Comprehensive Physiology Wiley Online Library

Mechanisms of Glucocorticoid Actions in Stress and Brain Aging

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Glucocorticoids in Relation to Stress and Aging
1.1 Association of Glucocorticoids with Brain Aging
1.2 Experimental Interventions in Glucocorticoid Actions
1.3 Caloric Restriction
1.4 Possible Trophic Actions of Glucocorticoids
1.5 Studies in Humans
2 Modulation of the Adrenal Axis
2.1 Basic Regulatory Mechanisms: Systemic, Receptor, and Genomic Levels
2.2 Adrenocorticoid Receptors: Effects of Stress and Aging
3 Cellular Mechanisms of Neuronal Toxicity of Glucocorticoids
3.1 Excitotoxicity and Glucose Metabolism
3.2 Ion Channels and Calcium Homeostasis
4 Conclusion
Figure 1. Figure 1.

Examples of CA1 pyramidal cells in the soma layer in semithin sections from young rats (top), aged controls (middle), and aged rats adrenalectomized 9 months earlier (bottom). All sections are cut perpendicular to the somal layer, from the CA1 region just dorsal to the tip of the dorsal limb of the dentate gyrus granule cells. Neuronal nuclei and major glial species can be recognized—astrocytes with lucent cytoplasm and the darker microglia and oligodendrocytes, with chromatin clumps in the nucleus.

Reprinted with permission from Science Vol. 214, pp 581‐584. Copyright 1981 American Association for the Advancement of Science
Figure 2. Figure 2.

Pyramidal cell density values, expressed as number of nucleoli (mean ± SEM) per 100 μm of stratum pyramidale length, for young, midaged, and aged (nonstressed vs. stressed) rats. Main effects of age were observed, and chronic stress resulted in an increase in cell loss for the aged groups.

Reprinted with permission from the Journal of Neuroscience 11: 1316‐1324 from Kerr et al., 1991 69. Copyright Society for Neuroscience
Figure 3. Figure 3.

The glucocorticoid hypothesis of cognitive decline in aging. Stress increases pituitary release of corticotropin, which causes the adrenal gland to produce more glucocorticoids. Long‐term exposure to these stress hormones increases neuronal vulnerability to aging, extrinsic injuries, and disease, causing hippocampal deterioration and eventual cognitive decline.

Reprinted with permission from Nature Neuroscience 1: 3‐4, 1998, 127. Copyright Nature America
Figure 4. Figure 4.

Organization of the hypothalamo‐pituitary‐adrenocortical axis and glucocorticoid negative feedback pathways. Upon receipt of a secretory stimulus (for example, stress), hypophysiotrophic neurons of the medial parvocellular paraventricular nucleus (PVN) release corticotropin‐releasing hormone (CRH) and cosecretagogs (such as arginine vasopressin [AVP]) into the hypophysial portal circulation at the level of the median eminence (ME). Secretagogs act at anterior pituitary corticotropes to release corticotropin, which travels by way of the systemic circulation to elicit secretion of glucocorticoids. Glucocorticoids can then act directly or indirectly to inhibit activation of medial parvocellular PVN neurons. Direct action of glucocorticoids can occur directly on CRH neurons, through nuclei that project directly to PVN neurons (for example, medial preoptic area), or through multisynaptic stress relays (for example, hippocampus, prefrontal cortex).

Figure 5. Figure 5.

Localization of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA in the rat hippocampus. Note the preferential localization of GR mRNA to CA1 and the dentate gyrus (DG); in contrast, MR mRNA is distributed throughout all hippocampal regions.

Figure 6. Figure 6.

Effects of age on up‐regulation of hippocampal corticosteroid receptors (group means ± SEM). Young animals were 3‐4 months of age; aged animals were 24‐26 months of age; young, 2 days post ADX (n = 10), aged, 2 days (n = 9), young, 7‐10 days (n = 13), aged, 7‐10 days (n = 5). (A) Total receptor binding; age effect, F = 9.878, p < 0.005; time effect, F = 17.19, p < 0.001; (B) Type I binding; age and time effects, nonsignificant; (C) Type II binding; age effect, F = 6.829, p < 0.01; time effect, F = 15.415, p < 0.001.

From Eldridge et al., [38]. Reprinted from Brain Research 478: 248–256. Copyright 1989, with permission from Elsevier Science
Figure 7. Figure 7.

Representative single Ca2+ action potential from Cs+‐loaded, TTX‐treated CA1 neurons of young adult rats. (A) Young, intact cell (upper trace) and young, ADX cell (lower trace). Action potentials were elicited by a 40‐ms depolarizing constant current pulse through the intracellular pipette. In all cases, current intensity was set at 150% of the threshold amount of current required to trigger a Ca2+ action potential. The bottom trace shows the current pulse (0.5 nA) used to trigger the action potential in the ADX cell. Fast action potential amplitude, fast action potential width at the base, peak plateau amplitude, overall duration from onset to return to baseline, and area under the action potential curve were quantified for cells at three holding potentials, from −65 to −75 mV.

Reprinted with permission from Science 245: 1505‐1509. Copyright 1989 American Association for the Advancement of Science. (B). Dexamethasone enhances L‐type Ca2+ channel activity in primary rat hippocampal neurons. Cells were switched to serum‐free medium lacking corticosterone at 3 days in vitro (DIV). Ethanol vehicle or dexamethasone was added at the indicated concentrations at 3 and 6 DIV and electrophysiological recording performed on 7‐9 DIV. Representative traces of cell‐attached patch recordings obtained from control and Dexamethasone‐treated cells are shown


Figure 1.

Examples of CA1 pyramidal cells in the soma layer in semithin sections from young rats (top), aged controls (middle), and aged rats adrenalectomized 9 months earlier (bottom). All sections are cut perpendicular to the somal layer, from the CA1 region just dorsal to the tip of the dorsal limb of the dentate gyrus granule cells. Neuronal nuclei and major glial species can be recognized—astrocytes with lucent cytoplasm and the darker microglia and oligodendrocytes, with chromatin clumps in the nucleus.

Reprinted with permission from Science Vol. 214, pp 581‐584. Copyright 1981 American Association for the Advancement of Science


Figure 2.

Pyramidal cell density values, expressed as number of nucleoli (mean ± SEM) per 100 μm of stratum pyramidale length, for young, midaged, and aged (nonstressed vs. stressed) rats. Main effects of age were observed, and chronic stress resulted in an increase in cell loss for the aged groups.

Reprinted with permission from the Journal of Neuroscience 11: 1316‐1324 from Kerr et al., 1991 69. Copyright Society for Neuroscience


Figure 3.

The glucocorticoid hypothesis of cognitive decline in aging. Stress increases pituitary release of corticotropin, which causes the adrenal gland to produce more glucocorticoids. Long‐term exposure to these stress hormones increases neuronal vulnerability to aging, extrinsic injuries, and disease, causing hippocampal deterioration and eventual cognitive decline.

Reprinted with permission from Nature Neuroscience 1: 3‐4, 1998, 127. Copyright Nature America


Figure 4.

Organization of the hypothalamo‐pituitary‐adrenocortical axis and glucocorticoid negative feedback pathways. Upon receipt of a secretory stimulus (for example, stress), hypophysiotrophic neurons of the medial parvocellular paraventricular nucleus (PVN) release corticotropin‐releasing hormone (CRH) and cosecretagogs (such as arginine vasopressin [AVP]) into the hypophysial portal circulation at the level of the median eminence (ME). Secretagogs act at anterior pituitary corticotropes to release corticotropin, which travels by way of the systemic circulation to elicit secretion of glucocorticoids. Glucocorticoids can then act directly or indirectly to inhibit activation of medial parvocellular PVN neurons. Direct action of glucocorticoids can occur directly on CRH neurons, through nuclei that project directly to PVN neurons (for example, medial preoptic area), or through multisynaptic stress relays (for example, hippocampus, prefrontal cortex).



Figure 5.

Localization of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA in the rat hippocampus. Note the preferential localization of GR mRNA to CA1 and the dentate gyrus (DG); in contrast, MR mRNA is distributed throughout all hippocampal regions.



Figure 6.

Effects of age on up‐regulation of hippocampal corticosteroid receptors (group means ± SEM). Young animals were 3‐4 months of age; aged animals were 24‐26 months of age; young, 2 days post ADX (n = 10), aged, 2 days (n = 9), young, 7‐10 days (n = 13), aged, 7‐10 days (n = 5). (A) Total receptor binding; age effect, F = 9.878, p < 0.005; time effect, F = 17.19, p < 0.001; (B) Type I binding; age and time effects, nonsignificant; (C) Type II binding; age effect, F = 6.829, p < 0.01; time effect, F = 15.415, p < 0.001.

From Eldridge et al., [38]. Reprinted from Brain Research 478: 248–256. Copyright 1989, with permission from Elsevier Science


Figure 7.

Representative single Ca2+ action potential from Cs+‐loaded, TTX‐treated CA1 neurons of young adult rats. (A) Young, intact cell (upper trace) and young, ADX cell (lower trace). Action potentials were elicited by a 40‐ms depolarizing constant current pulse through the intracellular pipette. In all cases, current intensity was set at 150% of the threshold amount of current required to trigger a Ca2+ action potential. The bottom trace shows the current pulse (0.5 nA) used to trigger the action potential in the ADX cell. Fast action potential amplitude, fast action potential width at the base, peak plateau amplitude, overall duration from onset to return to baseline, and area under the action potential curve were quantified for cells at three holding potentials, from −65 to −75 mV.

Reprinted with permission from Science 245: 1505‐1509. Copyright 1989 American Association for the Advancement of Science. (B). Dexamethasone enhances L‐type Ca2+ channel activity in primary rat hippocampal neurons. Cells were switched to serum‐free medium lacking corticosterone at 3 days in vitro (DIV). Ethanol vehicle or dexamethasone was added at the indicated concentrations at 3 and 6 DIV and electrophysiological recording performed on 7‐9 DIV. Representative traces of cell‐attached patch recordings obtained from control and Dexamethasone‐treated cells are shown
References
 1. Altman J., and S. A. Bayer. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J. Comp. Neurol. 301: 365–381, 1990.
 2. Antoni, F. A. Hypothalamic control of adrenocorticotropin secretion: Advances since the discovery of 41‐residue corticotropin‐releasing factor. Endocr. Rev. 7: 351–378, 1986.
 3. Applegate, M. D, and P. W. Landfield. Synaptic vesicle redistribution during hippocampal frequency potentiation and depression in young and aged rats. J. Neurosci. 8: 1096–1111, 1988.
 4. Arnsten, A.F.T. The biology of being frazzled. Science 280: 1711–1712, 1998.
 5. Aronsson, M., K. Fuxe, Y. Dong, L. F. Agnati, S. Okret and J.‐A. Gustafsson. Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization. Proc. Natl. Acad. Sci. U.S.A. 85: 9331–9335, 1988.
 6. Arriza, J. L., R. B. Simerly, L. W. Swanson, and R. M. Evans. Neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. Neuron 1: 887–900, 1988.
 7. Arriza, J. L., C. Weinberger, G. Cerelli, T. M. Glaser, B. L. Handelin, D. E. Housman, and R. M. Evans. Cloning of the human mineralocorticoid receptor complementary DNA: Structural and functional kinship with glucocorticoid receptor. Science 237: 268–275 1987.
 8. Attardi, B., K. Takimoto, R. Gealy, C. Severns, and E. S. Levitan. Glucocorticoid induced up‐regulation of a pituitary K+ channel mRNA in vitro and in vivo. Receptors and Channels 1: 287–293, 1993.
 9. Baldin, J. C. G. Gottfries, I. Karlsson, G. Lindstedt, G. Langstrom, and J. Walinder. Dexamethasone suppression test and serum prolactin in dementia disorders. Br. J. Psychiatry 143: 277–281, 1983.
 10. Beck K. D., and V. N. Luine. Food deprivation modulates chronic stress effects on object recognition in male rats: role of monoamines and amino acids. Brain Res. 830: 56–71, 1999.
 11. Bohn, M. C., E. Howard, U. Vielkind, and Z. Krozowski. Glial cells express both mineralocorticoid and glucocorticoid receptors. J. Steroid Biochem. Mol. Biol. 40: 105–111, 1991.
 12. Bohus, B. The hippocampus and the pituitary‐adrenal system hormones. In The Hippocampus, edited by R. L. Isaacson and K. H. Pribram. New York: Plenum Press, p 323–354, 1975.
 13. Bradbury, M. J., C. S. Cascio, K. A. Scribner, and M. F. Dallman. Stress‐induced adrenocorticotropin secretion: diurnal responses and decreases during stress in the evening are not dependent on corticosterone. Endocrinology 128: 680–688, 1991.
 14. Cahill, L., and J. L. McGaugh. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci. 21: 294–299, 1998.
 15. Cahill, L., B. Prins, M. Weber, and J. L. McGaugh. Beta‐adrenergic activation and memory for emotional events. Nature 371: 702–704, 1994.
 16. Caldji, C., B. Tannenbaum, S. Sharma, D. Francis, P. M. Plotsky, and M. J. Meaney. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc. Natl. Acad. Sci. U.S.A. 95: 5335–5340, 1998.
 17. Castren, M., and K. Damm. A functional promoter directing expression of a novel type of rat mineralocorticoid receptor mRNA in brain. J. Neuroendocrinol. 5: 461–466, 1993.
 18. Chao, H. M., P. H. Choo, and B. S. McEwen. Glucocorticoid and mineralocorticoid receptor mRNA expression in the rat brain. Neuroendocrinology 50: 365–371, 1989.
 19. Choi, D. W. Ionic dependence of glutamate neurotoxicity. J. Neurosci. 7: 369–379, 1987.
 20. Cintra, A., J. Lindberg, G. Chadi, B. Tinner, A. Miller, J.‐A. Gustafsson, E. R. De Kloet, M. Oitzl, K. Nishikawa, L. F. Agnati, and K. Fuxe. Basic fibroblast growth factor and steroid receptors in the aging hippocampus of the Brown Norway rat: Immunocytochemical analysis in combination with stereology. Neurochem. Int. 25: 39–45, 1994.
 21. Cizza, G., A. E. Calogero, L. S. Brady, G. Bagdy, E. Bergamini, M. R. Blackman, G. P. Chrousos, and P. W. Gold. Male Fischer 344/N rats show a progressive central impairment of the hypothalamic‐pituitary‐adrenal axis with advancing age. Endocrinology 134: 1611–1620, 1994.
 22. Coleman, P. D., and D. G. Flood. Neuron numbers and dendritic extent in normal aging and Alzheimer's disease. Neurobiol. Aging 8: 521–545, 1987.
 23. Coplan, J. D., M. W. Andrews, L. A. Rosenblum, M. J. Owens, S. Friedman, J. M. Gorman, and C. B. Nemeroff. Persistent elevations of cerebrospinal fluid concentrations of corticotropin‐releasing factor in adult non‐human primates exposed to earlylife stressors: implications for psychopathology of mood and anxiety disorders. Proc. Natl. Acad. Sci. U.S.A. 93: 1619–1623, 1996.
 24. Coplan, J. D., R. C. Trost, M. J. Owens, T. B. Cooper, J. M. Gorman, C. B. Nemeroff, and L. A. Rosenblum. Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions. Arch. Gen. Psychiatry 55: 473–477, 1998.
 25. Dachir, S., T. Kadar, B. Robinzon and A. Levy. Cognitive deficits induced in young rats by long‐term corticosterone administration. Behav. Neural. Biol. 60: 103–109, 1993.
 26. De Kloet, E. R., E. C. Azmitia and P. W. Landfield (eds). Brain corticosteroid receptors: studies on the mechanism action and neurotoxicity of corticosteroid action. Ann. N.Y. Acad. Sci. 746: 8–21, 1994.
 27. De Kloet, E. R., E. Vreugdenhil, M. S. Oitzl, and M. Joëls. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19: 269–301, 1998.
 28. DeKosky, S., S. Scheff, and C. Cotman. Elevated corticosterone levels. A possible cause of reduced axon sprouting in aged animals. Neuroendocrinology 38: 33–38, 1984.
 29. de Leon, M. J., T. McRae, J. R. Tsai, A. E. George, D. L. Marcus, M. Freedman, A. P. Wolf, and B. S. McEwen. Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy. Lancet 2: 391–392, 1988.
 30. de Quervain, D. J., B. Roozendaal, and J. L. McGaugh. Stress and glucocorticoids impair retrieval of long‐term spatial memory. Nature 394: 787–90, 1998.
 31. Diamond, D. M., M. C. Bennett, M. Fleshner and G. M. Rose. Inverted‐U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2: 421–430, 1992.
 32. Diamond, D. M., M. Fleshner, N. Ingersoll, and G. M. Rose. Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function. Behav. Neurosci. 110: 661–672, 1996.
 33. Diorio, D., V. Viau, and M. J. Meaney. The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamo‐pituitary‐adrenal responses to stress. J. Neurosci. 13: 3839–3847, 1993.
 34. Disterhoft, J. F., W. H. Gispen, J. Traber, and Z. S. Khachaturian (eds). Calcium hypothesis of aging and dementia. Ann. N.Y. Acad. Sci. 747: 382–406, 1994.
 35. Disterhoft, J. F., J. R. Moyer, L. T. Thompson, and M. Kowalska. Functional aspects of calcium‐channel modulation. Clin. Neuropharmacol. 16 (Suppl. 1): S12–S24, 1993.
 36. Drouin, J., Y. L. Sun, S. Tremblay, P. Lavender, T. J. Schmidt, A. deLeon and M. Nemer. Homodimer formation is rate limiting for high affinity binding by the glucocorticoid receptor. Mol. Endocrinol. 6: 1299–1309, 1992.
 37. Eldridge, J. C., A. Brodish, T. E. Kute, and P. W. Landfield. Apparent age‐related resistance of type 2 hippocampal corticosteroid receptors to down‐regulation during chronic escape training. J. Neurosci. 9: 3237–3242, 1989.
 38. Eldridge, J. C., D. G. Fleenor, D. S. Kerr and P. W. Landfield. Impaired up‐regulation of type II corticosteroid receptors in hippocampus of aged rats. Brain Res. 478: 248–256, 1989.
 39. Elliott, E. M., and R. M. Sapolsky. Corticosterone impairs hippocampal neuronal calcium regulation‐possible mediating mechanisms. Brain Res. 602: 84–90, 1993.
 40. Evans, R. M., and J. L. Arriza. A molecular framework for the actions of glucocorticoid hormones in the nervous system. Neuron 2: 1105–1112, 1989.
 41. Everitt, A. V., and J. Meites. Minireview: Aging and anti‐aging effects of hormones. J. Gerontol. 44: 139–147, 1989.
 42. Finch, C. E. The regulation of physiological changes during mammalian aging. Quat. Rev. Biol. 51: 49–83, 1976.
 43. Findlay, T. Role of the neurohypophysis in the pathogenesis of hypertension and some allied disorders associated with aging. Am. J. Med. 7: 70–84, 1949.
 44. Fomina, A. F., E. S. Levitan, and K. Takimoto. Dexamethasone rapidly increases calcium channel subunit messenger RNA expression and high voltage‐activated calcium current in clonal pituitary cells. Neuroscience 72: 857–862, 1996.
 45. Frame, L. T., R. W. Hart, and J. E. Leakey. Caloric restriction as a mechanism mediating resistance to environmental disease. Environ. Health Perspect. 106 (Suppl. 1): 313–324, 1998.
 46. Francis, D., J. Diorio, D. Liu, and M. J. Meaney. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286: 1155–1158, 1999.
 47. Francis, D., and M. J. Meaney. Maternal care and the development of stress responses. Curr. Opin. Neurobiol. 9: 128–134, 1999.
 48. Gearing, K., W. Cairns, S. Okret, and J.‐A. Gustafsson. Heterogeneity in the 5′untranslated region of the rat glucocorticoid receptor mRNA. J. Steroid Biochem. Mol. Biol. 46: 635–639, 1993.
 49. Gibson, G. E., and C. Peterson. Calcium and the aging nervous system. Neurobiol. Aging 8: 329–43, 1987.
 50. Gould, E., C. S. Woolley, and B. S. McEwen. Short‐term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus. Neuroscience 37: 367–375, 1990.
 51. Gould, E., C. S. Woolley, and B. S. McEwen. Adrenal steroids regulate postnatal development of the rat dentate gyrus: I. Effects of glucocorticoids on cell death. J. Comp. Neurol. 313: 479–485, 1991.
 52. Herman, J. P. Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system. Cell. Mol. Neurobiol. 13: 349–372, 1993.
 53. Herman, J. P., D. Adams, and C. M. Prewitt. Regulatory changes in neuroendocrine stress‐integrative circuitry produced by a variable stress paradigm. Neuroendocrinol. 61: 180–190, 1995.
 54. Herman, J. P., K.‐C. Chen, R. Booze, and P. W. Landfield. Upregulation of alpha 1D Ca2+ channel subunit mRNA expression in the hippocampus of aged F344 rats. Neurobiol. Aging 19: 581–587, 1998.
 55. Herman, J. P., W. E. Cullinan, M. I. Morano, H. Akil, and S. J. Watson. Contribution of the ventral subiculum to inhibitory regulation of the hypothalamo‐pituitary‐adrenocortical axis. J. Neuroendocrinol. 7: 475–482, 1995.
 56. Herman, J. P., P. D. Patel, H. Akil, and S. J. Watson. Localization and regulation of glucocorticoid and mineralocorticoid receptor messenger RNAs in the hippocampal formation of the rat. Mol. Endocrinol. 3: 1886–1894, 1989.
 57. Herman, J. P., S. J. Watson, H. M. Chao, H. M. Coirini, and B. S. McEwen. Diurnal regulation of glucocorticoid receptor and mineralocorticoid receptor mRNAs in the rat hippocampus. Mol. Cell. Neurosci. 4: 181–190, 1993.
 58. Herman, J. P., S. J. Wiegand, and S. J. Watson. Regulation of basal corticotropin‐releasing hormone and arginine vasopressin messenger ribonucleic acid expression in the paraventricular nucleus: effects of selective hypothalamic deafferentations. Endocrinology 127: 2408–2417, 1990.
 59. Iacopino, A. M., and S. Christakos. Specific reduction of calcium‐binding protein (28‐kilodalton calbindin‐D) gene expression in aging and neurodegenerative diseases. Proc. Natl. Acad. Sci. U.S.A. 87: 4078–4082, 1990.
 60. Issa, A. M., W. Rowe, S. Gauthier, and M. J. Meaney. Hypothalamic‐pituitary‐adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J. Neurosci. 10: 3247–54, 1990.
 61. Jack, C. R. Jr., R. C. Petersen, Y. C. Xu, P. C. O'Brien, G. E. Smith, R. J. Ivnik, B. F. Boeve, S. C. Waring, E. G. Tangalos, and E. Kokmen. Prediction of AD with MRI‐based hippocampal volume in mild cognitive impairment. Neurology 52: 1397–1403, 1999.
 62. Jack, C. R. Jr., R. C. Petersen, Y. C. Xu, P. C. O'Brien, G. E. Smith, R. J. Ivnik, E. G. Tangalos, and E. Kokmen. Rate of medial temporal lobe atrophy in typical aging and Alzheimer's disease. Neurology 51: 993–999, 1998.
 63. Joëls, M. and E. R. De Kloet. Effects of glucocorticoids and norepinephrine in the hippocampus. Science 245: 1502–1505, 1989.
 64. Joëls, M., and E. R. De Kloet. Control of neuronal excitability by corticosteroid hormones. Trend Neurosci. 15: 25–30, 1992.
 65. Jones, M. T., and B. Gillham. Factors involved in the regulation of adrenocorticotropic hormone/‐lipotropic hormones. Physiol. Rev. 68: 743–818, 1988.
 66. Kalinyak, J. E., R. I. Dorin, A. R. Hoffman, and A. J. Perlman. Tissue‐specific regulation of glucocorticoid receptor mRNA by dexamethasone. J. Biol. Chem. 262: 10441–10444, 1987.
 67. Kang, C. M. B. S. Kristal, and B. P. Yu. Age‐related mitochondrial DNA deletions: effect of dietary restriction. Free Radic. Biol. Med. 24: 148–154, 1998.
 68. Keller‐Wood, M., and M. F. Dallman. Corticosteroid inhibition of ACTH secretion. Endocr. Rev. 5: 1–24, 1984.
 69. Kerr, D. S., L. W. Campbell, M. D. Applegate, A. Brodish, and P. W. Landfield. Chronic stress‐induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging. J. Neurosci. 11: 1316–1324, 1991.
 70. Kerr, D. S., L. W. Campbell, S‐Y Hao, P. W. Landfield. Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science 245: 1505–1509, 1989.
 71. Kerr, D. S., L. W. Campbell, O. Thibault, and P. W. Landfield. Hippocampal glucocorticoid receptor activation enhances voltage‐dependent calcium conductances: relevance to brain aging. Proc. Natl. Acad. Sci. U.S.A. 89: 8527–8531, 1992.
 72. Khachaturian, Z. S. The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging 1: 17–34, 1989.
 73. Kim, J. J., M. R. Foy, and R. F. Thompson. Behavioral stress modifies hippocampal plasticity through N‐methyl‐D‐aspartate receptor activation. Proc. Natl. Acad. Sci. U.S.A. 93: 4750–4753, 1996.
 74. Kirschbaum, C., O. T. Wolf, M. May, W. Wippich, and D. H. Hellhammer. Stress‐and treatment‐induced elevations of cortisol levels associated with impaired declarative memory in healthy adults. Life Sci. 58: 1475–1483, 1996.
 75. Klebanov, S., S. Diais, W. B. Stavinoha, Y. Suh, and J. F. Nelson. Hyperadrenocortism, attenuated inflammation, and the life‐prolonging action of food restriction in mice. Sci. Med. Sci. 50: B78–B82, 1995.
 76. Krozowski, Z. S., and J. W. Funder. Renal mineralocorticoid receptors and hippocampal corticosterone binding species have identical intrinsic steroid specificity. Proc. Natl. Acad. Sci. U.S.A. 80: 6056–6060, 1983.
 77. Kwak, S. P., P. D. Patel, R. C. Thompson, H. Akil, and S. J. Watson. 5′‐heterogeneity of the mineralocorticoid receptor messenger ribonucleic acid: differential expression and regulation of splice variants within the rat hippocampus. Endocrinology 133: 2344–2350, 1993.
 78. Landfield, P. W. Modulation of brain aging correlates by long‐term alterations of adrenal steroids and neurally‐active peptides. Prog. Brain Res. 72: 279–300, 1987.
 79. Landfield, P. W., R. K. Baskin and T. A. Pitler. Brain aging correlates: retardation by hormonal‐pharmacological treatments. Science 214: 581–584, 1981.
 80. Landfield P. W., and J. C. Eldridge. Increased affinity of type II corticosteroid binding in aged rat hippocampus. Exp. Neurol. 106: 110–113, 1989.
 81. Landfield, P. W., and J. C. Eldridge. Evolving aspects of the glucocorticoid hypothesis of brain aging: hormonal modulation of neuronal calcium homeostasis. Neurobiol. Aging 15: 579–588, 1994.
 82. Landfield, P. W., and T. A. Pitler. Prolonged Ca2+‐dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 226: 1089–1092, 1984.
 83. Landfield, P. W., T. A. Pitler, M. D. Applegate. The effects of high Mg2+‐to‐Ca2+ ratios on frequency potentiation in hippocampal slices of young and aged rats. J. Neurosci. 56: 797–811, 1986.
 84. Landfield, P. W., D. K. Sundberg, M. S. Smith, J. C. Eldridge, and M. Morris. Mammalian brain aging: theoretical implications of changes in brain and endocrine systems during mid‐and late‐life. Peptides 1 (Suppl 1): 185–196, 1980.
 85. Landfield, P. W., O. Thibault, M. L. Mazzanti, N. M. Porter, and D. S. Kerr. Mechanisms of neuronal death in brain aging and Alzheimer's disease: role of endocrine‐mediated calcium dyshomeostasis. J. Neurobiol. 23: 1247–1260, 1992.
 86. Landfield, P. W., J. L. Waymire, and G. S. Lynch. Hippocampal aging and adrenocorticoids: quantitative correlations. Science 202: 1098–1102, 1978.
 87. Leal‐Cerro, A., E. Venegas, F. Garcia‐Pesquera, L. M. Jimenez, R. Astorga, F. F. Casanueva, and C. Dieguez. Enhanced growth hormone (GH) responsiveness to GH‐releasing hormone after dietary restriction in patients with Cushing's syndrome. Clin. Endocrinol. 48: 117–121, 1998.
 88. Leverenz, J. B., C. W. Wilkinson, M. Wamble, S. Corbin, J. E. Grabber, M. A. Raskind, and E. R. Peskind. Effect of chronic high‐dose exogenous cortisol in hippocampal neuronal number in aged nonhuman primates. J. Neurosci. 19: 2356–2361, 1999.
 89. Liao, B., B. Miesak, and E. C. Azmitia. Loss of 5‐HT1A receptor mRNA in the dentate gyrus of the long‐term adrenalectomized rats and rapid reversal by dexamethasone. Brain Res. Mol. Brain Res. 19: 328–332, 1993.
 90. Liu, D., J. Diorio, B. Tannenbaum, C. Caldji, D. Francis, A. Freedman, S. Sharma, D. Pearson, P. M. Plotsky, and M. J. Meaney. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic‐pituitary‐adrenal responses to stress. Science 277: 1659–1662, 1997.
 91. Lowy, M. T., L. Gault, and B. K. Yamamoto. Adrenalectomy attenuates stress‐induced elevations in extracellular glutamate concentrations in the hippocampus. J. Neurochem. 61: 1957–60, 1993.
 92. Luine, V., M. Villegas, C. Martinez, and B. S. McEwen. Repeated stress causes reversible impairments of spatial memory performance. Brain Res. 639: 167–170, 1994.
 93. Lupien, S. J., M. de Leon, S. de Santi, A. Convit, C. Tarshish, N. P. Nair, M. Thakur, B. S. McEwen, R. L. Hauger, and M. J. Meaney. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat. Neurosci. 1: 69–73, 1998.
 94. Lupien, S. J., S. Gaudreau, B. M. Tchiteya, F. Maheu, S. Sharma, N. P. Nair, R. L. Hauger, B. S. McEwen, and M. J. Meaney. Stress‐induced declarative memory impairment in healthy elderly subjects: relationship to cortisol reactivity. J. Clin. Endocrinol. Metab. 82: 2070–2075, 1997.
 95. Magarinos, A. M., B. S. McEwen, G. Flugge, and E. Fuchs. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J. Neurosci. 16: 3534–3540, 1996.
 96. Magarinos, A. M., J. M. Verdugo, and B. S. McEwen. Chronic stress alters synaptic terminal structure in hippocampus. Proc. Natl. Acad. Sci. U.S.A. 94: 14002–14008, 1997.
 97. Major, D. E., J. P. Kesslak, C. W. Cotman, C. E. Finch, and J. R. Day. Life‐long dietary restriction attenuates age‐related increases in hippocampal glial fibrillary acidic protein mRNA. Neurobiol. Aging 18: 523–526, 1997.
 98. Makino, S., M. A. Smith, and P. W. Gold. Increased expression of corticotorpin‐releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology 136: 3299–3309, 1995.
 99. Mann, D.M.A. The neuropathology of Alzheimer's disease: a review with pathogenetic, etiological and therapeutic considerations. Mech. Ageing Dev. 31: 213–255, 1985.
 100. Markowska, A. L. Life‐long diet restriction failed to retard cognitive aging in Fischer‐344 rats. Neurobiol. Aging 20: 177–189, 1999.
 101. May, P. C., N. Telfore, D. Salo, C. I. Anderson, S. G. Kohama, C. E. Finch, R. L. Walford, and R. Weindruch. Failure of dietary restriction to retard age‐related neurochemical changes in mice. Neurobiol. Aging 13: 787–791, 1992.
 102. McEwen, B. S. Re‐examination of the glucocorticoid hypothesis of stress and aging. Prog. Brain Res. 93: 365–381, 1992.
 103. McEwen, B. S. Corticosteroids and Hippocampal plasticity. In: Brain Corticosteroid Receptors: Studies on the mechanism action and neurotoxicity of corticosteroid action, edited by E. R. De Kloet, E. C. Azmitia, and P. W. Landfield. Ann. N.Y. Acad. Sci. 746: 134–142, 1994.
 104. McEwen, B. S., E. R. De Kloet, and W. Rostene. Adrenal steroid receptors and actions in the nervous system. Physiol. Rev. 66: 1121–1188, 1986.
 105. McEwen, B. S., and E. Gould. Adrenal steroid influences on the survival of hippocampal neurons. Biochem. Pharm. 40: 2393–2402, 1990.
 106. Meaney, M. J., D. H. Aitken, S. Bhatnagar, C. H. Van Berkel, and R. M. Sapolsky. Postnatal handling attenuates neuroendocrine, anatomical, and cognitive impairments related to the aged hippocampus. Science 238: 766–768, 1988.
 107. Meaney, M. J., D. H. Aitken, S. Sharma, and V. Viau. Basal ACTH, corticosterone, and corticosterone‐binding globulin levels over the diurnal cycle, and age‐related changes in hippocampal type 1 and type 2 corticosteroid receptor binding capacity in young and aged, handled and nonhandled rats. Neuroendocrinology 55: 204–213, 1992.
 108. Meza, U., G. Avila, R. Felix, J. C. Gomora, and G. Cota. Long‐term regulation of calcium channels in clonal pituitary cells by epidermal growth factor, insulin, and glucocorticoids. J. Gen. Physiol. 104: 1019–1038, 1994.
 109. Michaelis, M. L., C. T. Foster, and C. Jayawickreme. Regulation of calcium levels in brain tissue from adult and aged rats. Mech. Ageing Dev. 62: 291–306, 1992.
 110. Minaker, K. L., G. S. Meneilly, and J. W. Rowe. Endocrine systems. In Handbook of the Biology of Aging, edited by C. E. Finch and E. L. Schneider. New York: Van Nostrand Reinhold, pp 435–456, 1985.
 111. Morano, M. I., and H. Akil. Effects of aging on hippocampal glucocorticoid and mineralocorticoid receptors. Society for Neuroscience (Abstracts) 16: 1071, 1990.
 112. Mueller, E. A., M. M. Moore, D. C. Kerr, G. Sexton, R. M. Camiciolli, D. B. Howieson, J. F. Quinn, and J. A. Kaye. Brain volume preserved in healthy elderly through the eleventh decade. Neurology 51: 1555–1562, 1998.
 113. Nayler, W. G., P. A. Poole‐Wilson, and A. Williams. Hypoxia and calcium. J. Mol. Cell Cardiol. 11: 683–706, 1979.
 114. Nelson, J. E, C. Holinka, K. R. Latham, J. A. Allen, and C. E. Finch. Corticosterone binding in cytosols from brain regions of mature and senescent male C57BL/6J mice. Brain Res. 115: 345–351, 1976.
 115. Newcomer, J. W., S. Craft, T. Hershey, K. Askins, and M. E. Bardgett. Glucocorticoid‐induced impairment in declarative memory performance in adult humans. J. Neurosci. 14: 2047–2053, 1994.
 116. Newcomer, J. W., G. Selke, A. K. Melson, T. Hershey, S. Craft, K. Richards, and A. L. Anderson. Decreased memory performance in healthy humans induced by stress‐level cortisol treatment. Arch. Gen. Psychiatry 56: 527–533, 1999.
 117. Oakley, R. H., and J. A. Cidlowski. Homologous down‐regulation of the glucocorticoid receptor: the molecular machinery. Crit. Rev. Eukaryot. Gene Expr. 3: 63–88, 1993.
 118. O'Donnell, D., and M. J. Meaney. Aldosterone modulates glucocorticoid receptor binding in hippocampal cell cultures via the mineralocorticoid receptor. Brain Res. 636: 49–54, 1994.
 119. Orchinik, M., T. T. Murray, and F. L. Moore. A corticosteroid receptor in neuronal membranes. Science 252: 1848–1851, 1991.
 120. Orrenius, S, D. J. McConkey, G. Bellomo, and P. Nicotera. Role of Ca2+ in toxic cell killing. Trends Pharmacol. Sci. 10: 281–285, 1989.
 121. O'Steen, W. K., L. B. Cadwallader, S. Vinsant, and P. W. Land‐field. Biomarkers of hippocampal and retinal aging are not altered by dietary restriction. Society for Neuroscience (Abstract). 16: 1161, 1990.
 122. O'Steen, W. K., and P. W. Landfield. Dietary restriction does not alter retinal aging in the Fischer 344 rat. Neurobiol. Aging 12: 455–462, 1991.
 123. Ouanounou, A., L. Zhang, M. P. Charlton, and P. L. Carlen. Differential modulation of synaptic transmission by calcium chelators in young and aged hippocampal CA1 neurons: evidence for altered calcium homeostasis in aging. J. Neurosci. 19: 906–915, 1999.
 124. Patel, P. D., S. P. Kwak, J. P. Herman, E. A. Young, H. Akil, and S. J. Watson. Functional heterogeneity of type I and type II corticosteroid receptor expression in rat hippocampus. In Stress and Reproduction, edited by K. E. Sheppard, J. H. Boublik, and J. W. Funder. New York: Raven Press, p 1–17, 1992.
 125. Pearce, D., and K. R. Yamamoto. Mineralocorticoid and glucocorticoid receptor activities distinguished by nonreceptor factors at a composite response elements. Science 259: 1161–1165, 1993.
 126. Pitler, T. A., and P. W. Landfield. Postsynaptic membrane shifts during frequency potentiation of the hippocampal EPSP. J. Neurophysiol. 58: 866–882, 1987.
 127. Porter, N. M., and P. W. Landfield. Stress hormones and brain aging: adding injury to insult. Nat. Neurosci. 1: 3–4, 1998.
 128. Porter, N. M., V. Thibault, and P. W. Landfield. Chronic glucocorticoid treatment enhances high voltage‐activated calcium currents in rat hippocampal neurons in culture. Society for Neuroscience (Abstract). 21: 1577, 1995.
 129. Rachamin, G., W. G. Luttge, B. E. Hunter, and D. W. Walker. Do glucocorticoids play a role in hippocampal cell loss during chronic ethanol treatment. Society for Neuroscience (Abstract). 13: 509, 1987.
 130. Raskind, M., E. Peskind, F. Rivard, R. Feith, and R. Barnes. Dexamethasone suppression test and cortisol circadian rhythm in primary degenerative dementia. Am. J. Psychiatry 139: 1468–1471, 1982.
 131. Raskind, M. A., E. R. Peskind, and C. W. Wilkinson. Hypothalamic‐pituitary‐adrenal axis regulation and human aging. In Brain Corticosteroid Receptors: Studies on the mechanism action and neurotoxicity of corticosteroid action, edited by E. R. De Kloet, E. C. Azmitia, and P. W. Landfield, Ann. N.Y. Acad. Sci. 746: 327–335, 1994.
 132. Reul, J. M., and E. R. De Kloet. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117: 2505–2511, 1985.
 133. Reul, J. M., P. T. Pearce, J. W. Funder, and Z. S. Krozowski. Type I and type II corticosteroid receptor gene expression in the rat: effect of adrenalectomy and dexamethasone administration. Mol. Endocrinol. 3: 1674–1680, 1989.
 134. Reul, J. M., F. R. Van Den Bosch, and E. R. De Kloet. Relative occupation of type‐I and type‐II corticosteroid receptors in rat brain following stress and dexamethasone treatment: functional implications. J. Endocrinol. 115: 459–467, 1987.
 135. Robertson, O. H., and B. C. Wexler. Hyperplasia of the adrenal cortical tissue in Pacific Salmon (genus oncorhynchus) and Rainbow Trout (Salmo gairdnerii) accompanying sexual maturation and spawning. Endocrinology 65: 225–232, 1959.
 136. Rosenzweig, E. S., G. Rao, B. L. McNaughton, and C. A. Barnes. Role of temporal summation in age‐related long‐term potentiation‐induction deficits. Hippocampus 7: 549–558, 1997.
 137. Rosewicz, S., A. R. McDonald, B. A. Maddux, I. D. Goldfine, R. L. Meisfeld, and C. D. Logsdon. Mechanisms of glucocorticoid receptor down‐regulation by glucocorticoids. J. Biol. Chem. 263: 2581–2584, 1988.
 138. Roth, G. Reduced glucocorticoid binding site concentration in cortical neuronal perikarya from senescent rats. Brain Res. 107: 345–354, 1976.
 139. Rothman, S., and J. W. Olney. Glutamate and the pathophysiology of hypoxicischemic brain damage. Ann. Neurol. 19: 105–111, 1987.
 140. Rothuizen, J., J. M. Reul, F. J. Van Sluijs, J. A. Mol, A. Rijnberk, and E. R. De Kloet. Increased neuroendocrine reactivity and decreased brain mineralocorticoid receptor‐binding capacity in aged dogs. Endocrinology 132: 161–168, 1993.
 141. Rupprecht, R., J. L. Arriza, D. Spengler, J. M. Reul, R. M. Evans, F. Holsboer, and K. Damm. Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor. Mol. Endocrinol. 7: 597–603, 1993.
 142. Sabatino, F., E. J. Masoro, C. A. McMahan, and R. W. Kuhn. Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J. Gerontol. 46: 171–179, 1991.
 143. Sapolsky, R. M. Do glucocorticoid concentrations rise with age in the rat? Neurobiol. Aging 13: 171–174, 1991.
 144. Sapolsky, R. M. The physiological relevance of glucocorticoid endangerment of the hippocampus. Ann. N.Y. Acad. Sci. 746: 294–304, 1994.
 145. Sapolsky, R. M., L. C. Krey, and B. S. McEwen. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J. Neurosci. 5: 1222–1227, 1985.
 146. Sapolsky, R. M., L. C. Krey, and B. S. McEwen. The neuroen‐docrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7: 284–301, 1986.
 147. Sapolsky, R. M., H. Uno, C. S. Rebert, and C. E. Finch. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J. Neurosci. 10: 2897–2902, 1990.
 148. Sawchenko, P. E. Evidence for a local site of action for glucocorticoids in inhibiting CRF and vasopressin expression in the paraventricular nucleus. Brain Res. 403: 213–223, 1987.
 149. Scheff, S. W., L. S. Benardo, and C. W. Cotman. Hydrocortisone administration retards axon sprouting in the rat dentate gyrus. Exp. Neurol. 68: 195–201, 1980.
 150. Scriabine, A., T. Schuurman, and J. Traber. Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB J. 3: 1799–1806, 1989.
 151. Selye, H., and B. Tuchweber. Stress in relation to aging and disease. In: Hypothalamus, Pituitary and Aging, edited by A. V. Everitt, J. A. Burgess. Springfield, IL: Charles C. Thomas, p 553–569, 1976.
 152. Sheline, Y. I., M. Sanghavi M. A. Mintun, and M. H. Gado. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 19: 5034–5043, 1999.
 153. Shors, T. J., T. B. Seib, S. Levine, and R. F. Thompson. Inescapable versus escapable shock modulates long‐term potentiation in the rat hippocampus. Science 244: 224–226, 1989.
 154. Siesjo, B. K., and F. Bengtsson. Calcium fluxes, calcium antagonists, and calcium‐related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. Cereb. Blood Flow Metab. 9: 127–140, 1989.
 155. Simpkins, J. W., G. P. Mueller, H. H. Huang, and J. Meites. Evidence for depressed catecholamine and enhanced serotonin metabolism in aging male rats: Possible relation to gonadotropin secretion. Endocrinology 100: 1672–1678, 1977.
 156. Sirevaag, A. M., J. E. Black, and W. T. Greenough. Astrocyte hypertrophy in the dentate gyrus of young male rats reflects variation of individual stress rather than group environment complexity manipulations. Exp. Neurol. Ill: 74–79, 1991.
 157. Sloviter, R. S., A. L. Sollas, and S. Neubort. Hippocampal dentate granule cell degeneration after adrenalectomy in the rat is not reversed by dexamethasone. Brain Res. 682: 227–230, 1995.
 158. Sloviter, R. S., G. Valiquette, G. M. Abrams, E. C. Ronk, A. L. Sollas, L. A. Paul, and S. Neubort. Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 243: 535–538, 1989.
 159. Solez, C. Aging and adrenal cortical hormones. Geriatrics 7: 241–245, 1952.
 160. Sonntag, W. E., A. G. Goliszek, A. Brodish, and J. C. Eldridge. Diminished diurnal secretion of adrenocorticotropin (ACTH), but not corticosterone, in old male rats: possible relation to increased adrenal sensitivity to ACTH in vivo. Endocrinology 120: 2308–2315, 1987.
 161. Sousa, N., M. D. Madeira, M. M. Paula‐Barbosa. Structural alterations of the hippocampal formation of adrenalectomized rats: an unbiased stereological study. J. Neurocytol. 26: 423–438, 1997.
 162. Sousa, R. J., N. H. Tannery, and E. M. Lafer. In situ hybridization mapping of glucocorticoid receptor messenger ribonucleic acid in rat brain. Mol. Endocrinol. 3: 481–494, 1989.
 163. Spencer, R. L., E. A. Young, P. H. Choo, and B. S. McEwen. Adrenal steroid type I and type II receptor binding: estimates of in vivo receptor number, occupancy, and activation with varying level of steroid. Brain Res. 514: 37–48, 1990.
 164. Starkman, M. N., S. S. Gebarski, S. Berent, and D. E. Schteingart. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome. Biol. Psychiatry 32: 756–765, 1992.
 165. Stein‐Behrens, B., M. P. Mattson, I. Chang, M. Yeh, and R. M. Sapolsky. Stress exacerbates neuron loss and cytoskeletal pathology in hippocampus. J. Neurosci. 14: 5373–5380, 1994.
 166. Stein‐Behrens, B. A., W. J. Lin, and R. M. Sapolsky. Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J. Neurochem. 63: 596–602, 1994.
 167. Stumpf, W. E., C. Heiss, M. Sar, G. E. Duncan, and C. Craver. Dexamethasone and corticosterone receptor sites: differential topographic distribution in rat hippocampus revealed by high resolution autoradiography. Histochemistry 92: 201–210, 1989.
 168. Talmi, M., E. Carlier, W. Bengelloun, and B. Soumireu‐Mourat. Chronic RU486 treatment reduces age‐related alterations of mouse hippocampal function. Neurobiol. Aging 17: 9–14, 1996.
 169. Thibault, O., and P. W. Landfield. Increase in single L‐type Ca2+ channels in hippocampal neurons during aging. Science 111: 1017–1020, 1996.
 170. Tocco, G., T. J. Shors, M. Baudry, and R. F. Thompson. Selective increase of AMPA binding to the AMPA/quisqualate receptor in the hippocampus in response to acute stress. Brain Res. 559: 168–171, 1991.
 171. Tornello, S., E. Orti, A. F. DeNicola, T. C. Rainbow, and B. S. McEwen. Regulation of glucocorticoid receptors in brain by corticosterone treatment of adrenalectomized rats. Neuroen‐docrinology. 35: 411–417, 1982.
 172. Towle, A. C., and P. Y. Sze. Steroid binding to synaptic plasma membrane: differential binding of glucocorticoids and gonadal steroids. J. Steroid Biochem. 18: 135–143, 1983.
 173. Trapp, T., R. Rupprecht, M. Castern, J. M. Reul, and F. Holsboer. Heterodimerization between mineralocorticoid and glucocorticoid receptor: A new principle of glucocorticoid action in the CNS. Neuron 13: 1457–1462, 1994.
 174. Uht, R. M., J. F. McKelvy, R. W. Harrison, and M. C. Bohn. Demonstration of glucocorticoid receptor‐like immunoreactivity in glucocorticoid‐sensitive vasopressin and corticotropin‐releasing factor neurons in the hypothalamic paraventricular nucleus. J. Neurosci. Res. 19: 405–411, 1988.
 175. Van Eekelen, J.A.M., N. Y. Rots, W. Sutanto, and E. R. De Kloet. The effect of aging on stress responsiveness and central corticosteroid receptors in the brown Norway rat. Neurobiol. Aging 13: 159–170, 1992.
 176. Van Eekelen, J.A.M., N. Y. Rots, W. Sutanto, M. S. Oitzl, and E. R. De Kloet. Brain corticosteroid receptor gene expression and neuroendocrine dynamics during aging. J. Steroid Biochem. Molec. Biol. 40: 679–683, 1991.
 177. Veldhuis, H. D., C. Van Koppen, M. Van Ittersum, and E. R. De Kloet. Specificity of the adrenal steroid receptor system in the rat hippocampus. Endocrinology 110: 2044–2051, 1982.
 178. Watanabe, Y., E. Gould, and B. S. McEwen. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 588: 341–345, 1992.
 179. Wexler, B. C. Comparative aspects of hyperadrenocorticism and aging. In: Hypothalamus, Pituitary and Aging, edited by A. V. Everitt and J. A. Burgess, Charles C. Thomas: Springfield, IL, p 333–361, 1976.
 180. Whitnall, M. H. Regulation of the hypothalamic corticotropin‐releasing hormone neurosecretory system. Prog. Neurobiol. 40: 573–629, 1993.
 181. Wisniewski, H. M., and R. D. Terry. Morphology of the aging brain, human and animal. In: Progress in Brain Research, edited by D. M. Ford. Amsterdam: Elsevier, 40: 167–186, 1973.
 182. Woolley, C. S., E. Gould, R. R. Sakai, R. L. Spencer, and B. S. McEwen. Effects of aldosterone or RU28362 treatment on adrenalectomy‐induced cell death in the dentate gyrus of the adult rat. Brain Res. 554: 312–315, 1991.
 183. Xu, L., R. Anwyl, and M. J. Rowan. Behavioural stress facilitates the induction of long‐term depression in the hippocampus. Nature 387: 497–500, 1997.
 184. Yang, G., M. F. Matocha and S. I. Rapoport. Localization of glucocorticoid receptor ribonucleic acid in hippocampus of rat brain using in situ hybridization. Mol. Endocrinol. 2: 682–685, 1988.
 185. Yu, Z. F., M. P. Mattson. Dietary restriction and 2‐deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J. Neurosci. Res. 57: 830–839, 1999.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Nada M. Porter, James P. Herman, Philip W. Landfield. Mechanisms of Glucocorticoid Actions in Stress and Brain Aging. Compr Physiol 2011, Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms: 293-309. First published in print 2001. doi: 10.1002/cphy.cp070414