditions. Furthermore, a brief summary of non-rodent models and their potential applications has been discussed.

Neurodegenerative diseases are associated with progressive degeneration of neurons or death of nerve cells. This chapter emphasizes mainly on age-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Prion disease. Abnormal fibrous tangles, β sheet plaques, cholinergic deficits, chronic neuroinflammation, nerve cell death, oxidative stress, and inflammatory cascade are the common molecular and biochemical changes of Alzheimer’s disease. Aggregated neurofibrillary tangles and accumulated amyloid-beta(Aβ) are the defining pathological hallmarks of Alzheimer’s disease. Parkinson’s disease is a composite and multifactorial disease in which different factors concur with pathogenic factors. Prion disease is an infectious neurodegenerative disease characterized by misfolded prion protein accumulation in the brain and leads to nerve cell loss. Currently, different models have been established to understand the pathophysiology of these diseases and are also used to investigate new therapeutic compounds. Although various in-vivo models are used to study neurodegenerative diseases, in vitro models provide more insights on various pharmacological targets and mechanisms of disease during neurodegeneration. Human and animal cells derived cell cultures are used to study neurodegenerative diseases in order to accurately mimic brain environment and neuronal cell interactions. In vitro models show the reliable effect of compounds on various targets in the brain to study pathophysiological characteristics of the disease, and it also provides a controlled environment favourable to explore single pathogenic mechanisms. In this chapter, we discuss different in-vitro models used to study age-related neurodegenerative diseases.