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

Neurobiol Aging. 2019 Nov;83:11-20. doi: 10.1016/j.neurobiolaging.2019.08.007. Epub 2019 Aug 14.

Abstract

Debilitating, yet underinvestigated nonmotor 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, modeling 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 behavioral 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.

Keywords: Chronic stress; Conditioning; Depression; Neurodegeneration; Parkinson's disease; Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Brain / drug effects
  • Brain / pathology
  • Corticosterone / administration & dosage
  • Corticosterone / pharmacokinetics*
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / pathology
  • Male
  • Mice, Inbred C57BL
  • Parkinson Disease / drug therapy
  • Parkinson Disease / pathology*
  • Synucleinopathies / drug therapy*
  • alpha-Synuclein / metabolism

Substances

  • alpha-Synuclein
  • Corticosterone