to explore a novel stimulus than low reactors (Suomi 2004). Moreover, because even within genetically diverse species individual animals will vary on many dimensions, high levels of exploration may be the norm for some but not for others.

  1. Transgenic and knockout mouse models: Many genetic mouse models have intentional or incidental behavioral and/or physiological phenotypes relevant to stress. Disturbances in genes associated with brain stress-regulatory systems can elicit stress hyposensitivity (e.g., deletion of the corticotrophin-releasing hormone [CRH] gene; Muglia et al. 1995) or stress hypersensitivity (e.g., overexpression of CRH; Stenzel-Poore et al. 1994). Moreover, there are any number of transgenic/knockout phenotypes that affect behavioral or physiological indices of stress without producing overt stress or distress. For example, deletion of the S6 kinase gene produces a remarkably small animal, not because of the animal’s “failure to thrive” but rather because absence of this powerful cell-size regulator results in a smaller size of otherwise healthy cells (Thomas 2002). Thus, expressed phenotypes need to be considered when assessing stress and/or distress in genetically engineered animal models because their presence may be even more difficult to recognize and diagnose in these animals than in their control littermates.

  2. Rearing and postnatal separation: In most mammals, the early environment of the young animal is defined by the presence of its mother; therefore maternal characteristics can have a profound impact on the future behavior of adult offspring. There is ample scientific evidence that maternal environment can be an important epigenetic determinant of physiology and behavior, and should be considered as a variable for assessment of stress and distress. Offspring are generally reared with their mothers and may also be reared in larger social groups that include other offspring as well as adult males and females. Some species- or strain-typical behaviors, such as cross fostering, in which the offspring of one species are reared by the parents of another species or of the same species but a different strain, are more susceptible to parent-related environmental manipulations. The extent to which cross fostering may produce distress in the offspring

relatively mild environmental stressors with unusual behavioral disruption and physiological arousal including prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by plasma cortisol and adrenocorticotropic hormone (ACTH), increased cerebrospinal fluid levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol, heightened sympathetic nervous system activity as reflected in altered heart rate rhythms, and abnormal immune system response (Coe et al. 1989; Higley et al. 1991). The same stressors elicit only minor behavioral reactions and transient physiological responses in the remainder of the population (Suomi 2004).

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