Sex dependent influences of dexamethasone exposure in utero and stress and stress hormones in adulthood on a rat model of Parkinson's disease

Abstract

Stress is increasingly identified as a risk factor for brain disease, but the underlying processes are unkown. This thesis examines the influence of raised levels of the glucocorticoid (GC) stress hormone at different stages of life (during late gestation and/or in adulthood) on pathways known to be altered in parkinson’s disease (PD), and compares this with the effects of repeated adult stress. Adult stress or GC treatment produced complex, differential sex and region specific changes in these pathways. Notably, adult stress or GC treatment increased markers of nirosative stress in the male but not female rat substantia nigra (SN). Prenatal GC treatment produced long term effects on both dopamineric (DA) and noradrenergic (NA) nuclei, increasing the number of DA neurons in the SN and ventral tegmental area, and reducing the number of NA neurons in the locus coeruleus of adult rats. Furthermore microglial and astrocyte populations were increased and decreased respectively in these nuclei. Interestingly prenatal GC treatment rendered the male midbrain susceptible to a down regulation of DA measures in response to adult challenge, whereby the number of SN DA neurons and striatal and accumbal DA levels were attenuated. Fascinatingly adult stress or GC treatment, but not prenatal GC treatment exacerbated 6-hydroxydopamine-induced neurotoxicity, that was associated with increased microglial activation and protein nitration in the SN, in males, but afforded neuroprotection in females, neither of which were substantially altered by prenatal treatment. This is the first study to demonstrate that prenatal GC treatment can permanentlty alter the response of the midbrain DA pathways to adult challenge. Furthermore this is one of very few studies looking at male and female responses in parallel and thus highlights some striking sex differences in the response to stress and GCs. Together these novel data strongly support the premise that stress and GCs influence the functional integrity of pathways involved in PD, thereby potentially contributing to PD pathogenesis. The data also highlight the complex sexually dimorphic nature of their actions. Although further work is required to determine the functional consequences of these stress/GC related changes, these findings may have considerable implications for the use of GCs in clinical practice.