The Effects of Chronic Synthetic Glucocorticoid Treatment on Neuronal and Microglial Morphology in Rats

Abstract

Glucocorticoids (GCs) are an important regulator of circadian function and the stress response, whilst also playing roles in cardiovascular, metabolic, immunological and cognitive processes. Synthetic GCs such as methylprednisolone (MPL) are widely used as treatments for disorders such as asthma and rheumatoid arthritis due to their activity at the glucocorticoid receptor (GR), a ligand-activated transcription factor. However, synthetic GC treatment is associated with adverse effects including impaired neurological function, possibly due to disruption of rhythmic GR activity. In this thesis I administered a chronic course of MPL to male rats, a regimen previously demonstrated to impair synaptic plasticity in the hippocampus and perirhinal cortex (PrH) and memory forms reliant on these brain regions. I observed the abolishment of circadian GR activation in both brain regions following treatment, but with consistently higher GR activity in the hippocampus than in the PrH. Proteomic analysis of perirhinal synaptic and extrasynaptic fractions revealed dysregulation of proteins involved in synaptic plasticity mechanisms including AMPA and NMDA receptor subunits. Multiple testable hypotheses were then formed using the proteomics output. Firstly, pathway analysis suggested an MPL-induced dysregulation of the synaptogenesis pathway, which I investigated by visualizing and analysing perirhinal neuronal morphology using Golgi-Cox staining. I observed altered region-specific dendritic and dendritic spine morphology in layer 5 pyramidal neurons following treatment, which have both previously been linked to neurodegenerative diseases and cognitive dysfunction. Secondly, multiple proteins associated with glial cell function and neuroinflammation displayed MPL-induced dysregulation. Thus, I used clusterization techniques to explore microglial morphology, demonstrating layer-specific changes similar to those seen in inflammatory conditions associated with chronic stress and neurodegeneration. These results provide new evidence into the mechanisms through which chronic MPL treatment induces cognitive deficits in rats and reveal avenues through which clinical side-effects may be alleviated.

Date of Award	9 Dec 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Becky L Conway-Campbell (Supervisor), Zuner A Bortolotto (Supervisor), Stafford L Lightman (Supervisor) & Caroline A Rivers (Supervisor)