The rat brain contains two receptor systems for corticosterone: the type-I corticosterone-preferring receptor and the classical type-II glucocorticoid receptor. The two receptor populations can be distinguished in binding studies with the 'pure' synthetic glucocorticoid 11 beta,17 beta-dihydroxy-6-methyl-17 alpha (1-propynyl)-androsta-1,4,6-trione-3-one (RU 28362). In-vitro autoradiography and quantitative image analysis showed that the type-I receptor was localized almost exclusively in the hippocampus, whereas the type-II receptor extended throughout the brain, with the highest levels in the nucleus paraventricularis, nucleus supraopticus and in the thalamic, amygdaloid, hippocampal and septal regions. Unoccupied type-I and type-II receptor sites, as measured in vitro by cytosol binding of 3H-labelled steroids, displayed a large difference in the rate of appearance after adrenalectomy. The availability of type-I receptors exhibited a marked increase, reaching maximal levels within 4-7 h, and then remained constant until 2 weeks after adrenalectomy. The availability of type-II receptors did not change considerably during the first 24 h after adrenalectomy, but displayed a large increase in capacity during the subsequent 2 weeks. After adrenocortical activation as a consequence of exposure to a novel environment, plasma concentrations of corticosterone increased to reach a peak of 811 nmol/l after 30 min and attained the basal concentration (43 nmol/l) after 240 min. During this time, occupation of type-I receptors increased from 77.8% at 0 min to 97% at 30-60 min and then declined to 84.8% after 240 min. Occupation of the type-II receptors was 28.1% at 0 min, 74.5% after 30 min and 32.8% after 240 min.(ABSTRACT TRUNCATED AT 250 WORDS)

In this review, we summarize and discuss recent studies on structural plasticity changes, particularly apoptosis, in the mammalian hippocampus in relation to stress and depression. Apoptosis continues to occur, yet with very low numbers, in the adult hippocampal dentate gyrus (DG) of various species. Stress and steroid exposure modulate the rate of apoptosis in the DG. Contrary to earlier studies, the impact of chronic stress on structural parameters of the hippocampus like cell number and volume, is rather modest, and requires prolonged and severe stress exposure before only small reductions (< 10 %) become detectable. This does not exclude other structural parameters, like synaptic terminal structure, or dendritic arborization from being significantly altered in critical hippocampal subregions like the DG and/or CA3. Neither does it imply that the functional implications of the changes after stress are also modest. Of interest, most of the structural plasticity changes appear transient and are generally reversible after appropiate recovery periods, or following cessation or blockade of the stress or corticosteroid exposure. The temporary slowing down of both apoptosis and adult proliferation, i.e. the DG turnover, after chronic stress will affect the overall composition, average age and identity of DG cells, and will have considerable consequences for the connectivity, input and properties of the hippocampal circuit and thus for memory function. Modulation of apoptosis and neurogenesis, by drugs interfering with stress components like MR and/or GR, and/or mediators of the cell death cascade, may therefore provide important drug targets for the modulation of mood and memory.

Glucocorticoids (GCs) exert profound effects on a variety of physiological processes, including adaptation to stress, metabolism, immunity, and neuronal development. Cellular responsiveness to GCs depends on numerous factors, including the amount of the glucocorticoid receptor (GR) protein. We tested the hypothesis that micro-RNAs (miRs), a recently discovered group of noncoding RNAs involved in mRNA translation, might control GR activity by reducing GR protein levels in neuronal tissues. We tested a panel of five miRs consisting of 124aa, 328, 524, 22, and 18. We found that miRs 18 and 124a reduced GR-mediated events in addition to decreasing GR protein levels. miR reporter assays revealed binding of miR-124a to the 3' untranslated region of GR. In correspondence, the activation of the GR-responsive gene glucocorticoid-induced leucine zipper was strongly impaired by miR-124a and -18 overexpression. Although miR-18 is expressed widely throughout the body, expression of miR-124a is restricted to the brain. Endogenous miR-124a up-regulation during neuronal differentiation of P19 cells was associated with a decreasing amount of GR protein levels and reduced activity of luciferase reporter constructs bearing GR 3' untranslated regions. Furthermore, we show that miR-124a expression varies over time during the stress hyporesponsive period, a neonatal period when GC signaling is modulated. Our findings demonstrate a potential role for miRs in the regulation of cell type-specific responsiveness to GCs, as may occur during critical periods of neuronal development. Ultimately, our results may provide a better understanding of the etiology of stress-related diseases as well as the efficacy of GC therapy.

Corticosterone (CORT) binds to two receptor systems in rat brain: the type I CORT-preferring receptor (CR) and the type II glucocorticoid receptor (GR). Discrimination between the two receptor types can be achieved with the ‘pure’ synthetic glucocorticoid RU 28362. In this study, we show that the binding capacity of GR in the rat hippocampus exhibits a strikingly different response from CR to adrenalectomy (ADX), chronic steroid replacement, hypophysectomy (HYPOX) and during circadian variation. Under those experimental conditions neither receptor site showed changes in binding affinity. After ADX, CR number remained relatively constant for a period of 13 days, while GR capacity increased by 133%, a level which was reached 5 days post-surgery. CR capacity showed circadian variation, since CR number was 65% higher in the evening than in the morning. GR capacities at those two time points were not significantly different. Replacement with subcutaneous CORT implants (100-mg pellets) for 7 days following ADX rats did not affect CR number, but caused a 38% decrease in GR number compared to control animals (cholesterol-treated, 7-day-ADX rats). On the other hand, dexamethasone (DEX) implants (5-, 15-, 25-mg pellets) elicited a dose-dependent increase in CR capacity (up to 99%) and a dose-dependent decrease in GR capacity (40–44%). Finally, 2 weeks after HYPOX, CR and GR numbers were increased by 60 and 38%, respectively. We conclude that the type II GR capacity responds in an autoregulatory manner to changes in circulating plasma glucocorticoid levels, while type I CR does not.