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

followed by the add-back of hypothesized mediators. Such controlled removal and add-back can be achieved at the genetic, protein, physiological, behavioral, or social-environment level. Animal models also allow for invasive examination of organ, tissue, and region-specific mechanisms at the physiological, cellular, and molecular levels. Also animals with short reproductive 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 elucidation of inherited traits and genetic effects.

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, autoimmunity). 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 important 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 research 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 science, that have been well characterized in terms of the genetic, molecular,

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 hypothesized causal relations derived from correlational data in humans.

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 ecological 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 energetic 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 demands of winter.

In house sparrows, immune activity increases energy expenditure, illustrating 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 population 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).

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 demonstrate 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 commonly 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 commonality 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 independent 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 identification of transduction pathways from the social world to disease as well as the multiple functions of such pathways. Even such seemingly unique hu-

man social activities as making business decisions involve neuroendocrine mechanisms conserved across mammals, if not other species (Morse, 2006).

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 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 variations in DNA sequence or epigenetic characteristics). This broad conceptualization is essential because social influences on gene transcription are fairly well studied, while few studies have examined the relationships between social factors and genetic polymorphisms. That such effects exist is likely because structural polymorphisms generally exert their effects in the context of expressed genes.

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 responding 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 involve systemic hormone distribution (e.g., local effects of neurotransmitter release from autonomic or sensory neurons or neuropeptides such as vasopressin and oxytocin).

Part of the reason so few genetic determinants of immune response currently are presently known may be an overly restrictive focus on “immune system” genes. Polymorphisms in many “nonimmune” genes, which are regulated by the psychosocial environment through physiological systems, may also influence leukocyte function and/or the pathogenesis of

diseases involving immune or inflammatory components. For example, catecholamines 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). Glucocorticoids, 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).

Mediating and moderating variables often are inferred in human studies 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 criteria. Studies demonstrate “mediation” only when a hypothesized intermediate 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 experimentally 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 studies 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.

Behavioral ecologists have elegantly and dramatically revealed that we cannot expect human studies to reveal monolithic or simple linear relation-

ships among social behavior, hormones, immune function, and disease. The reality of surviving and reproducing over a lifetime in a changing environment 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 functions 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 neurons 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 enhancing 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 morphs—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 associated 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

be simpler. As research progresses, the concepts of genetic and physiological pleitropy, context dependence, and taking a life-span perspective on costs and benefits will be essential.

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). Moreover, 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 expression 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 transcription, ultimately reducing expression of hippocampal glucocorticoid receptors (Fish et al., 2004). Reduced receptor levels result in reduced sensitivity 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 behavioral 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 human subjects (Pruessner et al., 2004). In addition, pre- and postnatal exposure 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 masculinize 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

affect immune function and health. Other studies also have shown that early life experiences involving social stressors are related to increased alcohol 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 immune function in adulthood (Coe et al., 1992). Nonhuman primate studies also have shown that exposure to mild early life stressors strengthens emotional 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.

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 introverted 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 consequences 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 increased 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 information 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

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 parameters mediating differential disease vulnerability have not been well defined in humans. However, selective breeding of mice to enhance socially inhibited 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 potential, 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).

Observational epidemiologic and clinical studies in humans have repeatedly 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 responses 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 regimens). The relative contributions of behavioral versus neuroendocrine mechanisms 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 increase 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 leukocyte proliferative activity (Glaser et al., 1992; Pressman et al., 2005).

Social isolation, which generally consists of housing animals individually 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 sensitivity or reactivity of the animal to external stimuli (e.g., handling) when

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 isolation may increase stress reactivity or stress responsivity, which may be a potential confounder if it is not the focus of study.

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 female 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 effect 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 partner 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 behavior (Bielsky et al., 2004). Moreover, variations in microsatellite segments 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 receptor 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 reconciliatory behavior after aggressive encounters, which are thought to be important for maintaining cooperative social hierarchies (de Waal, 2000).

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,

2001): First is the presence of host immune response genes which carry the potential for autoimmunity. Second is exposure to a proinflammatory or antigenic challenge (which may include infection) that initiates the cascade of immune reactions that ultimately result in autoimmunity. Third is a dysregulation of the immune response to which a deficiency in the HPA axis responsivity is thought to contribute.

Studies have shown that hyporeactive stress responsivity can contribute to increased susceptibility to autoimmune and proinflammatory disorders (Mason et al., 1990; Sternberg et al., 1992a; Harbuz et al., 1997; Tonelli et al., 2001; Sternberg, 2001; Webster et al., 2002; Harbuz et al., 2003). In a series of seminal studies, Sternberg et al. (1989) showed that decreased HPA axis reactivity to inflammatory stimuli results in increased susceptibility to experimental arthritis (Sternberg et al., 1989a; Sternberg et al., 1989b; Sternberg et al., 1992b). These investigators studied the development of streptococcal cell wall (SCW)-induced arthritis in female rats belonging to the genetically related Lewis/N (LEW/N) and Fischer 344/N (F344/N) strains (Sternberg and Wilder, 1989; Sternberg et al., 1989a; Sternberg et al., 1989b; Webster et al., 2002). The F344/N strain is resistant to the development of SCW-induced arthritis, while the LEW/N strain is susceptible. Interestingly, the F344/N strain mounts a significantly greater corticosterone and adrenocorticotropin response than does the LEW/N strain when challenged with a variety of stressors or with inflammatory mediators such as SCW peptidoglycan polysaccharide or interleukin-1α (IL-1α) (Sternberg et al., 1989a; Sternberg et al., 1989b; Dhabhar et al., 1995a).

Compared to the F344 strain, the Lewis strain shows a significantly greater habituation or adaptation to an acute or chronic stressor (Dhabhar et al., 1997). F344/N rats treated with the glucocorticoid receptor antagonist RU486 are rendered susceptible to SCW-induced arthritis, indicating that they do carry the immune response genes with potential for triggering autoimmunity (Sternberg et al., 1989a; Sternberg et al., 1989b). Conversely, LEW rats treated with pharmacologic doses of dexamethasone become completely resistant to the development of SCW-induced arthritis (Sternberg et al., 1989a; Sternberg et al., 1989b). Furthermore, compared to Fischer 344 (F344) rats, adrenal steroid receptors in neural and immune tissues of LEW rats show a significantly lower magnitude of activation in response to stress-induced increases in plasma corticosterone (Dhabhar et al., 1993; Dhabhar et al., 1995a). Thus, strain differences in plasma corticosterone levels also are manifest as significant differences in the extent of activation of corticosterone receptors in target tissues.

Experimental allergic encephalomyelitis (EAE) is another animal model of an autoimmune disease in which a similar immunosuppressive role for the HPA axis has been proposed (for reviews see Mason et al., 1990; Mason, 1991; Whitacre et al., 1998). The Lewis strain shows a greater

susceptibility to EAE (Mason, 1991). Similar correlations between HPA axis hyporeactivity and susceptibility to autoimmune disease have been observed for autoimmune conditions in chickens (Wick et al., 1998) and mice (Lechner et al., 1996).

Complementing these animal studies, a series of elegantly conducted clinical studies (Torpy and Chrousos, 1996; Buske-Kirschbaum and Hellhammer, 2003) have shown that patients with atopic dermatitis (Buske-Kirschbaum et al., 1997; Buske-Kirschbaum et al., 1998; Buske-Kirschbaum et al., 2001) and asthma (Buske-Kirschbaum et al., 2003) show decreased HPA axis reactivity. Studies of pediatric rheumatic diseases suggest a similar HPA axis deficiency coupled with other proinflammatory hormonal biases (Chikanza et al., 2000). Differences in NK cell stress reactivity and beta(2)-adrenoreceptor upregulation on peripheral blood mononuclear cells have been observed in patients with systemic lupus erythematosus (Pawlak et al., 1999). A more complex role for sympathetic nervous system involvement in autoimmune disease also has been proposed (Kuis et al., 1996; Kavelaars et al., 1998).

Epidemiologic studies have repeatedly linked low social status with increased disease risk and mortality rates (Adler et al., 1994; Adler and Ostrove, 1999). Sapolsky has proposed that the magnitude of chronic stress experienced by individuals of different ranks within a social hierarchy depends on the individual’s personality as well as on the characteristics of social organization, such as dominance style, stability of ranks, availability of coping mechanisms, and ease of avoidance (for review see Sapolsky, 2005). Thus, despotic, top-down hierarchies maintained through aggression are more stressful for dominant animals, while those maintained through psychological intimidation are more stressful for subordinate animals (Sapolsky, 2005). Egalitarian, bottom-up hierarchies in which dominance is obtained through support from subordinate individuals are less stressful for all members. Unstable hierarchies are more stressful for dominant animals, while stable hierarchies can be more stressful for subordinate animals that have less access to food and mates. Societies that have a high availability of coping outlets (grooming, physical contact, coalition formation) are less stressful for all individuals, while those that have a low availability of coping outlets are more stressful for low-ranking individuals. Habitats that allow subordinates to easily avoid dominants are less stressful, while those that are not conducive to avoidance are generally more stressful for subordinate animals.

This highlights the fact that captive habitats that are not designed to

allow subordinates to “escape” may be particularly stressful. Personality also is important in determining the influence of the social environment, regardless of rank. Individuals who perceive and react to innocuous or neutral situations as threatening and/or who are not able to muster social support are likely to experience a greater stress burden (Sapolsky, 2005). Regardless of rank, individuals who are chronically stressed as a result of their social environment show higher basal glucocorticoid hormones levels, enlarged adrenal glands, and reduced sensitivity of the HPA axis to negative glucocorticoid feedback (Sapolsky et al., 1997; Sapolsky, 2005). Such stress profiles have been associated with decreased levels of high-density lipoprotein cholesterol (Sapolsky and Mott, 1987) and decreased hippocampal volume (Uno et al., 1989).

Studies also have shown that low social status in the context of an experimental social stress paradigm is associated with a greater susceptibility to experimental viral infection (Cohen et al., 1997). Studies by Capitanio et al. have shown that social stressors that include separations and housing relocation of macaques increase susceptibility to SIV (Capitanio et al., 1998; Capitanio and Lerche, 1998) and that personality characteristics of individual animals are related to stable HPA axis response characteristics (Capitanio et al., 2004). However, other studies have shown that exposure to mild early life stressors strengthens emotional and neuroendocrine stress responses in adulthood (Parker et al., 2005). Winslow and Insel showed that oxytocin, a neurohypophyseal peptide that is thought to modulate many aspects of social behavior, has different effects depending on the social status of pairs of male squirrel monkeys. Central oxytocin administration results in increased sexual behavior and aggression in dominant males and in increased associative and marking behaviors in subordinates (Winslow and Insel, 1991). It also has been shown that individual differences in the promoter for the serotonin transporter gene interact with early rearing conditions to affect behavioral development (Champoux et al., 2002), HPA axis reactivity, and vulnerability to alcoholism (Barr et al., 2004) in nonhuman primates. Tree shrews, which are thought to provide a model for early primate behavior, have been used to study chronic social stress, which is thought to model depression in subordinate animals (Fuchs et al., 2001; Fuchs, 2005). It has been suggested that the rhesus monkey provides a particularly attractive model for aging because of the similarities between human and rhesus aging phenotypes and the close genetic relationship of this species to humans (Roth et al., 2004). Therefore, nonhuman primate models provide a significant resource for examining interactions among social environment, behavior, and health outcomes. These models, although more difficult to study than rodent models, may offer the closest

approximation for humans. More research is needed to examine the health consequences of chronic social stressors and the contribution of genetic factors within these models.

Rodent models of social stressors include visible burrow systems that examine group housed animals under conditions that attempt to mimic their natural habitats (Blanchard et al., 1995) and models that use cage-housed animals to induce experimentally social confrontation (Stefanski et al., 1996; Stefanski et al., 2005), social disruption (Avitsur et al., 2002a), and social isolation (Sanchez et al., 1998). Using the visible burrow system, which consists of groups of male and female rats housed in a semi-natural, visible environment, the Blanchards and their colleagues have examined the deleterious consequences of chronic social stress on numerous brain, behavioral, and physiological parameters (for review see Blanchard et al., 2001). These include differences between subordinate and dominant animals in behavior (Blanchard et al., 1993), metabolism (Tamashiro et al., 2004), HPA axis reactivity (Blanchard et al., 1995), hippocampal 5HT1A receptor levels (McKittrick et al., 1995), and corticotropin releasing factor and arginine vasopressin mRNA expression in the paraventricular hypothalamic nucleus and amygdala (Albeck et al., 1997).

Stefanski and colleagues have used a rat model of social confrontation that involves introducing intruder rats to cages of established pairs of animals (Stefanski et al., 1996; Stefanski, 2001). In this model the intruder is attacked and generally defeated. The social confrontation is allowed to proceed for hours to days, and the endocrine and immune consequences of the defeated and undefeated animals are studied (Stefanski, 2001). Studies have shown social confrontation induces a significant increase in susceptibility to metastases of injected tumor cell lines (Stefanski and Ben-Eliyahu, 1996; Stefanski, 2001), changes in blood immune cell distribution (Stefanski and Engler, 1998), T-cell maturation (Engler and Stefanski, 2003), and circulating stress hormones (Stefanski, 2000).

Sheridan and colleagues have used a model of social disruption that involves placing an aggressive retired male breeder in a cage of male mice for several consecutive stress sessions. In this model, home cage animals are attacked by the aggressive intruder and are frequently wounded. Animals that show subordinate behavior are wounded to a larger extent (Avitsur et al., 2001). Animals that show a subordinate behavioral profile also develop glucocorticoid resistance, which is measured by their lipopolysaccharide stimulated splenocyte proliferation index in vitro being resistant to suppression by corticosterone (Stark et al., 2001). These authors have shown that this stressor also alters splenocyte distribution and function (Avitsur et al.,

2002b) and increases tumor necrosis factor-alpha secretion from in vitro lipopolysaccharide stimulated splenic macrophages (Avitsur et al., 2005). The critical role of aggressive physical contact that often results in wounding in this model of social stress is highlighted by studies that show that only mice that are physically in contact with the intruder animals show the development of splenocyte glucocorticoid resistance, which is the hallmark immunological effect of this stressor (Bailey et al., 2004).

Another example of the impact of social environment involves the Watanabe heritable hyperlipidemic rabbit, which has a genetic defect in lipoprotein clearance. This defect results in severe atherosclerosis in rabbits that are raised in isolation or in an unstable social situation in which unfamiliar rabbits are paired daily. In contrast, when the rabbits are paired stably with littermates across the period of the experiment, atherosclerosis is greatly reduced (McCabe et al., 2002)—a result that demonstrates how a positive social environment that provides increased support can ameliorate the health-damaging effects of a particular genetic variant. A most interesting parallel with this animal study finding is found in one of the studies (Kaufman et al., 2004) that found increased depression among maltreated children carrying the 5HTTLPR short allele: in those with higher quality and availability of social supports the effect of the short allele to increase depression levels was ameliorated.

Physiological stress responses involving neurotransmitters and hormones are likely mediators of effects examined in almost all of the animal models described above. Therefore, it is useful to understand the concept of stress and the role that it plays in the particular model systems under examination. Numerous definitions have been proposed for the word stress. Each definition focuses on an aspect of an internal or external challenge, disturbance, or stimulus; on perception of a stimulus by an organism; or on a physiological response of the organism to the stimulus (McEwen, 2002; Goldstein and McEwen, 2002; Sapolsky, 2004). Physical stressors have been defined as external challenges to homeostasis and psychological stressors as the “anticipation, justified or not, that a challenge to homeostasis looms” (Sapolsky, 2005). An integrated definition states that stress is a constellation of events, consisting of a stimulus (stressor) that precipitates a reaction in the brain (stress perception) that activates physiologic fight or flight systems in the body (stress response) (Dhabhar and McEwen, 1997). The ultimate effector molecules of stress are the neurotransmitters and hormones that are released during stress, the principle mediators being norepinephrine, epinephrine, and cortisol.

It often is overlooked that a stress response has salubrious adaptive

effects in the short run (Dhabhar et al., 1995b; Dhabhar and McEwen, 1996) although stress can be harmful when it is long lasting (Dhabhar and McEwen, 1997; McEwen, 1998; Glaser and Kiecolt-Glaser, 2005). Therefore, important distinguishing characteristics of stress include its duration and intensity. Acute stress has been defined as stress that lasts for a period of minutes to hours, and chronic stress as stress that persists for several hours a day for an extended period (generally months to years) (Dhabhar and McEwen, 1997). The magnitude of stress may be gauged by the peak levels of stress hormones, neurotransmitters, and other physiological changes such as increases in heart rate and blood pressure, and by the amount of time that these changes persist during and following stressor exposure. An important marker for deleterious amounts of chronic stress may be a dysregulation of the circadian corticosterone rhythm in rodents (Dhabhar and McEwen, 1997) and cortisol rhythm in humans (Sephton et al., 2000). It has been shown that moderate chronic stress experienced during UV exposure results in a significant increase in susceptibility to skin cancer (squamous cell carcinoma). This increase is mediated by a stress-induced suppression of Type 1 cytokine gene expression, a decrease in numbers of protective T cells, and an increase in numbers of suppressor T cells. Interestingly, the effects of stress on gene expression and immune cell numbers are accompanied by a disruption of the diurnal corticoster-one rhythm and observed nine months after the cessation of stress (Saul et al., 2005). This indicates that stressors experienced during critical moments of immune challenge or activation may have long-term consequences.

Stress has long been suspected to play a role in the etiology of many diseases, and numerous studies have shown that stress can dysregulate or suppress immune function and hence may be detrimental to health (Herbert and Cohen, 1993; Straub and Schedlowski, 2002; Sapolsky, 2005; Glaser and Kiecolt-Glaser, 2005). Although decades of research have examined the pathological effects of stress on immune function and on health, the study of the salubrious or health-promoting effects of stress is relatively new (Dhabhar and McEwen, 1996). Much work remains to be done to elucidate the biological mechanisms mediating these bidirectional effects of stress on health and to translate basic findings regarding the adaptive effects of stress from the bench to the bedside. For a given stimulus or stressor, individual differences in genetic factors may interact with social factors to affect the degree and nature of psychological stress perception and/or the kinetics and magnitude of the physiological stress response. Therefore, when examining interactions between genes, social environment, and health, it may be critical to keep in mind the overall stress reactivity and stress status of the individual or populations being studied.

Extensive epidemiological work and clinical genetics on families indicated that there must be a gene on chromosome 17(q) whose heritable mutation increased susceptibility to breast and ovarian cancer. With positional cloning, BRCA1 (BReast CAncer1) was identified (Futreal et al., 1994) and subsequently many different mutations have been described in diverse populations, including Ashkenazi Jewish, Japanese, Korean, African, and Chinese families (Katagiri et al., 1996; Okobia and Bunker, 2003; Ademuyiwa and Olopade, 2003; Lynch et al., 2004; Judkins et al., 2005; Kim et al., 2006; Song et al., 2006).

Rodent models in which the homolog of BRCA1 is knocked out (Brodie and Deng, 2001; Zan et al., 2003) have elucidated a variety of environmental, hormonal, and genetic factors that increase the penetrance of BRCA1 mutations causing breast and ovarian cancer. Such work is impossible in humans. For example, conditional inactivation of BRCA1 in the epithelial tissue of mice led to cancer development in organs other than the breast and ovary (Berton et al., 2003). Other genes have been identified and manipulated, such as ataxia telangiectasia mutated (Atm) heterozygosity and p53, demonstrating their interaction with BRCA1 to increase mammary cancer (Bachelier et al., 2005; Bowen et al., 2005). In this mouse model, even though mammary tumors were estrogen receptor negative, removing the ovaries nonetheless reduced the development of mammary tumors late in the life span. However, in a wild-type rat model, phytoestrogen-rich diets increased the BRCA1 mRNA, but not protein produced by the tumor suppressor gene. Thus, the rodent models have the potential to manipulate the environmental, hormonal, and genetic mechanisms affecting the expression of BRCA1 mutations in order to determine which are mediators and only modulate their effect on mammary tumorigenesis.

New models may not be necessary, but they could be useful. The quest for new and improved models should continue. However, promising existing models also should be nurtured, fine-tuned, and developed further.

Animal models have a great deal to offer in furthering our understanding of the impact of interactions among social, behavioral, and genetic

factors on health and can provide an important complement to clinical and community-based research. Therefore the committee makes the following recommendation:

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; recognize, account for, and preferably measure unintended physiological consequences of experimental manipulations when generating data and interpreting 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 different research groups (i.e., once ecological and ethological factors are established, 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 different opinions on what ethologically and ecologically relevant conditions are and how they should be replicated in the vivarium. However, not standardizing 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).

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