The Molecular and Physiological Effects of Synthetic Glucocorticoid Treatment

  • Matthew Birnie

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

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.
Date of Award25 Sep 2018
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorBecky L Conway-Campbell (Supervisor), Georgina M Russell (Supervisor) & Stafford L Lightman (Supervisor)

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