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(The FASEB Journal. 1999;13:115-122.)
© 1999 FASEB

Research Communications

Plasticity of hippocampal corticosteroid receptors during aging in the rat

A. H. S. Hassana, V. K. Patcheva, P. Von Rosenstiela, F. Holsboera and O. F. X. Almeidaa,1

a Max Planck Institute of Psychiatry, D-80804 Munich, Germany


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aging is commonly associated with dysregulation of the hypothalamo-pituitary-adrenal axis and cognitive impairment. On the basis of suggestions that these disruptions ensue from changes in the hippocampal complement of corticosteroid (mineralocorticoid and glucocorticoid) receptors (MR and GR), we examined the availability of hippocampal MR and GR by measuring the in vivo uptake of 3H-aldosterone and 3H-dexamethasone (selective MR and GR agonists, respectively); MR and GR mRNA levels were also measured. We observed age-related declines in both the synthesis of MR and GR and the uptake of their respective ligands. Whereas MR mRNA levels and ligand uptake declined in parallel, GR binding declined more steeply than GR mRNA. This latter result, together with our finding that aged rats show impaired corticosteroid receptor mRNA and protein up-regulation after corticosteroid withdrawal, indicates decreased transcription of MR and GR genes and posttranslational modification of GR mRNA during aging. Given that corticosteroids can influence MR and GR synthesis and binding, and based on the finding that aged subjects show reduced basal secretion of corticosterone, we propose that this relative hypocorticalism may be responsible for the changes observed in MR and GR activity, which then leads to disturbances in neuroendocrine regulation and cognitive function in aged subjects.—Hassan, A. H. S., Patchev, V. K., von Rosenstiel, P., Holsboer, F., Almeida, O. F. X. Plasticity of hippocampal corticosteroid receptors during aging in the rat. FASEB J. 13, 115–122 (1999)


Key Words: 3H-dexamethasone uptake • 3H-aldosterone uptake • hippocampus • mineralocorticoid and glucocorticoid receptors • aging


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CORTICOSTEROIDS EXERT POTENT effects on cognitive, behavioral, and physiological functions (1). These actions are mediated by cytoplasmic receptors that, upon activation, translocate to the nucleus where they serve as transcriptional factors. The mammalian brain is endowed with two types of corticosteroid receptors (CR),2 the type I CR and the type II CR, also referred to as mineralocorticoid (MR) and glucocorticoid (GR) receptors, respectively (2, 3). The prototypic endogenous MR ligand is aldosterone (ALDO). However, under normophysiological conditions, ALDO does not have access to brain MR, and corticosterone (CORT) is the preferential ligand of central MR. When CORT levels exceed a given threshold (e.g., during the diurnal peak of adrenocortical activity, after stress), GR also become occupied. Despite the sharing of a common ligand by MR and GR, receptor-specific actions are nevertheless seen due to the fact that MR have an approximately 10-fold higher affinity for CORT as compared to GR (3–5).

The highest concentrations of MR and GR in the brain are found within the pyramidal cell layers and dentate gyrus of the hippocampal formation; these cell populations have not only been implicated in cognitive processes, but also in mediating corticosteroid negative feedback upon the hypothalamo-pituitary-adrenal (HPA) axis (3, 5). Distinctions between MR and GR binding sites have been greatly aided by the availability of the synthetic GR-specific drug dexamethasone (DEX, also available as 3H-DEX) and the MR-specific ligand 3H-ALDO. The original distribution maps for MR and GR that were generated by in vivo autoradiography (6–9) have been more recently confirmed by immunocytochemistry (10) and in situ hybridization histochemistry (ISHH) using cRNA probes (11). The latter have also been widely used as a more convenient method to make inferences about changes in corticosteroid receptor synthesis.

We recently demonstrated that the selective activation of GR by DEX led to apoptosis in the rat dentate gyrus (12). In contrast, treatment with low doses of CORT (in order to selectively occupy MR) did not result in neuronal death. Further, we found that occupation of MR prior to that of GR abolished the cell death-inducing effects of GR activation. Dichotomous actions of MR and GR ligands on hippocampal neuronal activity (13), neurogenesis in the postnatal dentate gyrus (14, 15), and hippocampal regulation of the HPA axis (5) have also been described. It seems plausible that not only the opposing biological effects of MR vs. GR occupation, but also their counteractive actions (12), may be an attribute of their ability to form either homo- or heterodimers, with the heterodimers having gene transactivational properties quite distinct from those of the homodimers (16).

The present study was designed to reexamine purported changes in MR and GR availability during aging in the rat hippocampal formation. This question has attracted much research over the last decade in view of reports that HPA negative feedback and cognitive performance are impaired during aging in laboratory animals and humans (for reviews, see refs 1 and 17). Some difficulties in interpreting the literature arise from the apparent assumption that levels of mRNA encoding MR and GR necessarily parallel the number of receptor binding sites, and so both measures were performed here in order to clarify this point. Receptor synthesis was assessed by ISHH; binding sites were visualized and quantified using in vivo autoradiography in which 3H-DEX and 3H-ALDO served as GR and MR ligands, respectively. It is also important to note that the subject is complicated by parallel reports of age-related neuronal losses in the various hippocampal subfields (18–21). Although the latter view has been challenged (22), we nevertheless considered it appropriate to evaluate MR and GR mRNA and binding site numbers in the context of aging. Our results indicate that there are indeed age-related decreases in MR and GR mRNA levels and binding site numbers. However, we observed nonparallelism between the last two parameters, which we infer as age-related alterations in mRNA translation. We also observed that aged rats show a decline in the availability of the `protective' MR. These observations, coupled with the previously reported decline in CORT secretion with advancing age (12), may help explain some of the factors underlying age-related changes in hippocampal structure and function.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
Male Wistar rats, aged 4 months (ca. 300 g B.W.), 12 months (ca. 660 g B.W.), 24 months (ca. 860 g B.W.), and 32 months (ca. 1000 g B.W.) were used in these experiments. Rats were group-housed under standard laboratory conditions and provided with free access to food and water under controlled illumination (12 h light, 12 h dark). All procedures were approved by the local animal welfare regulatory authorities.

Surgery
One day before the tritiated steroid injections, all animals were bilaterally adrenalectomized (ADX) under halothane anesthesia in order to ensure a maximum number of free mineralocorticoid and glucocorticoid. Animals were maintained on a drinking solution containing 0.9% NaCl after ADX.

In vivo autoradiography
The protocol used was based on that described previously (6). Briefly, ADX animals (four rats per group) were given two intraperitoneal (i.p.) injections of either 3H-dexamethasone (3H-DEX, specific activity 83 Ci/mmol; Amersham, Braunschweig, Germany) or 3H-aldosterone (3H-ALDO, specific activity 76 Ci/mmol; Dupont-NEN, Bad Homburg, Germany); there was a 2 h interval between each pulse of 3H-DEX (120 µCi/100 g) and 3H-ALDO (150 µCi/100g). Subgroups of animals (n=4) were pretreated (i.p.) with a 100-fold excess of unlabeled DEX [70 µg/100 g; crystalline DEX (obtained from Sigma Chemicals, St. Louis, Mo.) was solubilized 2-hydroxypropyl-ß-cyclodextrin; ß-cyclodextrin was purchased from Research Biochemicals Int., Natick, Mass.] and/or ALDO (65 µg/100 g; crystalline ALDO (Sigma) was dissolved in ß-cyclodextrin) 30 min before the first labeled steroid injections in order to determine nonspecific binding. One hour after the second tritiated steroid injection, animals were killed and their brains were rapidly removed, frozen on dry ice, and stored at -70°C before being cryosectioned (5 µm) through the dorsal hippocampus. A minimum of six anatomically matched coronal sections, between Bregma -3.3, -3.8, and -4.3 (see ref 23) were selected from each brain; each selected section was separated by 50 µm so as to circumvent the need for correction of counting error during quantification. Frozen sections were thaw-mounted onto gelatin-subbed glass slides, air-dried, and immediately exposed to 3H-Hyperfilm (Amersham) for 12–16 wk alongside 3H-standards (Amersham); the latter were subsequently used to quantify gray levels. The autoradiographic signals in the hippocampus were quantified by computer-assisted densitometry (NIH Image 1–52, Bethesda, Md.). Specific binding was computed after correcting for nonspecific binding values.

In situ hybridization histochemistry (ISHH)
ADX rats (n=5) were used to determine the steady-state levels of mRNAs coding for MR and GR in the hippocampus. ISHH was performed on 12 µm-thick frozen sections, through the dorsal hippocampus, and at the same levels mentioned before (see in vivo autoradiography). Sections were thaw-mounted on gelatin-coated slides; fixation, permeabilization, hybridization, and washing at high stringency were performed as described elsewhere (24). The plasmids containing the probes for the rat MR and GR were kindly provided by Dr. L. Brady (NIMH, Bethesda, Md.). After linearization, 35S-dUTP-labeled cRNA probes were generated by transcription from the SP6 (antisense) and T7 (sense) promoter, respectively. Autoradiographs from hybridized sections were generated by exposure to Hyperfilm Bmax/ßmax (Amersham) for standardized periods. Specificity of the hybridization signals was monitored using adjacent sections that were hybridized with the corresponding sense probes. Autoradiographic signals were quantified by computer assisted densitometry (see above).

Data analysis
Data were analyzed for significant differences using analysis of variance, followed by appropriate post hoc tests.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Marked differences were observed in the uptake of 3H-DEX and 3H-ALDO by the different hippocampal subfields. Inspection of the autoradiograms generated from the dorsal hippocampus revealed intense labeling of the dentate gyrus and CA1 areas with 3H-DEX, whereas the CA1-CA3 areas were less intensely labeled with this specific GR ligand; lesser labeling was noticed in the CA2-CA3 areas ( Fig. 1a, b). Labeling with 3H-ALDO revealed a different pattern of distribution of MR binding sites: whereas the CA2, CA1, and dentate gyrus were strongly labeled with this specific MR agonist, the CA1 showed only moderate labeling ( Fig. 2a, b). There was a close match between the pattern of distribution of GR and MR binding sites and the mRNAs encoding these receptors ( Fig. 1c, d; Fig. 2c, d).



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  		Figure 1. Glucocorticoid receptor (GR) binding sites in the hippocampal formation of young (a) and old (b) rats. GR binding sites were revealed by in vivo labeling with 3H-dexamethasone (3H-DEX). The lower panels show the steady-state mRNA levels encoding GR in young (c) and old (d) rats, as measured by in situ hybridization histochemistry. The scale bar represents 300 µm.



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  		Figure 2. Mineralocorticoid receptor (MR) binding sites in the hippocampal formation of young (a) and old (b) rats. MR binding sites were revealed by in vivo labeling with 3H-aldosterone (3H-ALDO). The lower panels show the steady-state mRNA levels encoding MR in young (c) and old (d) rats, as measured by in situ hybridization histochemistry. The scale bar represents 300 µm.

Semiquantitative image analysis of the autoradiograms ( Fig. 3a, b) revealed a steep decline in GR binding sites with advancing age; thus, as compared to 4-month-old animals, those aged 12, 24, and 32 months, respectively, displayed approximately 20%, 70%, and 75% less 3H-DEX uptake in the dentate gyrus and CA1-CA2 regions. The differences in binding were significant (P<0.05) between all age groups except for between the groups of animals aged 24 and 32 months; the lack of a statistical difference between the density of binding sites in the 24- and 32-month-old rats indicates a `plateau' effect beyond 24 months. As shown in Fig. 1, the aged rats showed narrower bands of labeled cells than did the younger animals. The age-related changes observed in 3H-DEX uptake were matched by declining levels of steady-state GR mRNA levels in all the hippocampal subfields examined. However, as shown in Fig. 3a, b, there was a lack of parallelism (or proportionality) between the magnitude of changes in GR gene transcription and density of 3H-DEX binding sites beyond 12 months of age. Thus, rats aged 12, 24, and 32 months showed approximately 24%, 32%, and 50% less GR-encoding mRNA as compared to 4-month-old rats; all pairwise comparisons between the different age groups proved to be significant (P<0.05).



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  		Figure 3. Age-related changes in the in vivo uptake of 3H-dexamethasone (DEX) by glucocorticoid receptors (GR) and in steady-state levels of the mRNA encoding for GR, in the CA1–2 pyramidal cell area (a) and the granule cell layer (b) of the dentate gyrus. The data were obtained from adult male Wistar rats aged 4, 12, 24, and 32 months. Means ±SEM are depicted (n=4 in the 3H-DEX uptake studies; n=5 for the mRNA studies).

An age-related decrease in 3H-ALDO uptake was also observed ( Fig. 4), although the decrease was less pronounced than that observed for the 3H-DEX (cf. Fig. 3). As compared to 4-month-old rats, animals aged 12, 24, and 32 months, respectively, showed approximately 12%, 23%, and 50% decreases in the density of MR binding sites in the dentate gyrus and CA1-CA2 hippocampal regions (P<0.05 in all pairwise comparisons) . Further, as depicted in Fig. 4, the age-associated decrease in MR uptake closely followed the pattern of decline in MR gene transcription in all hippocampal subfields examined.



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  		Figure 4. Age-related changes in the in vivo uptake of 3H-aldosterone (ALDO) by mineralocorticoid receptors (MR), and in steady-state levels of the mRNA encoding for MR in the CA1–2 pyramidal cell area (a) and the granule cell layer (b) of the dentate gyrus. The data were obtained from adult male Wistar rats aged 4, 12, 24, and 32 months. Means ±SEM are depicted (n=4 in the 3H-ALDO uptake studies; n=5 for the mRNA studies).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Cognitive impairment is thought to be one consequence of brain aging (17, 25–27). For more than a decade, researchers have been seeking suitable models and measures that might serve as markers and/or provide insights into the mechanisms involved in age-related cognitive dysfunction. In the brain, most studies have focused on the hippocampus, a structure that in both humans and animals seems to play an important role in processing information related to learning and memory (for review, see ref 1). This brain region contains the highest density of corticosteroid receptors, of which there are two: the mineralocorticoid (MR or type I) and glucocorticoid (GR or type II) receptors (3–5). Whereas MR exert a tonic influence on pituitary-adrenal activity, including the circadian rhythm of CORT secretion, GR are mainly responsible for curtailing the HPA response to stress through negative feedback mechanisms (5). Feedback inhibition may also involve the participation of MR insofar as they are thought to determine the threshold or sensitivity to stress (5, 28, 29). The loss or functional impairment of corticosteroid receptors has been suggested to account for the tendency for aged human and animal subjects to show blunted diurnal adrenocortical secretory rhythms, and exaggerated and delayed `shutoff' of the pituitary-adrenal response to stress (19, 30–34); however, in most cases basal secretion remains unchanged (35, 36). Last, MR and GR have been implicated in hippocampal neuron survival and proliferation (MR), as well as hippocampal cell death (GR) (12, 14, 15). It is in the context of the latter that HPA activity, as well as changes in hippocampal MR and GR levels, are thought to provide a `window' into how age-related changes in hippocampal structure and function may be involved in altered cognitive performance. Indeed, corticosteroid-mediated hippocampal cell losses have been frequently implicated in both, the dysregulation of the HPA axis and the cognitive decline associated with aging (37, 38); however, recent work applying newer stereological methods has raised questions about whether corticosteroids and aging (22) lead to hippocampal damage that can, in turn, be related to cognitive processes. Thus, current thinking about the interaction between aging, corticosteroid secretion, cognition, and structural changes in the hippocampus remains equivocal (see ref 21).

In this paper, we have returned to a previously addressed question: Is there a progressive change in the synthesis and binding pattern of MR and GR in the pyramidal cell fields and dentate gyrus of the rat hippocampus? Few previous studies measured both receptor synthesis and binding in parallel, a factor that may underlie some of the confusion in the literature. Our work was also conducted on the premise that changes in MR and GR binding, and therefore transcriptional activity, may represent a form of neuronal plasticity relevant to cognition and neuroendocrine homeostasis.

We found that the in vivo uptake of both, 3H-aldosterone (ALDO; a selective MR ligand) and 3H-DEX (a selective GR ligand) by the aging rat hippocampus are markedly reduced; uniform reductions were found in the pyramidal and dentate subfields. In rats older than 12 months, the relative decrease in 3H-DEX uptake was more severe than that observed for 3H-ALDO. These findings are largely consistent with previous reports using in vitro receptor binding assays (39–41). Although not measurable in our in vivo autoradiographic assay, it is interesting that previous authors failed to observe any significant age-related changes in the kinetics and affinity of these receptors; it is also relevant that age does not appear to interfere with MR and GR nuclear translocation and transcriptional activity (41). In keeping with standard practice (6), our uptake studies were performed in adrenalectomized (ADX, 1 day) rats in order to ensure complete unoccupancy of MR and GR by endogenous ligands and to maximize receptor availability through up-regulatory mechanisms. The possibility therefore exists that the reduced ligand uptake by older rats in fact reflects their reduced capacity to up-regulate MR and GR. One reason for this might be that, as reported for different species and rat strains, basal levels of CORT decline markedly with advancing age (12, 42–44); thus, it is plausible that older animals may be less sensitive to the effects of ligand deprivation (e.g., by ADX). Support for this view is provided indirectly by the fact that MR binding was less severely reduced than GR binding in the aged rat, a finding that may be attributed to the higher (10-fold) affinity of the MR for CORT (5). The issue of receptor up- and down-regulation will be discussed later.

Consistent with earlier reports, we observed that steady-state levels of the mRNAs encoding MR and GR were also markedly reduced during aging; both mRNAs were reduced to a similar extent at 32 months of age (to ca. 50% of levels in young 4-month-old animals). Since ADX is known to up-regulate the transcription of both MR and GR coding genes (11, 24, 45), our results indicate that MR and GR gene transcription is impaired during aging. Although it is tempting to explain the reduced levels of MR and GR mRNA in the older animals in terms of age-associated hippocampal cell losses, this hypothesis becomes untenable in light of newer studies in which aged rats were found to have similar total numbers of pyramidal and dentate cells (22). Instances of ligand-mediated positive autoregulation of MR and GR have been reported (46), and it therefore seems likely that the age-related reductions in the levels of CORT may be responsible for the inefficient transcription of the MR and GR genes; indeed, steroid hormone effects on gene transcription are known to involve chromatin remodeling (47), and age has been shown to influence the transcriptional rate, stability, and processing of mRNA (48–50). The impaired transcription of the MR (but not GR) gene may be remedied by CORT replacement in old rats (41). The latter may have important implications for the treatment of cognitive deficits given that 1) MR occupation appears to be important for memory formation through the process of sensory integration, and 2) GR activation, in an inverted U-shaped fashion, has a positive influence on the acquisition of memory and its consolidation and retrieval (1, 34).

A striking feature of the data depicted in Figs. 3 and 4is that, whereas there was a close parallelism between the mRNA and binding profiles for MR, the patterns for GR gene expression and binding diverged in a pronounced fashion beyond 12 months of age, with reductions in GR mRNA being much smaller than the reductions in 3H-DEX uptake. Thus, in addition to the apparent inadequate transcription of the MR and GR genes, aged animals also seem to be burdened by translational and/or posttranslational deficits in the case of GR at least (age has been shown to influence the fidelity with which mRNA is translated as well as the posttranslational processing and stability of proteins; refs 49, 51, 52). This conclusion is consistent with that of some previous reports (40, 53). Since much evidence points to the GR as the dominant mediator of corticosteroid negative feedback (5, 34, 54), decreased levels of this receptor most likely explain the delayed shutoff response of the pituitary-adrenal unit of aged subjects after experience of a stressful stimulus (34, 55). It needs to be emphasized here that since the rats in the present experiment were adrenalectomized prior to the in vivo binding studies, the reduced levels of GR binding sites could not be due to stress-induced down-regulation of receptor availability (cf. refs 5, 56, 57).

We suggest that previous reports on particular strains of rats (usually Fisher vs. the Wistar strain used here) that display increased adrenocortical activity with increasing age (55, 56–58) may have contributed to some of the confusion over the role of corticosteroid hypersecretion (and possible cellular losses in the hippocampus) in age-associated cognitive deficits (21, 22). First, as already mentioned, the majority of rat strains studied show adrenocortical hyposecretion rather than hypersecretion. Second, the view that high corticosteroid levels may lead to hippocampal cell losses has been challenged recently (22). Furthermore, clinical observations suggest that corticosteroid-induced neuronal losses per se may not be responsible for impairments in cognition since Cushing's patients show reversal of such impairments upon remission of their hypercortisolemia (59); the latter results are consistent with the cognition impairing effects of high corticosteroid levels (1, 34). Although the functional importance of corticoid- or age-related cell losses in the dentate gyrus remain unknown, it should be recalled that the results of our earlier study (12) suggested that the reduced availability of CORT may make the dentate gyrus more vulnerable to the cell death-inducing effects of DEX and that the ratio of MR to GR occupation (cf. ref 16) may be a crucial factor in determining neuronal survival in that area. Age-related changes in the availability of MR and GR binding sites, as shown here, add another dimension to the view that MR-GR homeostasis (cf. ref 5) may be important in maintaining physiological and behavioral processes at an optimal level (refs 35, 36).

In summary, our results show that aging in the rat is accompanied by inadequate biosynthesis of hippocampal MR and GR and, further, that the aged subject is unable to effectively translate GR mRNA into functionally active receptors. The consequences of these defects in corticosteroid receptor gene transcription and translation into receptor protein are suggested to account for the altered neuroendocrine responses to stress by aged subjects and, possibly, cognitive changes. Further, we infer from our results that the primary cause of all these negative symptoms may be the age-related decline in adrenocortical secretory output, which subsequently has repercussions on MR and GR protein availability. These findings and their interpretation provide a new perspective with which to consider how aging may influence corticosteroid negative feedback mechanisms and cognitive processes, independent of the need to consider the controversial issue of whether aging is accompanied by structural damage to the hippocampus.


   ACKNOWLEDGMENTS
 
The authors are grateful to Dr. Gillian Condé for constructive comments on the manuscript, Dr. Linda Brady for the rat MR and GR probes, Dieter Fischer and Julia Deicke for excellent technical assistance, and Carola Hetzel for secretarial help.


   FOOTNOTES
 
1 Correspondence: Max Planck Institute of Psychiatry. Kraepelinstrasse 2–10, D-80804 Munich, Germany. E-mail: osa{at}mpipsykl.mpg.de

2 Abbreviations: ADX, adrenalectomy; ALDO, aldosterone; CORT, corticosterone; CR, corticosterone receptor(s); DEX, dexamethasone; GR, glucocorticoid receptor; HPA, hypothalamo-pituitary-adrenal; i.p., intraperitoneal; ISHH, in situ hybridization histochemistry; MR, mineralocorticoid receptor(s).

Received for publication April 21, 1998. Revision received August 19, 1998.
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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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