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Expansion of a polyglutamine repeat within the spinocerebellar ataxia type 1 (SCA1)-encoded protein, ataxin-1, causes the neurodegenerative disease, SCA1. Animal models have been generated that recapitulate many of the aspects of SCA1 pathogenesis. These provide a good example of how animal models can be used to examine the pathogenesis of a human neurological disease. Studies using these animal models have led to numerous conclusions regarding the pathogenic potential of mutant ataxin-1. The data indicate that protein folding and clearance pathways are important in the development of disease. Aggregation of mutant ataxin-1 is not required for initiation of disease. In the case of SCA1, Purkinje cells are the last neurons to aggregate the mutant protein but the most susceptible to the toxic effects of mutant ataxin-1, suggesting that aggregation may be a protective event. Nuclear localization of mutant ataxin-1 is necessary but not sufficient to induce pathogenesis. A single amino acid, serine 776, within ataxin-1 was found to be important in disease progression. Serine 776 of both wild-type and mutant ataxin-1 is phosphorylated. Preventing phosphorylation of this residue by replacing it with an alanine results in a mutant protein found in the nucleus that is not pathogenic. Other modifiers of ataxin-1-induced neurodegeneration include components of RNA-processing and protein-processing pathways. Importantly, because wild-type ataxin-1 is found in the nucleus and is phosphorylated at serine 776, the disease pathway likely overlaps with the normal cellular pathway(s) in which ataxin-1 participates. [ABSTRACT FROM AUTHOR]

Bipolar disorder (also known as manic-depressive illness) is distinctive among psychiatric illnesses in that it is characterized by spontaneously alternating episodes of depression and mania. Over the years, extensive research into the pathophysiology of bipolar disorder has resulted in a growing understanding of the cellular, biochemical, and molecular changes associated with bipolar disorder and its treatment. However, given its unique nature, developing an animal model for bipolar disorder in which all aspects of the illness are emulated is challenging. Indeed, fully validated animal models of bipolar disorder are not available and a variety of models are used to represent a single manic or depressive episode, with some models possibly representing the progressive nature of the disorder. Nonetheless, targeted mutations of specific neurotransmitter systems, including receptors and transporters, as well as genetic manipulations of cellular signaling pathways, produce a variety of changes in affective-like behavior, with most changes consistent with manic-like behavior. As such, these mutant mouse models (with their own limitations) could contribute to the research of the underlying brain mechanisms of mania and/or bipolar disorder. In this chapter, we present an overview of neurochemical, neuroendocrine, and behavioral changes in bipolar disorder, and of the available mutant mouse models in which some aspects of the disorder are emulated. The mutant mouse models include targeted overexpression or knockout/knock-down of genes coding for corticotropin-releasing factor, glucocorticoid receptor, serotonin transporters, and dopamine transporters, and of genes involved in intracellular signaling pathways. [ABSTRACT FROM AUTHOR]

Mood and anxiety disorders represent some of the most common and proliferating health problems worldwide, but are inadequately treated by existing therapeutic interventions. Valid animal models of anxiety and depression have a critical role to play in identifying novel therapeutic targets for these debilitating conditions. The emergence of techniques that allow genetic manipulation of specific molecules in mice has added a valuable new dimension to this field of research. In this chapter, we discuss some of the conceptual issues surrounding the use of mutant mice to study anxiety and depression, the behavioral tasks commonly used for assessment, and important caveats associated with the use of mutant mice. Anxietyrelated behavior is most commonly assayed in mice using tests based on exploratory approach/ avoid conflict (e.g., elevated plus maze, open field, light-dark exploration, and hyponeophagia), although a variety of alternatives exist (e.g., stress-induced hyperthermia, mouse defense test battery, Vogel conflict, shock-probe burying, four-plate test, marble burying, and separation-induced pup ultrasonic vocalizations). Mouse tests for depressionrelated behaviors include models based on "behavioral despair" (forced-swim test, tail-suspension test, and learned helplessness), as well as chronic mild stress, olfactory bulbectomy, and psychostimulant withdrawal. Various factors can confound performance and complicate interpretation of the behavior of mutant mice on anxiety- and depression-related tasks, including genetic background, abnormal motor and sensory phenotypes, previous test history, and variability in early life environment and parental behavior. In addition, lifelong constitutive mutations can recruit compensatory changes that occlude the normal function of a molecule in neural circuits mediating emotion-related behaviors. Mutant mice provide a particularly valuable approach to the study of anxiety disorders and depression and their treatment when used in conjunction with other techniques to generate converging lines of evidence regarding the role of a molecule in these circuits. When viewed as such, we believe that mutant mice will continue to foster the study of anxiety and depression. [ABSTRACT FROM AUTHOR]

Anxiety is a complex neurobehavioral disorder that often includes co-morbid features, e.g., obsessive-compulsive behavior. Animal models can be generated by several techniques, one of which includes transgenic and knockout technologies. Although anxiety can be assessed in various environments, we examine our animals in a naturalistic or ethological setting in what we call the mouse defense test battery (MDTB), in which predator model-induced anxiety and fear responses are studied. Additionally, we use several pharmacological agents known to induce or reduce fear and anxiety in humans. The pharmacological data gathered from the MDTB demonstrated that panic-modulating agents specifically and appropriately affect the flight responses of mice. Using the principles of ethology, we also examined motor and posture patterns of Alzheimer' disease mouse mutants (PD- APP), and found abnormalities not associated with learning and memory but suggestive of alterations in fear responses and anxiety. Animal models such as the PD-APP mouse may, thus, allow investigators to screen existing and novel drugs for their ability to alter noncognitive traits, including anxiety, in apreclinical setting. [ABSTRACT FROM AUTHOR]

Although the thinking and affective and social disturbances of psychosis and schizophrenia may not be easily modeled, if at all, in infrahuman species, animal models can clarify genetic and developmental lesions leading to disruption of some of the key anatomical circuitry involved in their pathophysiology. Increasingly, it is appreciated that patients with schizophrenia manifest symptoms in a variety of discrete domains of psychopathology, including positive (e.g., hallucinations), negative (e.g., affective flattening and social withdrawal), cognitive (e.g., concretization of thought), mood (e.g., anhedonia), and motor (e.g., mannerisms and posturing) symptoms. These symptoms may reflect, in part, the spatially and temporally integrated outputs from these disrupted or faulty circuits. Major goals of current descriptive and pathological research in schizophrenia include the development of sensitive behavioral rating instruments for the assessment of the presence and severity of symptoms in discrete psychopathological domains, elucidation of unique neurotransmitter abnormalities that may underlie each of these discrete domains of psychopathology, and determining the quantitative contribution of each of these discrete domains of psychopathology to the functional disability manifested by patients with schizophrenia and other psychosis. Thus, animal models that reflect nondopaminergic neurotransmitter abnormalities implicated in the pathophysiology of these discrete domains of psychopathology are especially useful. In addition to clarifying aspects of the pathophysiology of these disorders, animal models are crucial for identifying candidate compounds that may be developed as medications; novel medications are especially needed for the negative and cognitive symptom domains of psychopathology, which may be less dependent on abnormalities of dopaminergic neurotransmission. The contributions of dopaminergic abnormalities to the pathophysiology of schizophrenia have been studied most intensively. The focus on dopaminergic abnormalities in schizophrenia was prompted by the complementary observations in humans that psychosis can be elicited by psychostimulant medications such as d-amphetamine, especially when they are abused, whereas the ability to inhibit competitively the binding of dopamine to the D2 type of dopamine receptor is a pharmacological property shared by all of the conventional antipsychotic medications. Psychostimulant medications are either indirect or directly acting dopamine agonists. These pharmacological observations in humans stimulated interest in the quantitative characterization of a variety of "hardwired" rodent behaviors elicited by dopamine agonists such as apomorphine and d-amphetamine; these behaviors include a variety of stereotypic behaviors (e.g., rearing, grooming, and sniffing), horizontal locomotion and "mouse climbing," among other behaviors. These animal procedures have served as valuable screens for the identification of "dopamine blockers" and medications whose primary pharmacological actions involve modulation (dampening) of dopaminergic neurotransmission, which have proven especially effective in the attenuation of positive symptoms. However, the negative and cognitive symptom domains of psychopathology, which contribute very significantly to the functional disability of schizophrenia and other psychotic disorders, are not dramatically affected by these primarily dopaminergic interventions.… [ABSTRACT FROM AUTHOR]

The mental well-being of humans depends on the discovery of the causes of mental illnesses and the use of this knowledge to direct the generation of new treatments and the development of preventive measures. In this context, defining how we can exploit the power of animal models in investigative strategies designed to understand and manipulate candidate causal factors remains a critical challenge. The fact that mental illnesses are uniquely human disorders does not negate the feasibility of developing and using relevant animal models, but only defines the challenge and sets the limitations of an animal model. Because the field is still in its infancy, addressing the roles and targets of animal models of mental illnesses effectively and responsibly will require additional empirical data, as well as critical thinking from scientists, journal editors, and funding agencies. In this chapter, we discuss some general guidelines for the development of genetic mouse models of psychiatric disorders and offer a theoretical framework for the interpretation of their analysis. At the end, we discuss some results and practical issues emerging from our ongoing work on a genetic mouse model of schizophrenia. [ABSTRACT FROM AUTHOR]

The mysterious human propensity for acquiring speech and language has fascinated scientists for decades. A substantial body of evidence suggests that this capacity is rooted in aspects of neurodevelopment that are specified at the genomic level. Researchers have begun to identify genetic factors that increase susceptibility to developmental disorders of speech and language, thereby offering the first molecular entry points into neuronal mechanisms underlying human vocal communication. The identification of genetic variants influencing language acquisition facilitates the analysis of animal models in which the corresponding orthologs are disrupted. At face value, the situation raises aperplexing question: if speech and language are uniquely human, can any relevant insights be gained from investigations of gene function in other species? This chapter addresses the question using the example of FOXP2, a gene implicated in a severe monogenic speech and language disorder. FOXP2 encodes a transcription factor that is highly conserved in vertebrate species, both in terms of protein sequence and expression patterns. Current data suggest that an earlier version of this gene, present in the common ancestor of humans, rodents, and birds, was already involved in establishing neuronal circuits underlying sensory-motor integration and learning of complex motor sequences. This may have represented one of the factors providing a permissive neural environment for subsequent evolution of vocal learning. Thus, dissection of neuromolecular pathways regulated by Foxp2 in nonlinguistic species is a necessary prerequisite for understanding the role of the human version of the gene in speech and language. [ABSTRACT FROM AUTHOR]

This chapter describes a number of genetic mouse models of syndromic and nonsyndromic mental retardation (MR), focusing primarily on X-linked retardation models: the fragile X model, involving the fragile site mental retardation 1 gene (FMR1) the FRAXE model, involving the fragile site mental retardation 2 gene (FMR2); the Coffin-Lowry syndrome model, involving ribosomal S6 kinase 2 (RSK2); models involving GDP dissociation inhibitor (GDI)-1 mutations; the Rett syndrome model, involving the methyl-CpG-binding protein 2 (MECP2); the lacking angiotensin receptor 2 (AGTR2) model; the corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus (CRASH) syndrome model, involving mutations of the cell adhesion molecule, L1; and models involving mutations of rho guanine nucleotide exchange factor 6 (ARHGEF6). Autosomal dominant models include neurofibromatosis type 2 (NF1) and phenylketonuria (PAH). The phenotypes of experimentally altered mouse genes mostly include relatively moderate pleiotropic changes in neuroanatomy, electrophysiology, and behavioral test scores, the latterrarely matching the severity of the human phenotype. Interpretation is hampered by a general lack of understanding the causation of mental variation, and by neglecting species-specific peculiarities of mouse neuinvaluable tools for an empirical analytical approach deciphering the complex pathways between genotype and mental phenotype, chiefly because the developmental end point is, at least for nonsyndromic human MR, always severely impaired cognition. This is not the case for mouse models generated on the basis of theoretical expectations for memory and learning. [ABSTRACT FROM AUTHOR]

Genetic susceptibility to common psychiatric disease arises from the complex interactions between a multitude of genes and an unknown number of relevant environments. However, a common method for investigating gene function involves the creation of a mouse knockout of a candidate gene. Although this approach seems inappropriate to model such complexity, genetic effects on behavior attributable to null mutants in the mouse are in fact subject to the same set of complications, the same gene by environment and epistatic interactions that characterize genetic effects in psychiatric illness. Consideration of the genetic architecture of behavior indicates that even when the molecular lesion is sufficient to inactivate the gene or in other ways alter its function substantially, the effect on the phenotype is typically very mild. Overall, the explanation for the behavior may not be as complex, but it is the product of the same factors. Consequently, it may be possible to take apart the pathway from gene to psychiatric illness. [ABSTRACT FROM AUTHOR]

The advent of advanced molecular genetics methods has revolutionized biology, both in terms of identifying gene candidates and, once identified, in terms of manipulating gene function in the experimental setting to address issues of causality and mechanism. Mice are currently the most genetically tractable animal model available and have contributed significantly to furthering our understanding of gene action across multiple areas of biology and medicine. However, using mice to model psychiatric conditions raises particular challenges because of the complex and perhaps unique phenotypes affected by disorders such as autism, schizophrenia, attention deficit hyperactivity disorder, depression, and personality disorder. In this chapter, we present a realistic view of what can be modeled in this area. We discuss the concept of endophenotypes (intermediate traits), and how endophenotypes can be used to address the complexity of the clinical conditions. We also discuss the practicalities of carrying out valid behavioral studies in mice, taking in the issues raised by the ethobiological vs artificial approach debate and emphasize the positive contribution made by the increasing use of operant behavioral paradigms in mice. We conclude that, although we are very much at the "work in progress" stage, it is likely that mouse models will be of major importance in ensuring that psychiatry gets its share of the genomic dividend. [ABSTRACT FROM AUTHOR]

It is argued that the more removed the things investigated are from those about which knowledge is sought, the more susceptible to misinterpretation is the knowledge achieved. By this logic, scientific propositions pertaining to human psychiatric disorders derived from investigative contacts with mutant mice under contrived conditions deserve special scrutiny. Of particular importance, in this regard, is the adequacy with which characteristic features of the original phenomena are represented in the models under investigation. We contend that adequacy in this regard cannot be achieved for events of the psychological domain because human behavior has a unique characteristic that so profoundly affects the psychological experiences of human beings that it renders them incomparable to those of other species. We conclude that scientific propositions pertaining to the psychological components of human psychiatric disorders are not possible to construct on the basis of observational contacts with animals. [ABSTRACT FROM AUTHOR]

Humans have long distinguished themselves from infrahuman organisms. Modern notions of humans and infrahuman animals, however, date from the mid-19th century and are essentially derived from Darwin's The Origin of Species. Although Darwin differentiated between acquired habits in humans and inherited instincts in animals, his theory of evolution embraced the notion of continuity of species. Late-19th and early-20th century animal psychologists debated this issue; particularly, whether animals had minds, and, if so, whether they were capable of the same thought and emotion evinced in humans. To avoid the problems created by mentalism and consciousness in animal behavior, many leading psychologists of the time adopted the mechanistic assumption, as extant among the British associationists. Others, however, subscribed to the belief that animals were capable of problem solving that went beyond the simple conditioning paradigm incorporating the principle of reinforcement. As a formal approach, operant conditioning was instrumental in providing many important results and was an effective epistemological framework in which to view animal and human behavior. For many psychologists, however, behaviorism seemed limited to what could be inferred from bar pressing and key pecking. As enthusiasm for behaviorism ebbed, cognitive psychology began to assert its influence, restoring the concepts of mentalism to and consciousness in animals, and directing its research efforts to intelligence and problem solving. At approximately the same time, other related areas in science—neurobiology, genetics—converged onto issues related to learning and memory, the result of which was the emergence of cognitive neuroscience. The revolution in genetics brought about by the discovery of the structure of DNA, along with the discovery of genetic abnormalities associated with learning disabilities, accelerated research into genetics factors that produced mental retardation and psychopathology. Cognitive psychology and cognitive neuroscience provided the epistemological justification for using animal models to explore various forms of human cognitive impairment. Studies in neuroscience using recently developed behavioral procedures have identified brain structures associated with certain features of learning and emotion. Successful development of knockout and transgenic technologies, followed by the creation of mouse models of genetic disorders, were used to identify many of the neurobiological and neurophysiological functions associated with neurobehavioral disorders. However, mice are not humans and the question regarding whether studies of animal behavior are relevant to human thought, problem solving, intelligence, and emotions has not been resolved. [ABSTRACT FROM AUTHOR]

The standard investigation for suspected chromosomal rearrangements in patients is cytogenetic analysis at a 400-550 band resolution, yet this cannot routinely detect rearrangements smaller than 5 Megabases (Mb), and much larger abnormalities escape notice if they occur in regions where the banding pattern is not distinctive. In the future, this problem will largely be solved by the use of high resolution micro-arrays that will allow the entire genome to be investigated for submicroscopic chromosomal rearrangements. However, until this technology becomes routine, the only way of achieving increased reliability and resolution is to focus on specific chromosomal regions such as the ends of chromosomes (telomeres). [ABSTRACT FROM AUTHOR]