Decrements in Nuclear Glucocorticoid Receptor (GR) Protein Levels and DNA Binding in Aged Rat Hippocampus

Murphy, Erin; Spencer, Robert L.; Sipe, Kimberly J.; Herman, James P.

doi:10.1210/endo.143.4.8740

Cited by 65 publications

(25 citation statements)

References 61 publications

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“…These findings agree with evidence that increased stress reactivity is mediated in part by diminished glucocorticoid feedback sensitivity with aging in adult rhesus monkeys, baboons, and healthy humans (Sapolsky and Altmann, 1991;Gust et al, 2000;Wilkinson et al, 2001). Diminished sensitivity to glucocorticoid feedback during aging results from decreased glucocorticoid receptor densities (Sapolsky, 1999) and age-related impairments in glucocorticoid receptor signaling (Murphy et al, 2002) in the adult rodent hippocampus. Glucocorticoid receptors are expressed throughout the hippocampus and neocortex in squirrel monkeys (Patel et al, 2000b) and rhesus macaques (Sanchez et al, 2000), but little is known about age-related changes in glucocorticoid receptors in primates.…”

Section: Discussionsupporting

confidence: 88%

Cognitive Correlates of White Matter Growth and Stress Hormones in Female Squirrel Monkey Adults

Lyons¹,

Yang²,

Eliez³

et al. 2004

J. Neurosci.

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Neurobiological studies of stress and cognitive aging seldom consider white matter despite indications that complex brain processes depend on networks and white matter interconnections. Frontal and temporal lobe white matter volumes increase throughout midlife adulthood in humans, and this aspect of aging is thought to enhance distributed brain functions. Here, we examine spatial learning and memory, neuroendocrine responses to psychological stress, and regional volumes of gray and white matter determined by magnetic resonance imaging in 31 female squirrel monkeys between the ages of 5 and 17 years. This period of lifespan development corresponds to the years 18 -60 in humans. Older adults responded to stress with greater increases in plasma levels of adrenocorticotropic hormone and modest reductions in glucocorticoid feedback sensitivity relative to young adults. Learning and memory did not differ with age during the initial cognitive test sessions, but older adults more often failed to inhibit the initial learned response after subsequent spatial reversals. Impaired cognitive response inhibition correlated with the expansion of white matter volume statistically controlling for age, stress hormones, gray matter, and CSF volumes. These results indicate that instead of enhancing cognitive control during midlife adulthood, white matter volume expansion contributes to aspects of cognitive decline. Cellular and molecular research combined with brain imaging is needed to determine the basis of white matter growth in adults, elucidate its functions during lifespan development, and provide potential new targets for therapies aimed at maintaining in humans cognitive vitality with aging.

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Section: Discussionsupporting

confidence: 88%

Cognitive Correlates of White Matter Growth and Stress Hormones in Female Squirrel Monkey Adults

Lyons¹,

Yang²,

Eliez³

et al. 2004

J. Neurosci.

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“…However, we should bear in mind the fact that these findings are based on analysis of GR or HSPs denatured by SDS prior to analysis, therefore the association between GR and HSPs was not tested in our experiments and needs to be proved in future by co-immunoprecipitation. Nevertheless, the fact that both GR and HSP levels are modulated in a similar way by different types of stress suggests that stress might affect GR association with HSPs and in this way affect its function, such as binding activity, transformation to DNA-binding state, translocation to the nucleus and/or transactivation of gene expression; namely, decreased Hsp90 and Hsp70 expression, determined by Western blot technique, and was previously related to the impairment in nuclear GR protein levels and DNA binding [43] .…”

Section: Discussionmentioning

confidence: 95%

Stress Type Dependence of Expression and Cytoplasmic-Nuclear Partitioning of Glucocorticoid Receptor, Hsp90 and Hsp70 in Wistar Rat Brain

Djordjević¹,

Adžić²,

Djordjević³

et al. 2009

Neuropsychobiology

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Chronic exposure to stress is associated with different behavioral and neurological syndromes including impaired excitability of nerve cells in hippocampus (HIPPO) and prefrontal cortex (PFC), regions of the brain that are important for adaptation. The successful adaptation to stress involves negative feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis provided by the glucocorticoid receptor (GR), which is a steroid-dependent transcription factor found in a heterocomplex with heat shock proteins Hsp90 and Hsp70. In Wistar rats, chronic social isolation leads to a significant decrease in serum corticosterone (CORT), probably due to alterations in the GR signaling pathway. We exploited this type of stress, alone or in combination with acute immobilization, to define changes in the expression level and compartmental distribution of GR, Hsp90 and Hsp70 in HIPPO and PFC. The results indicated that in acute and combined stress, when CORT was increased, GR was translocated to the nucleus in both brain structures. Under chronic stress, when CORT was below the control level, GR was retained in the cytoplasm of PFC, and evenly distributed between compartments in HIPPO. Simultaneously, heat shock proteins partitioning in HIPPO seemed to be mainly stress type-independent, while that of PFC was dependent on stress type. Thus, the stress type-specific responses of GR and heat shock proteins were mainly detected in PFC rather than in HIPPO of Wistar rats. The observed alterations in protein expression and cytoplasmic-nuclear partitioning of the GR, Hsp90 and Hsp70 proteins may be related to maladaptive response of the HPA axis under chronic stress.

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“…2. n 6±8 each group; ÃÃ P < 0.01. aged rats (Murphy et al, 2002). Future studies examining the alteration of sgk expression during ageing and the relationship between sgk and diseases associated with ageing should help further clarify the role of sgk in neuroplasticity.…”

Section: Discussionmentioning

confidence: 97%

Enrichment enhances the expression of sgk, a glucocorticoid‐induced gene, and facilitates spatial learning through glutamate AMPA receptor mediation

Lee

Hsu

et al. 2003

Eur J of Neuroscience

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We have previously demonstrated that the serum and glucocorticoid-inducible kinase (sgk) gene plays a causal role in facilitating memory performance in rats. Environment enrichment is known to facilitate spatial learning. We therefore examined the effect of enrichment on sgk expression. We also examined the role of sgk in spatial and nonspatial learning and the regulation of sgk expression by activation of different glutamate receptors. Both real-time polymerase chain reaction and Western blot analyses revealed that enrichment training preferentially increased sgk mRNA and protein levels in the hippocampus. Transfection of sgk mutant DNA to the hippocampal CA1 area markedly impaired spatial learning, fear-conditioning learning and novel object-recognition learning in rats, but enrichment training effectively reversed these learning deficits. Meanwhile, S422A mutant DNA transfection prevented enrichment-induced spatial learning facilitation. In studying glutamate receptor regulation of sgk expression, we found that blockade of N-methyl-d-aspartate (NMDA) receptors in general, and the NR2B subunit in particular both effectively blocked enrichment-induced spatial learning facilitation, but they did not block enrichment-induced sgk expression. Upon various glutamate agonist infusions, only alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) increased sgk mRNA levels significantly in the hippocampus. Furthermore, blockade of AMPA receptors effectively blocked both enrichment-induced spatial learning facilitation and sgk expression. These results indicate that there is a dissociation between NMDA receptor activation and sgk expression. Enrichment enhanced spatial learning through both NMDA and AMPA receptor activation, whereas enrichment-induced sgk expression is specifically mediated through AMPA receptors. These results suggest that sgk could serve as a novel molecular mechanism, in addition to the NMDA receptor NR2B, underlying enrichment-induced learning facilitation.

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Decrements in Nuclear Glucocorticoid Receptor (GR) Protein Levels and DNA Binding in Aged Rat Hippocampus

Cited by 65 publications

References 61 publications

Cognitive Correlates of White Matter Growth and Stress Hormones in Female Squirrel Monkey Adults

Cognitive Correlates of White Matter Growth and Stress Hormones in Female Squirrel Monkey Adults

Stress Type Dependence of Expression and Cytoplasmic-Nuclear Partitioning of Glucocorticoid Receptor, Hsp90 and Hsp70 in Wistar Rat Brain

Enrichment enhances the expression of sgk, a glucocorticoid‐induced gene, and facilitates spatial learning through glutamate AMPA receptor mediation

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