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Séminaire - Becky Conway-Campbell,Slave to the Rhythm: Mechanisms underlying normal ultradian corticosterone gene regulation in the rat hippocampus and consequent effects of rhythm dysregulation.

Abstract :

Glucocorticoids (GCs: corticosterone in rodents; cortisol in humans) are secreted in hourly pulses, establishing an ultradian pattern. We have shown in vitro and in vivo that ultradian GC exposure induces a functional output in individual cells. The intracellular GC receptor (GR) is activated in distinct pulses and transmits this signal to the nucleus of cells, causing a gene pulsing effect. In contrast, constant GC treatment causes a highly aberrant overexpression of target genes in cell culture models and in vivo. We have assessed the effect of altering the corticosterone ultradian pattern on transcriptional output in the rat hippocampus. RNA-SEQ expression profiling on hippocampus from adrenalectomised rats replaced with pulsatile or constant corticosterone showed specific pattern-dependent regulation of GC-targets genes.

Chromatin immunoprecipitation assays for GR, and RNA Pol2 during the peak and trough of the pulsatile corticosterone infusion indicated that even subtle changes the pulse characteristics resulted in a disruption of the normal ultradian rhythm of transcriptional activity at the DNA template. Notably, with larger amplitude pulses we detected significantly dysregulated GR activity and gene-expression profiles. This may be of clinical relevance as the larger cortisol pulse mass has been reported in patients with obstructive sleep apneoa. These patients also present with metabolic, cognitive and affective dysfunction.
After treatment, their cortisol patterns normalise, along with an improvement in their clinical profile. Our data shows that this larger pulse mass disrupts the timing of the ultradian transcriptional rhythm and loss of pulsatile activity, and therefore may contribute to the associated cognitive and affective dysfunction in these patients.

Chronic treatment with synthetic GCs can also disrupt the endogenous GC profile.  Synthetic GCs such as methyl-prednisolone (MPL) are potent anti-inflammatory agents and therefore widely used in the clinic. However their benefits must be weighed against their side-effects. In addition to well-documented adverse metabolic effects, there is evidence for memory impairments in these patients. GCs are known to have effects on memory, either enhancing or impairing depending upon timing of exposure.

Therefore we have characterised the molecular, physiological and cognitive impairments arising from chronic MPL treatment. Notably, we report prolonged GR activation profiles, loss of circadian and ultradian GC rhythms, disruption of circadian GR activity, along with disruption circadian activity and body temperature profiles in the treated rats’. Short-term memory (1hour) was intact, however longer-term (6 and 24 hour) memory consolidation was impaired. Our experimental model may provide a robust method for determining the mechanisms underlying memory deficits in patients treated with prednisolone and other synthetic GCs.

Selected publications

Shewitz-Bowers L, Lait P, Schewitz-Bowers LP, Lait PJ, Copland DA, Chen P, Wu W, Dhanda AD, Vistica BP, Williams EL, Liu B, Jawad S, Li Z, Tucker W, Hirani S, Wakabayashi Y, Zhu J, Sen N, Conway-Campbell BL, Gery I, Dick AD, Wei L, Nussenblatt RB, Lee RW (2015) Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A. Proc Natl Acad Sci U S A. 112(13):4080-5

Conway-Campbell BL, Pooley JR, Hager GL, Lightman SL (2012) Molecular dynamics of ultradian glucocorticoid receptor action. Mol Cell Endocrinol 348(2):383-93

Dawson C, Dhanda A, Conway-Campbell BL, DiMambro A, Lightman SL and Dayan C (2011) NFκB and glucocorticoid receptor activity in steroid resistance. Journal of Receptors and Signal Transduction 32(1):29-35

Biddie SC, Conway-Campbell BL, Lightman SL (2011) Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology doi:10.1093/rheumatology /ker215

Conway-Campbell BL, George CL, Pooley JR, Knight DM, Norman MR. Hager GL, Lightman SL (2011) The HSP90 molecular chaperone cycle regulates cyclical transcriptional dynamics of the glucocorticoid receptor and its co-regulatory molecules CBP/P300 during ultradian ligand treatment. Molecular Endocrinol 25:944-54

Spiga F, Knight DM, Droste SK, Conway-Campbell BL, Kershaw Y, MacSweeney CP, Thomson FJ, Craighead M, Peeters BW, Lightman SL. (2011) Differential effect of glucocorticoid receptor antagonists on glucocorticoid receptor nuclear translocation and DNA binding. J Psychopharmacol 25:211-21