Modeling Neuropsychiatric Disorders in Laboratory Animals

Kurt Leroy Hoffman

• Publisher: Woodhead Publishing
• Year: 2015
• Print ISBN: 9780081000991
• eBook ISBN: 9780081001066
• Topic: Medicine
• Subtopic: Neurology

Modeling Neuropsychiatric Disorders in Laboratory Animals serves as a guide for students and basic investigators in the fields of behavioral sciences, psychology, neuroscience, psychiatry, and other professionals interested in the use of animal models in preclinical research related to human neuropsychiatric disorders.The text focuses on the rationale and theory of using animal behavior, both pathological and normal, as a tool for understanding the neural underpinnings of neuropsychiatric disorders. Chapters contain discussions on both classical and modern views on the validation of animal models for neuropsychiatric disorders, also discussing the utility of endophenotypes in modeling neuropsychiatric disease.Subsequent chapters deal with four specific classes of disorders, including anxiety disorders, depressive disorders, obsessive-compulsive and related disorders. Final sections discuss the future for the development, validation, and use of animal models in basic and preclinical research.- Focuses on the rationale and theory of using animal behavior, both pathological and normal, as a tool for understanding the neural underpinnings of neuropsychiatric disorders- Serves as a guide for students and basic investigators in the fields of behavioral sciences, psychology, neuroscience, psychiatry, and other professionals- Discusses specific classes of disorders, including anxiety disorders, depressive disorders, obsessive-compulsive and related disorders

1

What is an animal model of a neuropsychiatric disorder?

Abstract

Animal models are a central component of studies aimed at understanding the biologic bases of mental illnesses, and are essential for efforts to develop new, more effective therapies that are so desperately needed to treat them. An evolution—or revolution—in the way that mental illness is conceptualized and diagnosed is underway, as it is becoming increasingly appreciated that psychiatric “symptoms” often are continuous with normally expressed behavioral and cognitive characteristics. The “categorical” conception of mental illness (where individual disorders are distinct both from the healthy state and from other disorders) is giving way to a more “dimensional” view, where the borders between mental illnesses are blurred, and psychiatric symptoms represent extreme expressions of normally distributed quantitative traits. A similar evolution in our way of thinking about animal modeling of mental illness must also occur. In this chapter, several key concepts of animal modeling will be discussed, including the distinction between models and tests, state models versus trait models, as well as general types of models, including pharmacologic, lesion, genetic, and experience-based. The so-called “model animal” (as opposed to “animal model”) approach is also discussed. This comparative approach emphasizes taking advantage of unique characteristics of certain “nontraditional” species, including invertebrates, to define and characterize key physiologic processes relevant to psychopathology. The concept of validity of animal models is explained, and a broad overview of the many criteria for assessing the validity of animal models is presented, from the commonly encountered criteria of face, construct, and predictive validity to the less-frequently considered (but equally relevant) concepts of reliability, genetic and environmental construct validity, population validity, relevance, generalizability, and replicability. Finally, the usefulness of endophenotypes and biologic markers as phenotypical measures in animal modeling will be discussed.

Keywords

Animal model

Mental illness

Neuropsychiatric disorder

Psychopathology

Internalizing

Dimensional

Face validity

Construct validity

Predictive validity

Etiologic validity

Endophenotype

Biologic marker

1.1 Introduction

Neuropsychiatric disorders are conditions that have a significant and sometimes devastating impact on a large proportion of the human population. Mental health surveys carried out in the United States suggest that during any 1-year period, approximately 26% of the population will have a mental disorder, and almost 50% of all people will have mental illness sometime during their lifetime. Yearly, approximately 6% of the population experiences a very serious mental illness that involves a suicide attempt, significant work disability, or repeated serious violent behavior (Kessler et al., 2005). Yet, the currently available treatments for these mental illnesses are less than adequate. In the case of major depressive disorder, for example, the typical first-line pharmacotherapy, a 12-week treatment with a selective serotonin reuptake inhibitor, results in remission (complete or almost complete absence of symptoms) for approximately 30–50% of cases, and only 20–30% of people that do not respond to the first-line treatment will remit within 12 weeks of receiving an alternative pharmacologic treatment (Rush et al., 2006). Psychotherapy (without drug treatment) results in almost identical remission rates for major depressive disorder (Cuijpers et al., 2013). Similarly, the typical and atypical antipsychotics currently used to treat schizophrenia are mostly effective for a subset of schizophrenic symptoms (hallucinations, delusions, the so-called “positive” symptoms) while cognitive and negative symptoms (deficits in working memory and attention, negative affect, and anhedonia) remain mostly unresponsive to current pharmacologic therapies. Therefore, there is a strong motivation for understanding the biologic roots of these disorders, in order to develop new, potentially more effective treatments that are specifically targeted to correcting the relevant pathophysiologic mechanisms. Understanding the pathophysiology of neuropsychiatric disorders is challenging due to the inherent complexity of the human brain and the limited types of experimental methodologies that can be applied in human studies: there are obvious ethical constraints on the study of humans, and it is practically impossible to control for many important variables. These problems in part can be overcome through the study of nonhuman subjects, and a major research effort has focused on developing so-called “animal models” of human neuropsychiatric conditions. However, this effort has not been without its skeptics and critics, who justifiably question whether syndromes so complex—and so human—as schizophrenia and depression (just to name two examples) can really be observed and replicated in animals. So, what exactly constitutes an animal model of a neuropsychiatric disorder? The current chapter will explore this question, but first, it is necessary to start with a more basic question, that is, what is—and what is not—a neuropsychiatric disorder?

1.2 What is a neuropsychiatric disorder? (and what is not?)

This may seem as an odd place to start, but if an experimental paradigm is meant to model a neuropsychiatric disorder, then it is important to be clear on what exactly is meant by this term. And, as it turns out, the question is more difficult to answer than it might appear to be. Although the terms “disease” and “disorder” are often used interchangeably, a distinction is sometimes made between them: while both terms refer to “an abnormality or medical condition that confers harm or risk of harm” (Hyman, 2010), the term “disease” can imply that the etiology of the condition is known, whereas “disorder” is often taken to imply that underlying causal factors have not yet been identified. In the present context, the adjective “neuropsychiatric” could equally well be replaced by “psychiatric” or “mental,” but the term “neuropsychiatric” emphasizes that these disorders are assumed to have clear biologic roots that lie within the function of the nervous system.

Neuropsychiatric disorders are currently diagnosed and classified based on the systems outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V, American Psychiatric Association, 2013) or in the International Classification of Diseases, Tenth Revision (ICD-10, World Health Organization, 1992). Due to a growing appreciation of the diversity and complexity of neuropsychiatric disorders, the systems for diagnosing and classifying these conditions have evolved. While original classification schemes attempted to define individual neuropsychiatric disorders as conditions distinct both from the healthy state and from each other, current conceptualizations of psychopathology recognize the presence of considerable comorbidity of supposedly distinct disorders, as well as significant symptom sharing among them. To illustrate, in one survey on comorbidity of neuropsychiatric disorders (Kessler et al., 2005), almost half of those survey participants that had suffered from mental illness were diagnosed with two or more DSM-defined disorders. Moreover, it has become increasingly clear that many neuropsychiatric symptoms are represented in an attenuated form or at nonpathologic levels in individuals in the general population. As a step toward a more dimensional (and realistic) classification of psychopathology, DSM-V has regrouped categorically defined disorders into diagnostic categories (represented as individual chapters) based on certain validating criteria, including: (1) the presence of similar genetic markers, familial traits, temperament, and exposure to specific environmental conditions, or “antecedent validators”; (2) similarity of symptoms and emotional and cognitive processing, as well as similarity in the presence of biomarkers or neural substrates, or “concurrent validators”; and (3) “predictive validators,” which include similarities among disorders with respect to clinical course and treatment response. At present, given the relative paucity of information on the etiology of most neuropsychiatric disorders, similarities among disorders in their clinical course and treatment response remain the most clinically useful manner to define diagnostic categories.

DSM-V defines a mental disorder as “…a syndrome characterized by clinically significant disturbance in an individual’s cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biologic, or developmental processes underlying mental functioning … usually associated with significant distress or disability in social, occupational, or other important activities…” Emotional states that are culturally and contextually appropriate, such as the sadness experienced in response to the loss of a loved one or the relatively mild feelings of anxiety that are associated with common, every-day stressors, do not constitute disorders. Behavior that is considered socially deviant within political, religious, or sexual realms (for example), or conflicts between the individual and society are generally not considered disorders unless they are the result of a dysfunction in the individual as described above.

Unfortunately, giving a name to anything automatically grants it autonomy, conferring to it the status of an individual, distinct entity. Although the apparent dimensional nature of psychopathology is increasingly becoming appreciated, previous conceptualizations cannot be easily ignored and forgotten. For example, anxiety and depressive disorders remain separate diagnostic categories, even though they are often comorbid; schizophrenia and bipolar disorder are considered distinct conditions, even though, in clinical practice, they can be very difficult to distinguish. In the case of a disorder or disease, a categorical diagnostic system implies distinct etiologies and pathophysiologic boundaries, even though this most likely does not reflect reality. In fact, for most categorically defined neuropsychiatric disorders, our knowledge of their pathophysiology is far too inadequate to defend their existence as distinct pathophysiologic conditions. And therein lies a problem for animal modeling of a neuropsychiatric disorder: for example, if an animal preparation is meant to model depression, what phenotypic endpoint should be expected? Ideally, an animal model of a human condition should resemble that condition, both with respect to outward symptom expression as well as underlying pathology; however, in most cases the latter remains largely a mystery. Given that limitation, should we expect the animal to show “symptoms” consistent with depression, but not with anxiety, even though these conditions often coexist in humans? Should we expect the animal to show “symptoms of depressed mood or loss of pleasure in most activities,” along with at least three other diagnostic symptoms (as defined in DSM-V: weight changes, sleep changes, psychomotor changes, fatigue, feelings of worthlessness, inability to concentrate, recurrent thoughts of death)? Problems with this strategy immediately become obvious: how is “depressed mood” defined and measured in an animal, not to mention feelings of worthlessness and thoughts of death?

Given the increasing realization of the need to change the way that neuropsychiatric disorders are conceptualized and diagnosed in the clinic, our views on how animal models of these disorders are developed and validated need to adjust and evolve. The extensive comorbidity among neuropsychiatric disorders, the statistical clustering of neuropsychiatric symptoms and disorders within families and within individuals, and the growing appreciation that many neuropsychiatric symptoms may in fact represent the extreme ends of normally distributed quantitative traits (Plomin et al., 2009), all point to the need to adopt a dimensional or quantitative approach to thinking about mental disorders. For example, such an approach might define disorders based on one or more quantitative scales that are continuous with normal, where diagnostic thresholds are defined according to data that correlate the quantitative measures with specific clinical outcomes, such as quality-of-life measures. Future animal models that reflect this paradigm shift might therefore consider defining the animal homologs of these quantitative traits and focusing on individuals that show extreme expressions of these traits.

1.3 What is an animal model of a neuropsychiatric disorder?

A number of definitions for what constitutes an animal model have been elaborated in the literature. Many have focused on the idea of replicating certain aspects or characteristics of the disorder, symptomatologic or etiologic, in the experimental animal. These models have been traditionally assessed and validated with respect to how closely the animal preparation resembles the human condition, considering a number of criteria, which will be discussed in detail later in this chapter. An animal model of clinical or biologic relevance has been defined as “…a living organism that is used to study brain–behavior relations under controlled conditions, with the final goal to gain insight into, and to enable predictions about, these relations in humans or a species other than the one studied…” (Van der Staay, 2006). Geyer and Markou (1995) defined a preclinical animal model as “…any experimental preparation developed for the purpose of studying a condition in the same or different species…,” and emphasized that all experimental models can be deconstructed into independent and dependent variables: respectively, a specific experimental manipulation and the observed and measured effects of this manipulation. In the case of models of neuropsychiatric disorders, the independent variable is often chosen based on hypotheses on the etiology of the disorder in question. For example, the experimental manipulations involved in the learned helplessness and behavioral despair models of depression (discussed in Chapter 2) involve the controlled application of unpredictable and inescapable stress to the animal; such forms of stress are assumed to be an important etiologic factor in human depression. Other experimental manipulations include the administration of pharmacologic agents that are expected to replicate neurochemical dysfunction(s) that are hypothesized to underlie the disorder being modeled, such as the administration of amphetamines or the pharmacologic blockade of N-methyl-d-aspartate (NMDA) receptors, in order to mimic the hyperdopaminergic state and NMDA receptor hypofunction, respectively, that are believed to underlie symptoms of schizophrenia. The measured effects of these manipulations are most often changes in behavior. For example, learned helplessness and behavioral despair manipulations induce decreased locomotor activity, immobility, and deficits in the ability to learn to avoid an aversive stimulus, while amphetamines and NMDA receptor antagonists induce hyperlocomotory behavior and cognitive deficits. Generally, it is considered important that the observable and measurable effects of these manipulations should resemble or be homologous to the symptoms of the disorder being modeled.

1.3.1 Tests versus models

It is important to draw a distinction between a model and a test. An animal model, in effect, “…constitutes a theory of some aspect(s) of the psychopathology it models…,” thereby serving as a preclinical tool to generate, under experimentally controlled conditions, hypotheses and predictions about the disorder in question that then can be tested against the clinical reality (Willner, 1991). In contrast, a test is a standardized procedure used to measure a particular behavioral or physiologic response. Confusion arises when a certain behavioral paradigm can arguably be used either as a test (to assess behavioral responses to a given experimental manipulation) or as a model (as a representation of the condition that is being studied).

Models and tests are applicable in distinct circumstances and relevant for different experimental objectives...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Introduction
• About the author
• Acknowledgments
• 1: What is an animal model of a neuropsychiatric disorder?
• 2: What can animal models tell us about depressive disorders?
• 3: Modeling disorders of fear and anxiety in animals
• 4: Animal models for studying obsessive-compulsive and related disorders
• 5: New dimensions in animal modeling of neuropsychiatric disorders
• Index