Tissue metabolism of glucocorticoids: New controls of cognitive function and the stress response

Abstract

Glucocorticoids (Cortisol and corticosterone) have a host of biological effects inbrain and body, underpinning adaptive responses to stress and maintaining criticalaspects of basal metabolism (de Kloet 2004). Many neural and glial systems aremodified by glucocorticoids and their target genes include neurotransmitter systems,receptors, ion channels, cytoskeletal proteins, enzymes, second messengersystems, and metabolism. Acute rises of glucocorticoid levels are adaptive responsesto diurnal cues or stress, facilitating survival pathways and inhibiting immediatelyunhelpful processes such as digestion and inflammation. In contrast, chronicelevations of glucocorticoids (e.g., Cushing's syndrome) are detrimental to homeostasisat all phases of life from embryogenesis to senescence (de Kloet 1991, 2004).In the central nervous system (CNS), chronic glucocorticoid excess exerts profoundadverse effects, producing neuropsychiatric dysfunction (depression, psychosis),cognitive impairments, structural deterioration, and neuroendocrine abnormalities(McEwen 1999, 2003). Conversely, chronic severe deficiency of glucocorticoids(Addison's disease) is also deleterious, reducing an organism's survival in stressfulcircumstances and associating with reduced mood and hippocampal neuronal loss(Sloviter et al. 1989). Thus, it is obviously crucial that glucocorticoid levels arestrictly controlled. This is ensured by negative feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids act predominantly by binding tointracellular receptors of two types; lower-affinity, widely distributed glucocorticoidreceptors (GR) and higher-affinity mineralocorticoid receptors (MR), whichhave a restricted tissue distribution (de Kloet 1991, 2004). In the hippocampus,where GR and MR are both highly expressed, both receptors bind the same glucocorticoidligands in vivo. Because the genes regulated by GR and MR in the hippocampusare largely distinct (Vreugdenhil and de Kloet 1998), nuclear accessory factors(coactivators and corepressors (Jenkins et al. 2001)) and the fine kinetics ofreceptor-DNA binding are also likely to be important. However, is the product of circulating steroid levels and this transcriptional machinery all there is to glucocorticoidbiology?