7
Animal Models

ROLE OF ANIMAL MODELS1

Rationale

Most studies identifying gene-environment interactions that are risk factors for disease in humans rely on observational studies of naturally occurring genetic polymorphisms and environmental variability. These correlational research designs, although a rich source of testable hypotheses, cannot provide definitive evidence for the causal effects of genes, environments, or their interaction. Basic research using animal models is a feasible way to establish causal relationships in the reciprocal interactions among social, behavioral, and genetic contributors to health and disease. Thus, animal studies are an important complement to clinical and community-based research.

Specifically, animal models can be used to conduct studies for which different aspects of social, behavioral, and genetic factors can be controlled or standardized to a significantly larger extent than can be done in human studies. Animal models enable the manipulation of single variables or specific groups of variables in a highly controlled context. In some cases, animal models provide opportunities to establish causality through studies examining the temporal sequence of events or studies involving the removal

1

The commissioned paper submitted by Steve W. Cole was used in the preparation of this chapter.



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7 Animal Models ROLE OF ANIMAL MODELS1 Rationale Most studies identifying gene-environment interactions that are risk factors for disease in humans rely on observational studies of naturally occurring genetic polymorphisms and environmental variability. These cor- relational research designs, although a rich source of testable hypotheses, cannot provide definitive evidence for the causal effects of genes, environ- ments, or their interaction. Basic research using animal models is a feasible way to establish causal relationships in the reciprocal interactions among social, behavioral, and genetic contributors to health and disease. Thus, animal studies are an important complement to clinical and community- based research. Specifically, animal models can be used to conduct studies for which different aspects of social, behavioral, and genetic factors can be controlled or standardized to a significantly larger extent than can be done in human studies. Animal models enable the manipulation of single variables or spe- cific groups of variables in a highly controlled context. In some cases, animal models provide opportunities to establish causality through studies examining the temporal sequence of events or studies involving the removal 1The commissioned paper submitted by Steve W. Cole was used in the preparation of this chapter. 132

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133 ANIMAL MODELS followed by the add-back of hypothesized mediators. Such controlled re- moval and add-back can be achieved at the genetic, protein, physiological, behavioral, or social-environment level. Animal models also allow for inva- sive examination of organ, tissue, and region-specific mechanisms at the physiological, cellular, and molecular levels. Also animals with short repro- ductive cycles and life spans provide an invaluable tool for conducting developmental and life-span studies, and animal models enable the conduct of breeding experiments and genetic manipulation that facilitate the eluci- dation of inherited traits and genetic effects. Strategies for Linking Animal and Human Research Modeling Known Interactions and Diseases in Humans Animal research can serve as models of gene-environment interactions and diseases identified in humans. In the case of social control of disease processes, the choice of species to be studied depends on the level of social interactions that needs to be examined. For example, rodent models can demonstrate how differences in social status, population density, or early experiences interact with genetic makeup to affect susceptibility to disease (e.g., examine effects of social factors in knockout or knockin animals [or inbred strains] that differ in susceptibility to infection, cancer, autoimmu- nity). The advantages of rodent models include significant control over genetic, physiological, behavioral, and social factors and relatively short reproductive, developmental, and life cycles. They are amenable to studying a variety of important psychosocial variables, including social isolation, social relationships, attachment, parenting, temperament, and motivational states. However, nonhuman primate models, which offer limited control over genetic factors and have a longer life span, may be best suited to examine the consequences of more complex social factors, such as those involving cooperation or trust. For example, after bouts of aggression, nonhuman primates demonstrate reconciliatory behavior that is thought to be impor- tant for maintaining cooperative social hierarchies (de Waal, 2000). Some aspects of human behavior (e.g., optimism, hope, guilt) may be studied in animals only when the investigator can demonstrate a robust animal model with multiple behavioral paradigms as well as shared neural mechanisms. In addition, animal models developed for traditional biomedical re- search are also powerful models for studying the psychosocial modulation of known mechanisms of specific human diseases. There are many animal species, strains, and transgenic models developed through biomedical sci- ence, that have been well characterized in terms of the genetic, molecular,

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134 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT and cellular processes underlying human disease. Studying these animals in a variety of psychosocial paradigms, based on variables identified through survey, epidemiological, and human experimental research, can test hy- pothesized causal relations derived from correlational data in humans. Fundamental Biology: Nontraditional Laboratory Animals It is essential to study animals as evolved biological systems in which surviving and reproducing in particular social and physical environments have selected a constellation of interactions between social, behavioral, physiological systems, and gene function. Doing so reveals insights and principles that also underlie human health and disease but that are not salient in the modern world or in a typical biomedical approach. Moreover, ethology and evolutionary biology recognize that individual differences are not necessarily just “noise,” but represent different evolved strategies for survival in different contexts. Taking an ethological approach to variation in strategies reveals the range of gene-environment interactions that occur within species as they have evolved in their natural ethological and ecologi- cal contexts. Studies of deer mice (Peromyscus maniculatus), who live in highly seasonal environments, reveal that function of the immune system requires significant energy, so much so that during winter an animal trades off entering puberty and becoming reproductive in order to sustain the ener- getic requirements of fighting infectious disease (Prendergast and Nelson, 2001; Nelson, 2004). It is not the demands of the cold weather itself that signals this trade-off, but rather the shortened days that precede seasonal temperature change, allowing the animal to modulate relative balance of immune function and reproduction in anticipation of the energetic de- mands of winter. In house sparrows, immune activity increases energy expenditure, illus- trating the energetic costs of immune function that could otherwise be deployed to growth (Martin et al., 2003). Such animal research, set in an ecological context, provides a powerful animal model for such trade-offs in humans. When social structure restricts resources and results in a popula- tion living in an environment with a high pathogen load, slower growth can result, as is the case of children in the lowlands of Bolivia. This presumably happens because the allocation of energetic resources to immune function has been diverted from growth (McDade, 2005). This dynamic interaction between social access to energy stores, pathogen interaction, fat deposition, and growth likely involves leptin, a pleiotropic molecule with cytokine properties that is produced by fat cells during an inflammatory response (Faggioni et al., 2001; Fantuzzi, 2005).

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135 ANIMAL MODELS Limitations and Power for Generalization to Humans One danger in using animal models is “overspecifying” what is being measured—that is, interpreting the animal’s behavior anthropomorphically, without measuring different facets of the behavior in order to clearly dem- onstrate what behavioral system is being measured. For example, claims are made about genetic or brain mechanisms in spatial learning and intelligence when mice perform well or show deficits in a Morris water maze. In this task however, the mouse is required to do something it did not evolve to do—swim. Moreover, while swimming to avoid drowning, this non- aquatic species is required to navigate a circular pool to find a submerged platform—again, an improbable scenario. In fact, performance in a Morris water maze can be affected by the rodent’s ability to handle stress, degree of thigmotaxis (the tendency to stay close to a solid surface), and the ability to inhibit a fixed-action pattern (Day and Schallert, 1996). Thus, when an enriched environment aids recovery from a stroke, measured by improved performance in a Morris water maze, it is essential to determine which of these behavioral systems is being affected and not assume that it is spatial learning and cognitive performance, which is the most salient aspect of the test to human investigators (Ronnback et al., 2005). Conversely, it is also a mistake to assume that human psychosocial traits that affect disease are uniquely human and that humans do not have psychological processes in common with animals. This is an error com- monly made when human psychological states are measured with verbal accounts of subjective experience—for example, “I do not feel I have people I can turn to for social support” or “I feel overwhelmed.” Such verbal reports are certainly unique to humans, but nonetheless they are likely based on psychological processes and behavioral traits that have common- ality with animal systems, especially when their underlying neuroendocrine mechanisms are similar. The parallel is readily accepted in nonemotional domains. The study of human hunger utilizes self-reports: “I feel hungry” or “I feel sated.” Yet, few question that animals are an excellent model for teasing apart the diverse aspects of hunger and satiety as a motivational state. Indeed, rodent models have been a powerful tool for teasing apart multiple facets of hunger, ranging from taste, chewing, insulin, leptin, and hypothalamic activity to gastrointestinal activity; there are far more inde- pendent factors than have been intuitively obvious (White, 1986; Morley, 1990; Hall and Swithers-Mulvey, 1992; Williams et al., 2001; Changizi et al., 2002; Oka et al., 2003). Thus, social animals can be powerful models of psychosocial effects on disease and gene expression, enabling the identifica- tion of transduction pathways from the social world to disease as well as the multiple functions of such pathways. Even such seemingly unique hu-

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136 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT man social activities as making business decisions involve neuroendocrine mechanisms conserved across mammals, if not other species (Morse, 2006). DEFINITIONS FROM ANIMAL RESEARCH Animal research has clarified concepts that are key to understanding the effects of social environment on health and disease and gene function, extending and moderating the conclusions based on epidemiological studies in humans. These concepts include genetics, immune and neuroendocrine function, causality, pleitropy, and life-span fitness. Genetics Genetics requires a broad conception that includes both functional genomics (intra-individual changes in gene expression over time) and the more traditional topic of structural polymorphism (interindividual varia- tions in DNA sequence or epigenetic characteristics). This broad concep- tualization is essential because social influences on gene transcription are fairly well studied, while few studies have examined the relationships be- tween social factors and genetic polymorphisms. That such effects exist is likely because structural polymorphisms generally exert their effects in the context of expressed genes. Physiology: The Missing Link An essential role of animal research is to test the relationship between presumptive genetic influences (e.g., inferred from studies of heritability) and defined genetic influences (e.g., effects attributable to the expression of specific genes or epigenetic characteristics). The immune system includes classical immune cells (e.g., leukocytes) as well as other cellular contexts relevant to disease pathogenesis or host defense, such as somatic cells re- sponding to pathogens through innate immune responses (e.g., “danger signals” produced by Toll-like receptors, Type I interferon production). The neuroendocrine system also is broadly defined to include not only true neurally driven hormone production (e.g., hypothalamic-pituitary-adrenal [HPA] axis), but also neuroeffector processes that do not necessarily in- volve systemic hormone distribution (e.g., local effects of neurotransmitter release from autonomic or sensory neurons or neuropeptides such as vaso- pressin and oxytocin). Part of the reason so few genetic determinants of immune response currently are presently known may be an overly restrictive focus on “im- mune system” genes. Polymorphisms in many “nonimmune” genes, which are regulated by the psychosocial environment through physiological sys- tems, may also influence leukocyte function and/or the pathogenesis of

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137 ANIMAL MODELS diseases involving immune or inflammatory components. For example, cat- echolamines are known to influence several aspects of leukocyte function (Sanders and Straub, 2002; Kavelaars, 2002), and polymorphisms in genes encoding their alpha—and beta—adrenergic receptors are associated with differential incidence of asthma, parasitic infections, and cardiovascular disease (Ramsay et al., 1999; Ulbrecht et al., 2000; Ukkola et al., 2001; Weiss, 2005; Thakkinstian et al., 2005; Lanfear et al., 2005). Glucocorti- coids, another physiological system exquisitely sensitive to the psychosocial environment, play a key role in regulating inflammatory gene expression (Webster et al., 2002), and polymorphisms in the glucocorticoid receptor gene (NR3C1) have been linked to cardiovascular and autoimmune disease (Lin et al., 1999; Ukkola et al., 2001; Jiang et al., 2001; Dobson et al., 2001; van Rossum et al., 2002; Lin et al., 2003). Causality Mediating and moderating variables often are inferred in human stud- ies through multivariate statistical analysis (Baron and Kenny, 1986). A moderating variable is one that changes the way an independent variable is related to a dependent variable (e.g., sex differences in the relationship between reported symptoms and risk for cardiac disease). A mediating variable is one that statistically accounts for the association between an independent and dependent variable in a study (e.g., cortisol levels may be a better predictor of disease onset than feelings of stress). However, the disease process may be mediated by autonomic tone, not measured in the study, and not cortisol itself. In the animal literature, however, these terms have more stringent crite- ria. Studies demonstrate “mediation” only when a hypothesized intermedi- ate factor has been experimentally manipulated to block the effects of some upstream influence on a downstream outcome within a transitive causal chain. “Moderation” is reserved for cases in which one variable is experi- mentally manipulated to alter the causal effect of a second manipulated variable on an observed outcome. A statistical interaction is not sufficient. The strongest evidence for genetic moderation comes from studies in which both genes and environment are experimentally manipulated, but few stud- ies meet this criterion. Based on this fact alone, it can be concluded that much remains to be learned about the interaction between genes and the social environment in the context of immune system function and disease. Context, Pleitropy, and Lifetime Fitness Behavioral ecologists have elegantly and dramatically revealed that we cannot expect human studies to reveal monolithic or simple linear relation-

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138 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT ships among social behavior, hormones, immune function, and disease. The reality of surviving and reproducing over a lifetime in a changing environ- ment has selected for genetic and physiological traits that are highly context dependent. This is enabled in part by both genetic and physiological pleitropy, where the same gene or molecule can have very different func- tions in different physiological systems. For example, genes encoding for the major histocompatibility complex produce a molecule that is involved not only in the presentation of pathogen proteins to a T-cell, but also in selection of mates, choice of communal nesting partners, and guiding neu- rons in the development of the nervous system (Manning et al., 1992; Jordan and Bruford, 1998; Huh et al., 2000; Jacob et al., 2002; Rock and Shen, 2005). Social isolation in rats accelerates puberty, seemingly enhanc- ing fertility and fitness in the young animal, yet it accelerates reproductive senesce, reducing fitness when considered over the life span (LeFevre and McClintock, 1991; Zehr et al., 2001). A rich and rigorously tested example is the relationship between social interactions, immune function, fertility, and fitness in side-blotched lizards (Svensson et al., 2001). The females of this species have two genetic mor- phs—one with yellow throats and the other with orange. In addition, throat color is correlated with steroid hormones that have physiological pleitropic effects on behavior and fertility. In both morphs, high population density, and its attendant aggressive encounters and pathogen exposure, is associ- ated with a decreased antibody production to an antigen. One might assume, as is often is done in laboratory and human studies, that the lower antibody production is associated with greater mortality and lower fitness. In the field, however, this relationship to fitness (survival after the female’s first clutch) is seen only in the yellow morphs; in the orange morphs higher survival actually is associated with lower antibody production. The orange morph is particularly sensitive to the energetic costs of immune function, and at high densities it suppresses immunity as well as disperses. That is, within a species, immune function is density dependent. The orange morph invests in large clutches of eggs, consistent with reduced investment in immunity, and their daughters have reduced antibody production. The yellow morphs produce smaller clutches, and their daughters have high antibody production. This system has resulted in a strong correlation of traits driven by different loci—that is throat color and antibody production. Because males prefer to mate with females of the rare color morph at any given time, the population of females oscillates between predominantly yellow and orange morphs, each with a different relationship among antibody production, reproductive strategies, and fitness. The relationship of social interactions, genetics, and immunity in humans, with their exquisite adaptability to a wide variety of environments and social structures, cannot be expected to

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139 ANIMAL MODELS be simpler. As research progresses, the concepts of genetic and physiologi- cal pleitropy, context dependence, and taking a life-span perspective on costs and benefits will be essential. IDENTIFYING GENE-SOCIAL ENVIRONMENT INTERACTIONS AFFECTING HEALTH AND DISEASE Early Life Experience Meaney et al. have conducted a comprehensive series of studies showing that early life events, such as maternal separation, handling, or natural variations in maternal care, induce long-term changes in endocrine and behavioral responses to stress that are observed well into adulthood (Meaney, 2001). Using cross-fostering studies, these authors showed that changes in both maternal behavior and stress reactivity can be transmitted through nongenomic mechanisms across generations (Francis et al., 1999). More- over, these authors also showed that the changes resulting from differences in maternal care are due to “environmental programming” that permanently alters gene expression and has downstream effects on stress-axis responsivity (Meaney and Szyf, 2005). Such epigenetic programming of stress reactivity is mediated by changes in hippocampal glucocorticoid receptor gene expres- sion that are regulated by differences in maternal care and mediated by methylation of the consensus sequence for the transcription factor NGFI-A, which activates glucocorticoid receptor gene expression in the hippocampus (Fish et al., 2004). Increased DNA methylation prevents NGFI-A binding to the promoter for the glucocorticoid receptor gene and hence inhibits tran- scription, ultimately reducing expression of hippocampal glucocorticoid receptors (Fish et al., 2004). Reduced receptor levels result in reduced sensi- tivity to corticosterone-mediated negative feedback, which may result in increased and prolonged reactivity of the HPA axis. These studies illustrate that socially relevant environmental and behav- ioral factors can induce epigenetic changes in specific brain regions that translate into long-lasting differences in stress reactivity. These experiments provide an excellent example of the advantages that are found in the use of animal models. Aspects of these findings are now being translated to hu- man subjects (Pruessner et al., 2004). In addition, pre- and postnatal expo- sure to social stressors has been shown to induce significant effects on social and sexual behavior, endocrine responses, and brain sex steroid receptor distribution in adulthood in guinea pigs (Kaiser et al., 2003; Kaiser and Sachser, 2005), and prenatal social stress also has been shown to masculin- ize female behavior in adulthood (Sachser and Kaiser, 1996). It may be assumed from these studies that higher stress reactivity may transfer into greater chronic stress burden, which is known to adversely

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140 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT affect immune function and health. Other studies also have shown that early life experiences involving social stressors are related to increased alco- hol consumption (Fahlke et al., 2000) and dysregulated immune responses that last well into adulthood (Coe et al., 1989). However, some studies indicate that early life stressors actually enhance certain measures of im- mune function in adulthood (Coe et al., 1992). Nonhuman primate studies also have shown that exposure to mild early life stressors strengthens emo- tional and neuroendocrine stress responses in adulthood (Parker et al., 2005). Therefore, animal and human studies are needed to further examine the downstream psychophysiological and health consequences of variations in maternal care and other aspects of early life experience and to determine why factors such as early life stressors show adaptive effects in some studies but maladaptive effects in others. Temperament The earliest indications that social factors might affect individual health came from clinical observations of increased vulnerability to cancer and infectious disease among “socially withdrawn” individuals. A surprisingly large number of clinical studies have shown that socially inhibited or intro- verted individuals are at increased risk for immune-mediated infectious diseases, allergies, and hypersensitivity responses (Kagan et al., 1991; Cole et al., 1997; Cole et al., 1999; Cohen et al., 2003; Cole et al., 2003). Studies by Cavigelli and McClintock have demonstrated the long-term health con- sequences in rats of differences in temperament, such as increased fear of novelty (neophobia) and stress reactivity (Cavigelli and McClintock, 2003). Neophobia was measured using a modification of the open field arena that was designed to quantify an animal’s degree of locomotion and interaction with novel objects. The authors showed that males from the same litter that demonstrate a high degree of neophobia and corticosterone stress responses to novelty during infancy maintain these characteristics as adults. They also showed that the predominant cause of death is the development of tumors in neophobic and neophilic animals, and that high neophobic males die sooner than their low neophobic brothers. The authors suggest that in- creased neuroendocrine reactivity of the high neophobic animals may be a mechanism that contributes to increased mortality over the life span of the animal. These studies demonstrate the usefulness of using rodent models for conducting life-span studies. Other studies of social and behavioral development have linked socially inhibited behavior to individual differences in central nervous system infor- mation processing, brain neurotransmitter activity, and reactivity of the autonomic nervous system and HPA to social stimuli (Kagan et al., 1988; Kalin et al., 1998; Miller et al., 1999; Byrne and Suomi, 2002; Schwartz et

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141 ANIMAL MODELS al., 2003; Cavigelli and McClintock, 2003; Kalin and Shelton, 2003). In primate models, socially withdrawn behavior is a prospective risk factor for increased simian immunodeficiency virus (SIV) pathogenesis following a controlled viral challenge (Capitanio et al., 1999). Specific immune param- eters mediating differential disease vulnerability have not been well defined in humans. However, selective breeding of mice to enhance socially inhib- ited behavior has been found to induce correlated reductions in natural killer (NK) cell numbers and cytotoxic activity (Petitto et al., 1993; Petitto et al., 1999), and decreases in T lymphocyte numbers, proliferative poten- tial, and cyto-kine production (Petitto et al., 1994). Conversely, selective breeding for immune responses (e.g., antibody production) can produce correlated changes in social behavior (Vidal and Rama, 1994). Social Isolation Observational epidemiologic and clinical studies in humans have repeat- edly found increased morbidity and mortality among people with limited social contact (House, 2001; Hawkley and Cacioppo, 2003; Cacioppo and Hawkley, 2003; Cohen, 2004) and those recently bereaved of close social partners (Schaefer et al., 1995; Martikainen and Valkonen, 1996; Li et al., 2003). Experimental evidence from human laboratory studies suggests that social relationships protect health in part by decreasing neuroendocrine re- sponses to exogenous threats (Uchino et al., 1996; Sachser et al., 1998). Other behavioral mechanisms also may contribute to the health-protective effects of social relationships, including economic support (e.g., facilitating health care), reference group support for healthy behavior (e.g., discouraging tobacco or heavy alcohol use), and behavioral assistance with health services utilization (e.g., assistance in accessing treatment, adhering to medical regi- mens). The relative contributions of behavioral versus neuroendocrine mecha- nisms to isolation-linked health risks are not well understood in humans. However, experimental manipulation of social contact in animal models can alter long-term neuroendocrine function in ways that increase the risk of organic disease (e.g., isolation enhances hormone production rates to in- crease breast cancer incidence in social rodent models) (McClintock et al., 2005). In observational human studies, subjective social isolation (loneliness) has been linked to reduced vaccine-induced antibody responses and leuko- cyte proliferative activity (Glaser et al., 1992; Pressman et al., 2005). Social isolation, which generally consists of housing animals individu- ally instead of in groups, has been used as a stressor (Angulo et al., 1991; Chida et al., 2005). Isolation may indeed be stressful for animals that live in groups in their natural environments. However, it is important to keep in mind that some effects of isolation “stress” may be due to increased sensi- tivity or reactivity of the animal to external stimuli (e.g., handling) when

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142 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT the animal is no longer accustomed to being around or near other animals. Therefore, rather than or in addition to being a stressor itself, social isola- tion may increase stress reactivity or stress responsivity, which may be a potential confounder if it is not the focus of study. Social Affiliation and Support Studies using different species of voles have begun to elucidate genetic and hormonal mechanisms mediating complex social behaviors such as those involving monogamy versus polygamy (Young et al., 1998; Young et al., 2001). Male prairie voles show increased partner preference for a fe- male with whom they are paired following stressful conditions that result in elevations of plasma corticosterone or following pharmacologically induced increases in plasma corticosterone, with females showing the opposite ef- fect of exposure to stress (DeVries et al., 1996). Vasopressin-1a receptor (V1aR) gene transfer into the ventral forebrain region of male prairie voles (a monogamous species) increases affiliative behavior and strengthens part- ner preference (Pitkow et al., 2001). Interestingly, similar gene transfer into the ventral forebrain region of meadow voles significantly increased partner preference formation in this polygamous species (Lim et al., 2004), and transfer of vole V1aR in the rat septum increased social discrimination and social behavior in rats (Landgraf et al., 2003). In contrast, V1aR gene knockout mice show deficits in social recognition and anxiety-related be- havior (Bielsky et al., 2004). Moreover, variations in microsatellite seg- ments in the 5’ region of the transcription start site for the V1aR gene differs in terms of length and regulatory control of gene expression among different individuals and is associated with individual differences in recep- tor expression and behavioral characteristics (Hammock and Young, 2005). These studies suggest that some complex social and behavioral traits may be strongly modulated by changes in gene expression in critical areas of the brain. Such differences in regulation and expression of genes, their effects on social behavior, and ultimately on health, need to be investigated further. Moreover, more complex models of social affiliation may come from nonhuman primates that have been shown to demonstrate reconcilia- tory behavior after aggressive encounters, which are thought to be impor- tant for maintaining cooperative social hierarchies (de Waal, 2000). Genetic Differences in Stress-Responsivity and Susceptibility to Autoimmune Disease Evidence suggests that three contributing factors result in susceptibility to inflammatory and autoimmune disorders (Mason, 1991; Tsigos and Chrousos, 1994; Sternberg, 1995; Wick et al., 1998; Ermann and Fathman,

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150 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT factors on health and can provide an important complement to clinical and community-based research. Therefore the committee makes the following recommendation: Recommendation 6: Use Animal Models to Study Gene-Social En- vironment Interaction. The NIH should develop RFAs that use carefully selected animal models for research on the impact on health of interactions among social, behavioral, and genetic factors and their interactive pathways (i.e., physiological). The selection of the animal model should be based upon the type and complexity of the interaction to be explored. Furthermore, studies should be conducted using outbred, inbred, and wild caught animals. Appropriate animal models should be sensitive enough to register clinically relevant change in vivo; ensure that laboratory conditions are consistent with the ecological and ethological context in which the animals naturally live; rec- ognize, account for, and preferably measure unintended physiological con- sequences of experimental manipulations when generating data and inter- preting results; enable the examination and identification of psychological and/or physiological mediators of interactions among genes, behavior, and the social environment; enable the experimental testing of causality; and parallel human models when relevant and possible. It probably would be advisable to establish animal housing facilities that more closely approximate each animal’s natural habitat, but this would be difficult to implement. Care would need to be taken to ensure accuracy (i.e., thoroughly understand and replicate most if not all relevant ecological and ethological factors in the vivarium) and standardization across differ- ent research groups (i.e., once ecological and ethological factors are estab- lished, housing conditions designed to take them into account should be standardized across different laboratories). The standardization aspect may be a significant obstacle, because different research groups may have differ- ent opinions on what ethologically and ecologically relevant conditions are and how they should be replicated in the vivarium. However, not standard- izing housing could result in significant interlaboratory variations that may make studies difficult if not impossible to replicate and compare between laboratories. In contrast, it also may be beneficial to have multiple types of environments, as an approach that would more closely mimic human living conditions (e.g., country versus city dwelling). REFERENCES Ademuyiwa FO, Olopade OI. 2003. Racial differences in genetic factors associated with breast cancer. Cancer and Metastasis Reviews 22(1):47-53.

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