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266 EFFECTS OF STRESSin primates) from the adrenal cortex into circulation. An acute rise in cortisol levelscan be adaptive, because it serves to increase the availability of energy substrates,but persistent elevations can be maladaptive.The actions of cortisol are mediated by two types of receptors: mineralocorticoidreceptors (MRs) and glucocorticoid receptors (GRs), also referred to as Type Iand Type II receptors, respectively. MRs and GRs are two closely related membersof the steroid nuclear receptor family of transcription factors that bind cortisol.These receptors are present on many cells throughout the body, including thebrain, and they are pivotal in the self-modulation of the HPA axis. Thus glucocorticoidsact to suppress their own release through activation of MRs and GRs,which initiate both fast and slow acting negative feedback systems that inhibitACTH release. These feedback systems act through the hypothalamus and pituitary,although other regions are also implicated.The HPA-Hippocampal SystemThe hippocampus is relevant to functioning of the HPA axis for two reasons. First,as noted, it plays a role in modulation of the HPA system. This is presumed to bea consequence of steroid receptors on hippocampal neurons (Watzka et al., 2000).Second, the hippocampus may be uniquely sensitive to the adverse effects of sustained,high levels of glucocorticoid secretion (Charmandari et al., 2003; Dorn &Chrousos, 1997). Thus, heightened levels may have neurotoxic effects that structurallycompromise the hippocampus. For both of these reasons, an inverse relationbetween glucocorticoid levels and hippocampal volume would be predicted.Consistent with the hypothesized modulating role of the hippocampus, studiesusing rodent models have revealed an inverse relation between glucocorticoidlevels and hippocampal volume (Hibberd, Yau, & Seckl, 2000; Meaney et al.,1995; Meaney et al., 1996). Similar findings have been reported in the rhesus (Coeet al., 2003) and tree shrew (Ohl, Michaelis, Vollmann-Honsdorf, Kirschbaum,& Fuchs, 2000). A recent study suggests that the relation can be measured on thecellular level; in pigs exposed to chronic stress, basal cortisol is negatively correlatedwith hippocampal neuron number, as well as volume (van der Beek et al.,2004). These relations were most pronounced in the dentate gyrus.Subsequent neuroimaging studies of human subjects have also revealed a relationbetween glucocorticoid secretion and hippocampal volume. Consistent withthe notion of hippocampal negative feedback, the findings show an inverse relation.In patients with dementia, higher serum cortisol concentrations are associatedwith the reduction of cerebral volume in both the hippocampus and temporallobes (Ferrari, Fioravanti, Magri, & Solerte, 2000). Similarly, a longitudinal studyrevealed that in aged humans a measure of hippocampal atrophy was positivelycorrelated with both basal cortisol and the magnitude of cortisol elevation overtime (Lupien et al., 1998). Further, prolonged cortisol elevation was linked withhippocampus-dependent memory deficits. The link between hippocampal volume