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Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton (FL): CRC Press/Taylor & Francis; 2006.

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Animal Models of Cognitive Impairment.

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Chapter 1Introduction

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Animal models of cognitive impairment are critically important for determining the neural bases of learning, memory, and attention. These cognitive functions are the result of complex interactions of a variety of neural systems and thus cannot be well studied by simple in vitro models. Animal models of cognitive impairment are critical for determining the neural basis of cognitive function as well as for testing the efficacy of potential therapeutic drugs and the neurocognitive toxicity of environmental contaminants and drugs of abuse. A variety of models have used classic monkey, rat, and mouse models. Newer, nonmammalian complementary models with fish, flies, and flatworms are being developed. These will play an important role in both high-throughput screening of potential toxic or therapeutic compounds and in the determination of the neuromolecular bases of cognitive function.

Pharmacological models are the most commonly used models of cognitive dysfunction. They are key for determining how selected neurotransmitter-receptor systems are involved in various aspects of cognitive function such as learning, memory, and attention. Pharmacological models are also key for testing the possible use of cognition-enhancing drugs for potential treatment of cognitive impairments such as those seen in Alzheimer’s disease and other aging-related syndromes, attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, and schizophrenia. Acetylcholine is the best-characterized transmitter system in the basis of cognitive function. Both muscarinic and nicotinic cholinergic receptors have been found to be critically involved. Glutamate systems, particularly those using NMDA (N-methyl-D-aspartate) receptors, have also extensively been shown to be involved in cognition. Drugs of abuse can also produce syndromes of cognitive impairment. The best example is ethanol, which impairs a variety of cognitive functions. All of these areas are covered in detail in Section I of this book (Chapters 2, 3, 4, and 5).

Applications of animal models of cognitive impairment have been quite successful in the realm of neurobehavioral toxicology. Lead is the prime example. Persisting cognitive impairments after developmental exposure to lead have been quite well modeled in monkeys and rodents. Other metals, notably mercury, have also been well studied with animal models. The same approach can also be taken with nonmetal toxicants. Notably, polychlorinated biphenyls (PCBs) have been shown to cause persistent cognitive effects in monkey as well as rodent models. Neurotoxicants can be used in quite specific ways as probes of the involvement of particular brain systems in the basis of cognitive function. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is an excellent example of how this approach has worked both for the discovery of the importance of a particular neural system (midbrain dopamine neurons) in cognitive function and as a forum for the development of new drug treatments for a disease (e.g., Parkinson’s disease) involving that system.

Mice are becoming increasingly valuable in efforts to determine the molecular bases of cognitive function. In addition, genetically manipulated mice are increasingly being used in the development of models for new drug development. For these uses it is important to devise a valid, reliable, and quick battery of tests to determine cognitive function in mice. Application of transgenic mice to problems presented by amyloid deposition with aging is an especially promising forum for the development of new treatments for Alzheimer’s disease and other aging-related cognitive impairments. Pharmacological models have shown that acetylcholine plays key roles in the neural bases of cognitive functions. Cholinergic-receptor knockout mice are being used to good effect in determining the role of various aspects of the cholinergic systems in cognitive function.

Animal models can quite well simulate specific syndromes of cognitive impairment where the inciting faction is well known. Prime examples of this approach include studies of aging and neurotrauma. Aging studies, especially with long-lived species such as monkeys, readily demonstrate aging-induced cognitive impairment and serve as a fine basis for developing new treatments and novel drugs. Neurotrauma causes cognitive impairment in animal models in quite similar ways as in humans. The specific mechanisms underlying such impairment and the therapeutic treatments for it can be well studied in animal models.

New nonmammalian models of cognitive impairment are being developed. These models are sometimes called alternative models but are better termed complementary models, because they are best used not in place of mammalian models but to complement them. Mammalian and nonmammalian models each have their own sets of advantages and disadvantages, which can be used in a mutually complementary fashion in a strategy of research advancement. Mammals have a high degree of neuroanatomic similarity to humans, but they are generally expensive and time-consuming models to use. Nonmammalian models can be very useful in high-throughput studies for identifying potential toxicants and discovering potential therapeutic drugs, but they have a lower degree of similarity to the neural processes involved in cognitive function compared with humans. Historically, aquatic models began with the use of goldfish, but more recently the models have focused on zebrafish because of the great flowering of molecular information about neural processes in this species. Invertebrate models including flatworms (C. elegans) and insects (drosophila) show promise, but these need much more development to become generally useful.

Animal models of cognitive impairment play crucial roles in the characterization of toxicants that cause cognitive dysfunction and the identification of potential new drugs for treating cognitive dysfunction, as well as providing critical insight into the neural bases of cognitive function and dysfunction. There are a variety of important issues specific to each model and in general across models that must be considered if these models are to be used productively.

Copyright © 2006, Taylor & Francis Group, LLC.
Bookshelf ID: NBK2533PMID: 21204374

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