Chronic corticosterone aggravates behavioural and neuronal symptomatology in a mouse model of alpha-synuclein pathology

Abstract Debilitating, yet under-investigated non-motor symptoms related to mood/emotion, such as depression, are common in Parkinson’s disease. Here we explore the role of depression and of the amygdala, a brain region robustly linked to mood/emotion, in synucleinopathy. We hypothesized that mood/emotional deficits might accelerate Parkinson's disease-linked symptomatology, including the formation of α-synuclein pathology. We combined elevated corticosterone treatment, modelling chronic stress and depression, with a model of seeded α-synuclein pathology in mouse striatum and assessed behavioral parameters with a focus on mood /emotion, and neuropathology. We report behavioural resilience against α-synuclein proteinopathy in the absence of additional insults, potentially based on hormesis / conditioning mechanisms. Elevated corticosterone, however, reversed α-synuclein pathology induced behavioral adaptations, and was associated with increased dopaminergic cell loss as well as aggravated α-synuclein pathology in specific brain regions, such as the entorhinal cortex. These findings point to elevated glucocorticoids as a risk factor for Parkinson’s disease progression and highlight the potential of glucocorticoid level reducing strategies to slow down disease progression in synucleinopathy.