et al., 1997). Reduced levels of GH consequential to a disruption of personal ties can be involved in immune system function. In particular, current evidence suggests that GH promotes the efficacy of lymphocytes in responding to antigens, with its route of action being via the TH-1 and TH-2 helper cytokine system (Wu et al., 1999). Research is needed to clarify the details of this proposed process, including whether these perturbations in immune system parameters translate to downstream health outcomes. In addition, we need to understand how cumulative adversity in a variety of interpersonal relationships is connected to processes of gene expression that may culminate in impaired immune function and thereby contribute to a range of disease outcomes.


Although the above examples focus on human populations and important research agendas that follow from them, animal models have been and will continue to be a main route to achieving deeper understanding of mechanisms of gene expression. For example, the role and character of mother-child interactions that influence neural development have recently been studied in detail in rats (Lui et al., 1997; Caldji et al., 1998; Francis et al., 1999). Specifically, there are two forms of maternal behavior in the rat—licking and grooming of pups (LG) and arched-back nursing (ABN)—that appear to regulate the development of stress reactivity in the offspring. As adults the offspring of mothers exhibiting high levels of LG-ABN care showed reduced plasma ACTH and corticosterone responses to restraint stress. These animals also show significantly increased hippocampal glucocorticoid receptor mRNA expression, enhanced glucocorticoid negative feedback sensitivity, and decreased hypothalamic corticotropin-releasing hormone mRNA levels. The results of these studies suggest that the behavior of the mother toward her offspring can program the expression of genes regulating neuroendocrine response to stress in adulthood (Lui et al., 1997).

Support for this claim derives from the fact that as adults the offspring of low LG-ABN mothers exhibit increased fearfulness relative to offspring of high LG-ABN mothers (Caldji et al., 1998). They also show increased corticotropin-releasing factor (CRF) receptor levels in the locus coeruleus and decreased central benzodiazepine receptor levels in the basolateral and central nucleus of the amygdala, as well as increased CRF mRNA expression in the central amygdala. Predictably, stress-induced increases in levels of norepinephrine in the paraventricular nucleus of the hypothalamus were significantly higher in the offspring of low LG-ABN mothers (Francis et al., 1999). These are all neurophysiological signs of elevated reactivity to stress in adulthood.

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