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 . 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, . 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., []. 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 . 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, . 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., []. 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
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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