Glucocorticoids are one of the most frequently prescribed families of drugs. In addition to their anti-inflammatory efficacy, their use is complicated by many side effects, including sleep disturbance and memory impairment for which the underlying mechanism is unknown. In this thesis, I show that the therapeutic glucocorticoid methylprednisolone (MPL) disrupts the circadian regulation of the core clock genes Period1, Period2 and Bmal1 in the master clock, the suprachiasmatic nucleus (SCN). I also found that the Type II corticosteroid receptor mRNA is expressed in the SCN. RNAseq of whole hippocampi revealed a significant dysregulation of clock genes in the MPL treated rats. I demonstrate that locomotor activity is altered in the presence of MPL and that sleep architecture during the 6h memory consolidation period of a novel object location task is altered, leading to memory impairment. I therefore conclude that MPL acts directly on the SCN to dysregulate the central clock, leading to disrupted peripheral clocks and circadian rhythms, resulting in altered sleep and impaired hippocampal-dependent memory. These data reveal a novel role for glucocorticoids in the regulation of the master clock in the SCN and provides a potential mechanism to understand glucocorticoid related sleep disturbances and memory impairment in patients treated chronically with long acting synthetic glucocorticoids.
The Molecular and Physiological Effects of Synthetic Glucocorticoid Treatment
Birnie, M. (Author). 25 Sept 2018
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)