Circadian rhythmicity in hippocampus and perirhinal cortex is dysregulated during chronic methyl-prednisolone treatment

Rozwaha, Tom and Conway-Campbell, Becky and Birnie, Matthew (2017) Circadian rhythmicity in hippocampus and perirhinal cortex is dysregulated during chronic methyl-prednisolone treatment. Masters thesis, University of Bristol.

Abstract

As much as 2% of the general population will undergo corticosteroid therapy at some point in their lives - the side effects of which are extensive and, at times, severe. Among these side effects are marked learning and memory (LM) impairments. There is considerable evidence that LM is modulated in a circadian manner. Molecular clock machinery (MCM) is responsible for 24hr cycles of cellular, physiological and behavioural activity, and is composed of a series of tightly regulated transcriptional-translational feedback loops - entrained by the suprachiasmatic nucleus of the hypothalamus and maintained in peripheral tissues via endogenous glucocorticoid signalling. Synthetic corticosteroids have a longer half-life than endogenous corticosteroids, and have been shown to dysregulate: a) ultradian patterns of transcription, and b) the MCM in several peripheral tissues - via the endogenous corticosteroid receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). We have taken hippocampus and perirhinal cortex (PrhCx) from vehicle and methyl-prednisolone- (MPL) treated Lister-Hooded rats every 4hrs across a 24hr period. By interrogating a hippocampal RNA-sequencing dataset from this paradigm, we identified that 28/66 gene transcripts (identified as “glucocorticoid regulated” or “following circadian patterns of expression” in literature) were found to have significant differences: a) over the 24hr period, or b) following MPL treatment. Using real-time qPCR, we are the first to show oscillations of eight key clock genes in the PrhCx over the photoperiod, alongside the gene-specific dysregulation of these clock genes (at each timepoint) during chronic MPL treatment. In a separate experiment, we have shown differential GR:MR binding dynamics at GR regulatory elements (GREs) in the glucocorticoid target genes Per1 and Fkbp5. This preliminary research will inform vital future research into the molecular mechanisms underlying LM impairments and how best to attenuate these.