Emma L. Lane and Stephen B. Dunnett (eds.)NeuromethodsAnimal Models of Movement Disorders1Volume I10.1007/978-1-61779-298-4_1© Springer Science+Business Media, LLC 2011
1. Why Cannot a Rodent Be More Like a Man? A Clinical Perspective
(1)
The Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales, UK
Abstract
Neurodegeneration is largely limited to humans, with spontaneous neurodegenerative conditions being extremely rare in animals. However, whole animal models are crucial for a proper understanding of the neurodegenerative process as well as essential for preclinical assessment of novel therapies. Thus, it has been necessary to generate animal models of neurodegeneration using a combination of techniques, including injectable toxins and genetic manipulation. Given the constraints inherent in these approaches, how successful are animal models of neurodegeneration and how can such models be refined in the future?
Key words
Experimental medicineTranslationClinical studiesAnimal studiesValidity1 Introduction
The clinician’s perspective on the value, suitability and desirability of animal models does not differ markedly from that of the neurobiologist. From a clinical perspective, the need is to use animal models to understand more about the disease mechanisms, to test therapeutic options and to investigate disease clinical features in animals in a way that cannot be undertaken in humans for both ethical and practical reasons. For simplicity, the focus here is largely on rodent models of neurodegeneration, although it is acknowledged that a wide range of species, including worms, flies, toads, pigs, sheep and primates have all played a role in furthering our understanding of the brain more generally and neurodegenerative processes more specifically.
What one would really like of animal models is for them to represent all the pathological and clinical features of specific diseases seen in man. Ideally, this would utilize naturally occurring models (but there are very few of these indeed) that have “face” validity such that the abnormal movements and behaviours we see in man are accurately reflected in the animal. Moreover, the model should have “construct” validity such that it reflects the underlying pathological changes that are faithful to the disease process in man. The model should allow assessment of the full range of symptoms seen in man, including psychiatric, as well as cognitive and motor dysfunction. It should be accurate enough for testing the efficacy of new and emerging therapies. However, most of us are realistic enough to understand that this is unachievable and that it is inevitable that animal models are incomplete representations of the human condition. So the question is how good are the models to date, and how useful is an incomplete model?
First and foremost, by definition, the genetic backgrounds of rodents and humans are not identical and, as a complete understanding of all the genetic elements of any condition (even for a dominant condition with complete penetrance) is a long way off, it is not realistic at this stage to think in terms of manipulating the genetics to compensate for this. Furthermore, the brain of rodent models, and even of most primate models, may follow a similar structural plan to that of man, but is not identical. There are also well-documented differences in terms of the precise cellular content and neuronal connections of homologous structures – an example being the change in functional significance of the red nucleus in lower, compared to higher mammals (1) (see also Lemon, volume II of this series). There are many other differences, such as the rodent brain being set up with olfaction and whisker touch as the predominant special senses, as opposed to vision in man. Another important difference that almost certainly impacts on the validity of rodent–human extrapolations is the difference in lifespan of over 70 years. This may play a major role in the lack of clinical disease seen in many rodent disease models despite apparently appropriate disease processes at the cellular level, and this is not surprising when one takes into account that age is a major risk factor for many neurodegenerative conditions in adult humans (2). Given that most neurodegenerative diseases take decades to develop in man, it may simply be the case that the rodent lifespan is too short to manifest the disease phenotype.
The reality, of course, is that we must make do with models that are partial but nevertheless can provide valuable insights providing that we use them intelligently. A major route to using a model successfully is that it is well-characterized so that its strengths and limitations are well-understood. This can be a labour-intensive and expensive process, but is essential for understanding the appropriate use of a model for a specific need and also for using that model most efficiently. For example, Drosophila models exist for a number of neurodegenerative conditions, and although some of them may have behavioural phenotypes (3), the major value is their rapid life cycle, so allowing research that requires examination of multiple generations and their suitability for sophisticated genetic manipulation. In contrast, genetic manipulation of rodents is more time-consuming, expensive and complex, but rodents lend themselves much more readily to more sophisticated movement or cognitive analysis. Another example of the requirement for proper characterization is for testing of therapeutic agents, where the reliability, timing and nature of functional deficits need to be carefully defined in detail so that effects of the agent can be accurately assessed (4).
2 Do Models Have Face Validity?
In general, face validity in rodent neurodegenerative models is variable. Some animals with what appears to be the appropriate pathological lesion may demonstrate no discernible functional phenotype, whereas others may have a variety of functional deficits that have features suggesting that they are close correlates of the human condition. Given that rodents are nocturnal animals that walk on all fours, use their whiskers and olfactory system to sense their environment and for social interaction, it is perhaps not surprising that many neurodegenerative models have limited face validity, as it could be argued that rodents are set up rather differently to meet different challenges to those faced by man. This may explain to some extent why some of the deficits seen in rodent neurodegenerative models may be in the same domain as those in human, but are not precisely recognizable as the human counterpart. For example, in many of the available models of Huntington’s disease (HD), the animals display both motor and cognitive deficits that appear to approximate to those seen in man, but are not identical. One of the more striking features of the human condition is the chorea: purposeless involuntary movements that commonly increase in frequency and severity throughout the disease, but may wane in advanced disease as rigidity and dystonia come to dominate. Rodent models of HD do not show chorea-like movements of the type seen in the patients for reasons that are not yet clear. There are numerous possibilities. For example, toxin models, such as striatal injection of quinolinic acid or systemic injection of 3NP that replicate the selective loss of medium spiny neurons seen in the human condition, may be too acute and some symptoms may only emerge from gradual and progressive cell loss. Furthermore most models that show progressive cell loss are created using transgenic or knock-in technology and in order to see a phenotype within the lifetime of the rodent very large CAG repeats are used that may mean that the models are more representative of the juvenile disease (in which repeat numbers are high) than adult onset HD in which repeat numbers are typically between 40 and 50 (see Hickey and Chesselet, volume II of this series). The juvenile form of the human disease usually presents with a rigid/dystonic variant of the condition with chorea being uncommon. Other possibilities exist, for example the anatomical distribution of pathology induced in rodents may be sufficiently different to that in man to explain the difference in motor symptopmatology. Equally, one could speculate that the basal ganglia could have a different, although overlapping, functional profile in rodents and man, and the function in man that leads to striatal damage producing chorea (perhaps the capacity of the basal ganglia to “focus” movements and suppress extraneous movements) may be more prominent in man and of less importance in rodents.
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