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Maternal Programming of Defensive Responses 151ences on a wide range of functional outcomes. Importantly, prenatal adversity isalso associated with increased HPA and autonomic responses to stressors (Amiel-Tison et al., 2004; Chapillon et al., 2002; Maccari et al., 2003; Wadhwa et al.,2001; Weinstock, 2001).Support for the basic elements of stress diathesis models appears compelling.Adversity during perinatal life alters development in a manner that seems likelyto promote vulnerability, especially for stress-related diseases. Diathesis-stressmodels describe the interaction between development, including the potentialinfluence of genomic variations and the prevailing level of stress in predictinghealth outcomes. Such models could identify both the origins and the nature ofvulnerability. However, much of the evidence from both human and nonhumanmodels remains correlational. How might parental care affect the development ofneural systems that regulate stress responses? Are such effects apparent only underconditions of extreme adversity (physical or sexual abuse, persistent emotionalneglect, etc.), as some have suggested (Scarr, 1997)? Or, are parental effects partof normal developmental processes? We address these fundamental questions usingan animal model that examines the developmental consequences of variations inmother-infant interactions.Maternal Care in the Rat: Behavioraland Endocrine Responses to StressCentral corticotropin-releasing factor (CRF) systems furnish the critical signalfor the activation of behavioral, emotional, autonomic, and endocrine responsesto stressors. There are two major CRF pathways regulating the expression ofthese stress responses. First, a CRF pathway extends from the periventricularnucleus of the hypothalamus (PVNh) to the anterior pituitary, which serves asthe principal mechanism for the transduction of a neural signal into a pituitaryadrenalresponse (Antoni, 1993; Herman et al., 2003; Plotsky, 1991; Rivier &Plotsky, 1986; Whitnall, 1993). In responses to stressors, CRF, as well as cosecretagoguessuch as arginine vasopressin, are released from PVNh neuronsinto the portal blood supply of the anterior pituitary, where it stimulates thesynthesis and release of adrenocorticotropin hormone (ACTH). Pituitary ACTH,in turn, causes the release of glucocorticoids from the adrenal gland. CRF synthesisand release is subsequently inhibited through a glucocorticoid negativefeedbacksystem mediated by both mineralocorticoid and glucocorticoidreceptors in a number of brain regions including, and perhaps especially, in thehippocampus (de Kloet et al., 1998; Sapolsky et al., 2000). For example, selectivedisruption of the glucocorticoid receptor gene in the hippocampus and cortexthat is unique to adulthood results in negative feedback impairments andincreased HPA activity (Boyle et al., 2005).