ReviewThe use of pigs in neuroscience: Modeling brain disorders
Introduction
Rodents and primates have been the preferred animal species studied within neuroscience. However, within other research areas, such as toxicology (Lehmann, 1998), diabetes (Larsen and Rolin, 2004) and experimental surgery (Richer et al., 1998), the use of pigs has increased dramatically over the past few decades. The emergence of pig experimental models reflects the considerable resemblance of pigs to human anatomy and physiology. The pig is widely available due to commercial production, and vast species-specific knowledge has been obtained in Denmark and other pork-producing countries. This background has led to the development of standardized laboratory pigs, the use of which can present considerable advantages over primates, for ethical, and economic reasons.
Despite considerable progress in understanding neurobiological disorders, there is enormous scope for refinement of knowledge about the neurobiological processes underlying normal and the abnormal human behavior. In this context, the use of the pig (Sus scrofa) as an alternative animal species could be appropriate for obtaining advanced understanding of general neuronal and behavioral processes. Indeed, more than 40 years ago, the pig was first proposed as an excellent experimental animal for human medical research, due to the many similarities between human and porcine biology (Bustad and McClellan, 1965; Douglas, 1972). The potential for using pigs in pediatric brain research was recognized early (Glauser, 1966) due to the similarities in the extent of peak brain growth at the time of birth, the gross anatomy (i.e. gyral pattern, distribution of gray and white matter), and the growth pattern of neonatal porcine brain to that of human infants (Dickerson and Dobbing, 1966; Thibault and Margulies, 1998). Subsequently, a substantial body of evidence has been gathered supporting the wider use of pigs rather than rodents for neuroscience research.
As noted above, the pig has a long history for use in non-CNS-related biomedical research, while the extensive use of pigs within neuroscience has increased only in the past decade. A literature search of the PubMed database using the keywords “swine brain animal model” reveals four times as many hits in the period 1996–2005 than during the preceding 10-year period. The present paper is intended to serve as a broad introduction to the use of pigs as an experimental animal in CNS research, particularly studies modeling human brain disorders. The paper covers important practical and ethical aspects of the use of pigs as an experimental animal. In particular, emphasis is placed on practical considerations in relation to operation of laboratory animal facilities and the use of in vivo experimental brain techniques. An update on recent progress and future perspectives of gene-manipulating techniques of the pig is provided, and an analysis of ethical considerations related to the use of pigs as experimental animals is presented. Furthermore, selected areas of the current research literature on pigs within behavioral neuroscience and neurotoxicology are reviewed. It is our aim to encompass in this review key areas of pig CNS research, including neurobiology, neuroanatomy and cognitive neuroscience, and to present a critical evaluation of the scope and limitations of pigs as appropriate species for modeling human brain disease. Particular emphasis is placed on the potential of pigs for modeling symptoms or phenomena of neuropsychiatric diseases (viz. schizophrenia, Alzheimer's disease, Parkinson's disease), which may benefit from the validation of new animal models.
Section snippets
The pig as a laboratory animal
All purpose-bred laboratory pigs and most agricultural pigs are derived from the Eurasian wild boar, S. scrofa. However, selective breeding has resulted in a number of different breeds, varying in both anatomy and physiology. Agricultural pigs are most commonly used in research due to their ready availability and low price. The most common agricultural breeds in the western world are Landrace, Yorkshire, Hampshire and Duroc (Bollen et al., 2000). However, none of these breeds are globally
Comparative neuroanatomy
Whereas the rat cerebral cortex is lissencephalic, the pig brain cortical surface more closely resembles human gyrencephalic neocortex (Hofman, 1985). Similarities in the gross anatomy of pig brain to that of human brain has also been demonstrated for the hippocampus, a limbic structure (Dilberovic et al., 1986; Holm and Geneser, 1989), as well as for subcortical and diencephalic nuclei (Felix et al., 1999; Larsen et al., 2004), and brainstem structures (Freund, 1969; Ostergaard et al., 1992).
Behavioral testing of pigs
Behavioral recording is crucial for attempting to understand the neurobiological processes underlying normal as well as abnormal behavior. Several well-known behavioral tests are available for assessing porcine behavior.
The open field test is widely used for assessing locomotor activity and specific behaviors during a fixed interval after introduction of the animal to an enclosed arena. The behavioral response of pigs in an open field test is relatively stable if the test is performed a limited
Production of transgenic pigs by somatic cell nuclear transfer (SCNT)
In the decades since the first generation of transgenic mice produced by pronuclear injection (Gordon et al., 1980), transgenic animals have become indispensable tools for studying gene function, development, and regulation. Transgenic animals have already provided key insights into the brain and behavioral processes of relevance for human brain disorders.
The discovery of homologous recombination in cell cultures (Smithies et al., 1985), in conjunction with the development of embryonic stem
Discussion
The use of pigs in experimental brain research was advocated more than 30 years ago. However, factors favouring the continuing and nearly exclusive use of rodents include the ease of housing and handling of small laboratory rodents, and the low requirement of administered. In contrast, the use of non-human primates was favoured due to the inherently greater similarity to human brain function. Nonetheless, the use of pigs within neuroscience has increased in the past decade to an extent, which
Conclusions
The use of pigs within neuroscience has increased dramatically in recent. In spite of the disadvantages presented by housing requirements and large body size, the advantages of using pigs as an experimental animal for modeling human brain disorders has become increasingly evident. A considerable amount has been learned about pig brain anatomy and neurochemistry, but little is known about cortical function. The gyrencephalic pig brain is more similar to the human brain in anatomy, growth and
Acknowledgment
Thanks to Tim Dyrby for providing the magnetic resonance images.
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Present address: Rheoscience, Glerupvej 2, DK-2610 Rødovre, Denmark.