Disrupted Corticosterone Pulsatile Patterns Attenuate Responsiveness to Glucocorticoid Signaling in Rat Brain

Abstract

Chronically elevated circulating glucocorticoid levels are although to enhance vulnerability to psychopathology. Here we hypothesized that such sustained glucocorticoid levels, disturbing corticosterone pulsatility, attenuate glucocorticoid receptor signaling and target gene responsiveness to an acute challenge in the rat brain. Rats were implanted with vehicle or 40 or 100% corticosterone pellets known to flatten ultradian and circadian rhythmicity while maintaining daily average levels or mimic pathological conditions. Additionally, recovery from constant exposure was studied in groups that had the pellet removed 24 h prior to the challenge. Molecular markers for receptor responsiveness (receptor levels, nuclear translocation, promoter occupancy, and target gene expression) to an acute challenge mimicking the stress response (3 mg/kg ip) were studied in the hippocampal area. Implantation of 40 and 100% corticosterone pellets dose-dependently down-regulated glucocorticoid receptor and attenuated mineralocorticoid receptor and glucocorticoid receptor translocation to the acute challenge. Interestingly, whereas target gene Gilz expression to the challenge was already attenuated by tonic daily average levels (40%), Sgk-1 was affected only after constant high corticosterone exposure (100%), indicating altered receptor responsiveness due to treatment. Washout of 100% corticosterone recovered all molecular markers (partial), whereas removal of the 40% corticosterone pellet still attenuated responsiveness to the challenge. We propose that corticosteroid pulsatility is crucial in maintaining normal responsiveness to glucocorticoids. Whereas the results with 100% corticosterone are likely attributed to receptor saturation, subtle changes in the pattern of exposure (40%) induces changes at least as severe for glucocorticoid signaling as overt hypercorticism, suggesting an underlying mechanism sensitive to the pattern of hormone exposure.

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

“…We demonstrate that FKBP51 SUMOylation affects the expression of GILZ and SGK1, which are SUMOylation of FKBP51 regulates GR signaling M Antunica-Noguerol et al upregulated by GCs in the hippocampus. 33,34 In line with these results, our data show that GCs also induce the expression of SGK1 and GILZ in HT22 hippocampal neuronal cells. Moreover, we show that only SUMOylation-competent FKBP51 is involved in their regulation.…”

Unraveling the Time Domains of Corticosteroid Hormone Influences on Brain Activity: Rapid, Slow, and Chronic Modes

“…Repetitive corticosterone exposure results in transient cyclic recruitment and exchange of GR at regulatory sites in the genome (Stavreva et al, 2009;Conway-Campbell et al, 2010), whereas MR is retained in the nucleus (Conway-Campbell et al, 2007). Experimental evidence supports the idea that pulsatile patterns are necessary to safeguard GR sensitivity and downstream signaling in target tissues (Sarabdjitsingh et al, 2010b).…”

Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity

“…Similarly, it would be of interest to follow metaplastic changes for more than the current 2-h range. Finally, several studies have shown that nuclear GR signaling-e.g., translocation, binding, and transcription of target genes-normalizes to baseline levels between pulses (4,(6)(7)(8). It is therefore of great interest to resolve in detail if and particularly how a first pulse of CORT could lead to enhanced surface expression of GRs and which signaling pathways underlie the reversal exerted by the second pulse on processes activated by the first pulse.…”

“…Pulse amplitudes steeply rise some hours before awakening and then slowly diminish again (5). The functional relevance of ultradian pulses is only starting to be understood; recent evidence suggests that pulses are necessary to maintain optimal transcriptional activity of GRs (4)(5)(6)(7)(8), thus coordinating essential bodily functions in preparation of the active phase.…”